Дисертації: "Fibrosis"

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Enes, Giovana da Silva Tavares 1982. "Fibrose cística = estreitando laços maternos = Cystic fibrosis : strengthening maternal ties." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308361.

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Orientador: Antonio Fernando Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A Fibrose Cística é uma doença autossômica recessiva, sistêmica, hereditária, crônica e progressiva e pode levar à morte. São características da doença as secreções mucosas espessas e viscosas que obstrui os ductos das glândulas exócrinas e contribuem para o aparecimento de doença pulmonar obstrutiva crônica, insuficiência pancreática com má digestão e má absorção e conseqüente desnutrição secundária, além de níveis elevados de eletrólitos no suor. Por ser uma doença crônica, ela exige cuidados sistemáticos pela vida toda, e na maioria dos casos quem exerce a função de cuidadora é a mãe. Além de viver uma nova experiência de ser mãe, ela terá que conviver com a frustração dele ser doente.Com este estudo foi possível compreender a relação que mãe e filho doente crônico constroem desde o momento do diagnóstico e conhecimento do tratamento, permeados por sentimentos como culpa e solidão. Assim, essas mães renunciam suas próprias vidas em função do cuidado do filho. Cuidados esse compartilhado com uma equipe de saúde multiprofissional ainda deficitária. Apesar de ter sido avaliado por elas como positivo, as sugestões por melhorias também surgiram: como uma melhor articulação entre os serviços de saúde nos diversos níveis, uma maior divulgação da doença e o aumento do número de dias de atendimento. Outro aspecto importante encontrado foi sobre importância do papel do psicólogo não só na atuação com o paciente e a família durante todo o tratamento; mas também na necessidade de oferecer um espaço para que os profissionais de saúde despreparados pudessem compartilhar suas angústias e frustrações o que reflete diretamente na assistência prestada
Abstract: The Cystic Fibrosis is a disease systemic, hereditary, chronic and progressive and it can lead to the death. There are characteristic of the disease the thick and viscous mucous secretions what it obstructs the ducts of the exocrine glands and contribute to the appearance of chronic obstructive pulmonary disease, pancreatic insufficiency with bad digestion and bad absorption and consequent secondary malnutrition, besides elevated levels of electrolytes in the sweat. Because of being a chronic disease, she demands systematic cares for the life completely, and in most of the cases who plays the function of care is the mother. Besides surviving a new experience of being a mother, she will have to coexist in spite of the fact that his frustration to be doente.Com this study there were possible understood the relation what mother and chronic sick son build from the moment of the diagnosis and knowledge of the treatment, permeated by feelings as fault and solitude. So, these mothers renounce his lives themselves in function of the care of the son. Taken care this shared one with a team of still deficient multiprofessional health. In spite of having been valued by them like positive, the suggestions for improvements also appeared: like a better articulation between the health services in several levels, a bigger spread of the disease and the increase of the number of service days. Another considered important aspect was on importance of the paper of the psychologist not alone in the acting with the patient and the family during the whole treatment; but also in the necessity of offering a space so that the unprepared health professionals could share his anguishes and frustrations what thinks straightly about the given presence
Mestrado
Saude da Criança e do Adolescente
Mestre em Ciências

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2

Yi, Hao. "The Effect of Metformin on Inflammatory and Fibrotic Responses in Renal Fibrosis." Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21855.

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Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death. It is well recognised that renal fibrosis is the unifying pathology in almost all forms of progressive CKD. To date, kidney transplantation and dialysis are the only options for the management of end-stage kidney disease, which results in a significant burden on the health system. Hence innovative strategies are needed to both prevent and treat CKD. It is well recognised that inflammatory pathways play a central role in the progression of CKD and TGFβ-1 is a profibrotic cytokine found in CKD regardless of aetiology, which initiates and modulates a variety of pathophysiological processes. In renal disease, TGFβ-1 is upregulated and induces renal cells to produce extracellular matrix proteins leading to glomerulosclerosis as well as tubulointerstitial fibrosis. Different types of renal cells undergo different pathophysiological changes induced by TGF-β1, leading to apoptosis, hypertrophy and abnormalities of podocyte foot processes, which ultimately result in renal dysfunction. Regardless of the cause of CKD, multiple cytokines, growth factors, pro-inflammatory and fibrotic signalling pathways participate in the development of the pathological process in the kidney. Excessive deposition of extracellular matrix (ECM) is the most striking and common feature of renal fibrosis. Hence, targeting inflammatory and fibrotic responses, and ECM deposition, holds promise to limit fibrosis. Metformin, a biguanide, is a widely used drug in the treatment of type 2 diabetes mellitus (T2DM). It has been well-reviewed that metformin plays an important role in limiting cardiac and vascular fibrosis. Increasing evidence studies indicates metformin may be protective in renal fibrosis. However, the exact mechanisms of protection in renal injury are not fully understood or experimentally investigated. Thus, I initially examined the effect of metformin in TGFβ-1 induced fibrosis in human proximal tubular cells line (HK2 cells). Therefore, I further examined the effect of metformin on renal fibrosis in two mouse models of acute kidney injury (AKI; Folic Acid model (FA)) and chronic kidney injury (CKI, Adenine model). The studies have shown that metformin inhibited monocyte chemoattractant protein-1 (MCP-1) expression and TGFβ-1 signalling pathways in kidney proximal tubular cells exposed to TGFβ-1 by reducing mRNA, protein levels or phosphorylation of signalling molecules of non-Smad and Smad signalling pathways. Metformin also inhibited TGFβ-1 induced extracellular matrix deposition by reducing the expression of fibronectin and collagen IV in kidney proximal tubular cells exposed to TGF-β1. In animal studies, the acute phase of renal fibrosis was successfully established by giving folic acid via intraperitoneal injection, and then the antifibrotic effect of metformin was assessed by administering animals metformin or control for 14 days. The acute renal fibrosis mice model was successfully established by given adenine via gavage, and then treated with or without metformin for 14 days. The in vivo data has shown that folic acid induced impairment of renal function and the overexpression of fibronectin and collagen IV and inflammatory molecular MCP-1, F4/80 and intercellular adhesion molecule-1 (ICAM1) in kidneys compared to control groups; and the impaired renal function and inflammatory and fibrotic response were at least partially attenuated by metformin treatment. The chronic renal fibrosis mice model was successfully established by giving adenine through gavage daily and treatment with or without metformin for 21 days. The data showed that adenine induced renal dysfunction and the overexpression of fibronectin and collagen IV and inflammatory molecular MCP-1, F4/80 and ICAM in kidneys compared to control groups. Renal dysfunction and the inflammatory and fibrotic responses were reversed by metformin treatment. Collectively, these results suggest that metformin may have potential therapeutic value for the treatment of renal fibrosis independent of the cause of CKD.

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3

Correia, Cyntia Arivabeni de Araujo. "Estudo dos genes TNF alfa, ADIPOQ e STATH entre portadores de fibrose cistica." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308583.

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Orientador: Carmen Silvia Bertuzzo
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A Fibrose Cística (FC) possui uma grande variabilidade de expressão fenotípica, o que significa que crianças com o mesmo genótipo podem diferir quanto à sua apresentação. A proteína defeituosa formada é chamada CFTR (proteína reguladora da conductância iônica), causa transporte anormal de sódio e cloro através da membrana apical das células epiteliais das vias aéreas, pâncreas, intestino e aparelho reprodutor. Essa proteína é codificada por um único gene que recebe o mesmo nome da proteína, CFTR, e localiza-se no braço longo do cromossomo 7, região 7q3.1. Gêmeos monozigóticos apresentam maior concordância em relação à gravidade da doença pulmonar que os dizigóticos, sugerindo que a FC seja modulada por fatores genéticos secundários - genes modificadores - além do gene CFTR. A característica mais importante na FC é a sobrevida que é influenciada pela doença pulmonar. Portanto, genes que estejam envolvidos na imunidade, inflamação, reparação do epitélio e produção de muco são candidatos a genes modificadores da doença. Os objetivos foram: 1) determinar a prevalência dos polimorfismos -308G/A e -238G/A do gene TNF a entre portadores de FC e verificar existência de associação entre esses polimorfismos e a gravidade do quadro pulmonar, 2) identificar alterações de sequencia nos exons e junções exon/ intron dos genes ADIPOQ e STATH e verificar existência de associação entre possíveis variações nesses genes e a gravidade da FC. Foi realizada PCR seguida por digestão enzimática para o polimorfismo -308G/A do gene TNF a, reação em cadeia da polimerase ARMS para o polimorfismo -238G/A do gene TNF a, e para os genes ADIPOQ e STATH foi feita a triagem de mutações através de cromatografia líquida de alta resolução por desnaturação - DHPLC com posterior sequenciamento da região onde foi encontrada alteração. Foram analisados 49 pacientes com FC em seguimento no Ambulatório de Mucoviscidose do HC/UNICAMP, homozigotos para a mutação F508 ou heterozigotos compostos para mutações de classe I ou II ou homozigotos para mutações de classe II, que são alterações que não levam à formação de proteína funcional. Além disso, foram selecionados indivíduos que apresentem alteração de eletrólitos no suor. Para o polimorfismo -308G/A do gene TNFa os genótipos GG, AA e GA foram encontrados com as seguintes frequencias: 14,28, 67,35 e 18,36% respectivamente. Estes dados se opõem ao relatado na literatura. Tal diferença deve ocorrer pelas características populacionais da população brasileira. Para o polimorfismo -238G/A do gene TNFa, os genótipos GG e AG tiveram as seguintes frequencias: 79,59 e 20,41% respectivamente. O genótipo AA não foi encontrado na amostra analisada. A alta frequencia do genótipo GG comparado com o AA, concorda com a literatura. Não foi encontrada alteração na sequencia dos genes STATH e ADIPOQ. Não foi possível estabelecer uma associação entre a gravidade da FC e os genes TNFa, STATH e ADIPOQ, nas regiões analisadas.
Abstract: Cystic Fibrosis (CF) has a great variety expression, which means that the seriousness of the disease can vary a lot among people who have it. The defective protein, called CFTR (Cystic Fibrosis Transmenbrane Regulator), causes abnormal transportation of chloride and sodium through the apical membrane of the epithelial cells of the airway, liver, intestine and masculine reproductive tract. This protein is encoded by a single gene which has the same name, CFTR, and is located within the long arm of chromosome 7, region 7q3.1. CF is a disease which expressivity is much variable, with different degrees of damage and the age when the symptoms begins is also much variable, even within individuals of the same family, like twins. Because of it, it is been said that others genetic factors besides CFTR, can be modulating the clinical presentation. As the pulmonary state is the great responsible for the mortality of the disease genes that are involved in host defense, inflammation, epithelial repair, mucin production, and airway reponsiveness are of great interest. Base on this the objectives of this work were: determine the prevalence of the polymorphisms -308G/A e -238G/A from the TNF a gene and verify if there is an association between these polymorphisms pulmonary disease severity, and identify alterations on ADIPOQ and STATH genes and verify if there is an association between these polymorphisms and CF severity. PCR followed by restriction enzyme digestion was performed to detect the polymorphism -308G/A from the TNF a gene, ARMS PCR to the polymorphism -238G/A from the TNF a gene the DHPLC method associated to the sequencing to analyze ADIPOQ and STATH genes, were used. We performed analyses of 49 cystic fibrosis patients that are followed in a Cystic Fibrosis center from HC/UNICAMP, that are \F508 homozygous or compound heterozygous to mutations from class I or II, or that are homozygous to class II mutations, which are alterations that do not produce functional protein. Besides this, were selected individuals that have sweat test altered. To the polymorphism 308G/A from TNFa gene the genotypes GG, AA e AG were in the following frequencies: 14,28, 67,35 e 18,36%. This data is contradictory to the literature and may occur because of the racial admixture of the Brazilian population. To the polymorphism -238G/A from TNFa gene, the genotypes GG AG were in the following frequencies 79,59 e 20,41%. The genotype AA was not found in the analyzed group. The high frequency of the genotype GG is in agreement of the data. It was not possible to find any alteration on ADIPOQ and STATH genes. And also it was not possible to make any correlation between the severity of the CF disease and the genes TNFa, STATH and ADIPOQ between the analyzed regions.
Doutorado
Ciencias Biomedicas
Doutor em Ciências Médicas

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4

Chadwick, Helen Kay. "Cognitive function in cystic fibrosis and cystic fibrosis related diabetes (CFRD)." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/16912/.

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Cystic fibrosis (CF) is a complex multisystem disease caused by a gene mutation of a protein called the CF Transmembrane Conductance Regulator (CFTR). Glucose tolerance abnormalities are common in CF and the prevalence of CF related diabetes (CFRD), which shares clinical characteristics with type 1 (T1DM) and type 2 diabetes (T2DM), increases with age. Impaired glucose tolerance (IGT), T1DM and T2DM are associated with cognitive impairment relative to healthy controls. The overall aim of this thesis was to examine cognitive function in CF. Study 1 investigated the impact of CF on cognitive function, in people with CFRD (n=49), people with CF who are not diabetic (CFND, n=49) and healthy controls (n=49). Memory, attention and processing speed, and cognitive flexibility was impaired in CFRD, and to a lesser degree in CFND, relative to healthy controls. Study 2 assessed cognitive function over a 1-3 year period in people with CFRD (N=36) and found no evidence of cognitive decline despite a decline in lung function. Study 3 compared cognitive function in people with CFRD who were post transplant (CFRDTx, n=18), people with CFRD (who were not post transplant, n=18), and healthy controls (n=18). CFRD was associated with impairment in attention and processing speed, spatial working memory, cognitive flexibility and to a lesser extent verbal memory. Cognitive function did not improve post transplantation in people with CFRD. Study 4 followed up people with CFRDTx (N=8) over an 18±6 month period and found no decline in cognitive function. Taken together, the evidence presented in this thesis suggests that diabetes in CF is associated with cognitive impairment, and that maintaining glycaemic control protects against cognitive decline. The cognitive impairment observed in people with CF is of clinical significance and has implications for self care and disease management. The recent discovery that CFTR is present in the pancreas and the brain has important implications for the effects of the new CFTR potentiator and corrector therapies on cognitive function in CF.

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Karlas, Thomas, Joachim Berger, Nikita Garnov, Franziska Lindner, Harald Busse, Nicolas Linder, Alexander Schaudinn, et al. "Estimating steatosis and fibrosis." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-169692.

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6

Katre, Ashwini A. "Ozone and lung fibrosis." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009m/katre.pdf.

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7

Kahre, Tiina. "Cystic fibrosis in Estonia /." Online version, 2004. http://dspace.utlib.ee/dspace/bitstream/10062/577/5/KahrePhD.pdf.

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8

Dwyer, Tiffany Jane. "Exercise in cystic fibrosis." Thesis, The University of Sydney, 2010. http://hdl.handle.net/2123/6349.

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Exercise and physical activity have many benefits for adults with cystic fibrosis (CF), including the potential to aid mucus clearance, improve lung function, exercise capacity and quality of life. Despite the recommendations from consensus documents for CF adults to engage in regular physical activity, exercise participation amongst this population is often very low. No in-depth study has been undertaken to explore the determinants of exercise participation for this group and no studies have examined the benefits of habitual physical activity on the health status and quality of life of CF adults. As well, the current methods to quantify physical activity are problematic. The series of studies, involving CF adults, in this thesis was therefore undertaken in order to examine the physiological rationale for the use of exercise as an airway clearance technique, to understand the decision making process to engage in exercise, to determine if health status and quality of life were affected by exercise participation, and to establish the accuracy of a recently-developed objective measure of physical activity. The study in Chapter 2 provided some physiological rationale for choosing treadmill exercise to aid airway clearance in CF. The main findings were that a single bout of moderate intensity exercise increased the subjective ease of expectoration, most likely due to the increased ventilation with exercise, and that sputum viscoelasticity was favourably decreased immediately following treadmill exercise compared to cycle exercise and control. The studies in Chapters 3 and 4 identified the main beliefs regarding exercise for CF adults and highlighted that the main predictors of exercise intention and participation for this group were aspects of perceived and actual control to exercise, namely self-efficacy or confidence to exercise, feeling healthy, receiving encouragement to exercise, and rating exercise as a high priority treatment. Positive ratings of these aspects of control either increased exercise participation directly, indirectly by increasing intention, or strengthened the conversion of exercise intention to participation. Strategies aimed at targeting these aspects of control are therefore likely to be effective in increasing exercise participation for CF adults. The study in Chapter 5 demonstrated that CF adults, who reportedly performed at least 90 minutes of moderate to strenuous exercise per week, had significantly higher quality of life and fewer days in hospital over the following year than their peers, who exercised less. The difference in hospitalisation between the CF adults, who reportedly exercised more than 90 minutes per week and those who did not, was independent of baseline lung function, and the females who reportedly performed less than 90 minutes of exercise per week had three times as many days in hospital than their high-activity peers. The study in Chapter 6 showed that the SenseWear Pro3 Armband activity monitor provided a reasonable estimate of energy expenditure and step count. Also, its accuracy was not affected by diagnosis with CF, despite the potential for the high salt content in the sweat to interfere with the device’s physiological sensors placed on the skin. Overall, this series of studies adds to the growing evidence of the physical and psychological benefits from exercise participation for CF adults, as well as providing some empirical evidence upon which to base strategies to improve exercise participation for this group and support for an objective measure of physical activity.

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9

Dwyer, Tiffany Jane. "Exercise in cystic fibrosis." Discipline of Physiotherapy, Faculty of Health Sciences, University of Sydney, 2010. http://hdl.handle.net/2123/6349.

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Doctor of Philosophy (PhD)
Exercise and physical activity have many benefits for adults with cystic fibrosis (CF), including the potential to aid mucus clearance, improve lung function, exercise capacity and quality of life. Despite the recommendations from consensus documents for CF adults to engage in regular physical activity, exercise participation amongst this population is often very low. No in-depth study has been undertaken to explore the determinants of exercise participation for this group and no studies have examined the benefits of habitual physical activity on the health status and quality of life of CF adults. As well, the current methods to quantify physical activity are problematic. The series of studies, involving CF adults, in this thesis was therefore undertaken in order to examine the physiological rationale for the use of exercise as an airway clearance technique, to understand the decision making process to engage in exercise, to determine if health status and quality of life were affected by exercise participation, and to establish the accuracy of a recently-developed objective measure of physical activity. The study in Chapter 2 provided some physiological rationale for choosing treadmill exercise to aid airway clearance in CF. The main findings were that a single bout of moderate intensity exercise increased the subjective ease of expectoration, most likely due to the increased ventilation with exercise, and that sputum viscoelasticity was favourably decreased immediately following treadmill exercise compared to cycle exercise and control. The studies in Chapters 3 and 4 identified the main beliefs regarding exercise for CF adults and highlighted that the main predictors of exercise intention and participation for this group were aspects of perceived and actual control to exercise, namely self-efficacy or confidence to exercise, feeling healthy, receiving encouragement to exercise, and rating exercise as a high priority treatment. Positive ratings of these aspects of control either increased exercise participation directly, indirectly by increasing intention, or strengthened the conversion of exercise intention to participation. Strategies aimed at targeting these aspects of control are therefore likely to be effective in increasing exercise participation for CF adults. The study in Chapter 5 demonstrated that CF adults, who reportedly performed at least 90 minutes of moderate to strenuous exercise per week, had significantly higher quality of life and fewer days in hospital over the following year than their peers, who exercised less. The difference in hospitalisation between the CF adults, who reportedly exercised more than 90 minutes per week and those who did not, was independent of baseline lung function, and the females who reportedly performed less than 90 minutes of exercise per week had three times as many days in hospital than their high-activity peers. The study in Chapter 6 showed that the SenseWear Pro3 Armband activity monitor provided a reasonable estimate of energy expenditure and step count. Also, its accuracy was not affected by diagnosis with CF, despite the potential for the high salt content in the sweat to interfere with the device’s physiological sensors placed on the skin. Overall, this series of studies adds to the growing evidence of the physical and psychological benefits from exercise participation for CF adults, as well as providing some empirical evidence upon which to base strategies to improve exercise participation for this group and support for an objective measure of physical activity.

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Utley, Courtney, and Kristen L. McHenry. "Advances in Cystic Fibrosis." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/2546.

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The purpose of this review was to identify the history of and advances in cystic fibrosis (CF). New treatment plans, medication developments, and a historical perspective of airway clearance therapy (ACT) will be presented. The importance of treatment compliance and time management in the care of cystic fibrosis patients will also be discussed. Furthermore, the development of cystic fibrosis clinics and the pivotal role they play in the treatment of the disease will be addressed. Lastly, a brief discussion concerning the need for and process of lung transplantation will be reported.

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Álvarez, Fernández Antonio. "Fibrosis Quística: caracterización y particularidades de la edad adulta." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/673281.

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Aquesta tesi doctoral analitza les particularitats de la fibrosi quística (FQ) de l'adult mitjançant les dades clíniques, analítiques, radiològiques, funcionals, microbiològiques, genètics i de seguiment, recollides entre gener de 1983 i desembre de 2019 en 349 pacients amb FQ confirmada , controlats en la Unitat d'Adults de FQ de l'Hospital Vall d'Hebron. A més d'estudiar la població global, es van realitzar estudis de: diferències entre els pacients diagnosticats a la infància i en l'edat adulta; relació entre genotip i fenotip; variants deep intró; sub/infertilitat femenina i evolució de la funció pulmonar i supervivència a pacients gestants; l'absència bilateral de conductes deferents (ABCD) com sospita de FQ en homes infèrtils; evolució dels pacients trasplantats de pulmó; i supervivència i els seus factors modificadors. Per als estudis de supervivència i de trasplantament pulmonar es van analitzar 302 pacients després d'excloure als pacients perduts i derivats a altres centres; per als estudis de prevalença es van analitzar els 212 pacients actius en l'any 2018. Les conclusions més rellevants van ser: La FQ és també un diagnòstic en l'edat adulta, en el nostre estudi va representar el 38% dels pacients adults. El genotip amb dues variants de Classe I-III és el factor independent més important d'afectació pulmonar greu i de mortalitat. L'estudi genètic ha d'incloure a les variants deep intró. Els bacils gram negatius no fermentadors i les MNT són emergents en pacients adults. La FQ ha de ser descartada en homes amb ABCD. Els factors pronòstic més significatius en la supervivència dels pacients amb FQ són: el parell de variants, la prova de la suor, l'edat de diagnòstic, la infecció broncquial crònica per PsA i la realització d'exercici físic.
Esta tesis doctoral analiza las particularidades de la fibrosis quística (FQ) del adulto a través de los datos clínicos, analíticos, radiológicos, funcionales, microbiológicos, genéticos y de seguimiento, recogidos entre enero de 1983 y diciembre de 2019 en 349 pacientes con FQ confirmada, controlados en la Unidad de Adultos de FQ del Hospital Vall d'Hebron. Además de estudiar la población global, se realizaron estudios de: diferencias entre los pacientes diagnosticados en la infancia y en la edad adulta; relación entre genotipo y fenotipo; variantes deep intrón; sub/infertilidad femenina y evolución de la función pulmonar y supervivencia en pacientes gestantes; la ausencia bilateral de conductos deferentes (ABCD) como sospecha de FQ en varones infértiles; evolución de los pacientes trasplantados de pulmón; y supervivencia y sus factores modificadores. Para los estudios de supervivencia y de trasplante pulmonar se analizaron 302 pacientes tras excluir a los pacientes perdidos y derivados a otros centros; para los estudios de prevalencia se analizaron los 212 pacientes activos en el año 2018. Las conclusiones más relevantes fueron: La FQ es también un diagnóstico en la edad adulta, en nuestro estudio representó el 38% de los pacientes adultos. El genotipo con dos variantes de Clase I-III es el factor independiente más importante de afectación pulmonar grave y de mortalidad. El estudio genético debe incluir a las variantes deep intrón. Los bacilos gram negativos no fermentadores y las MNT son emergentes en pacientes adultos. La FQ debe ser descartada en varones con ABCD. Los factores pronóstico más significativos en la supervivencia de los pacientes con FQ son: el par de variantes, la prueba del sudor, la edad de diagnóstico, la infección broncquial cronica por PsA y la realización de ejercicio físico.
This doctoral thesis analyses the particularities of adult cystic fibrosis (CF) through clinical, analytical, radiological, functional, microbiological, genetic and follow-up data collected between January 1983 and December 2019 from 349 patients with confirmed CF, monitored at the Adult CF Unit of Vall d'Hebron Hospital. In addition to studying the overall population, studies were conducted on: differences between patients diagnosed in childhood and in adulthood; the relationship between genotype and phenotype; deep intron variants; female sub/infertility and evolution of lung function and survival in pregnant patients; the congenital absence of vas deferens (CAVD) as a suspicion of CF in infertile males; evolution of lung transplant patients; and survival and its modifying factors. For the survival and lung transplant studies, 302 patients were analysed after excluding missing patients and referrals; for the prevalence studies, the 212 active patients in 2018 were analysed. The most relevant conclusions were: CF is also a diagnosis in adulthood, in our study it represented 38% of adult patients. The genotype with two Class I-III variants is the most important independent factor of severe pulmonary involvement and mortality. The genetic study should include the deep intron variants. Non-fermenting gram-negative bacilli and NTM are emerging in adult patients. CF should be ruled out in males with CAVD. The most significant prognostic factors in the survival of CF patients are: the pair of variants, the sweat test, the age of diagnosis, chronic bronchial infection by PsA and the practice of physical exercise..
Universitat Autònoma de Barcelona. Programa de Doctorat en Medicina

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Mekus, Frauke. "Cystic fibrosis as a genetically complex disease Cystische Fibrose: eine genetisch komplexe Erkrankung /." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=959242287.

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13

Nyabam, Samuel. "Understanding the link between transglutaminase and the induction of fibrosis in cystic fibrosis (CF)." Thesis, Aston University, 2015. http://publications.aston.ac.uk/25336/.

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The emerging role of the multifunctional enzyme, Transglutaminase 2 (TG2) in Cystic Fibrosis (CF) has been linked to its increased expression and intracellular transamidating activity. However, a full understanding of the molecular mechanisms involved still remains unclear despite numerous studies that have attempted to delineate this process. These mechanisms include the NFκB and TGFβ1 pathway amongst others. This study reveals for the first time that the development of fibrosis in CF is due to a TG2-driven epithelial to mesenchymal transition (EMT) via a mechanism involving the activation of the pro-fibrotic cytokine TGFβ1. Using a human ΔF508/W1282X CFTR CF mutant bronchial cell (IB3-1), its CFTR corrected “add-back” cell (C38) as well as a primary human bronchial epithelial cell (HBEC), elevated TG2 levels in the CFTR mutant IB3 cell were shown to activate latent TGFβ1 leading to increased levels found in the culture medium. This activation process was blocked by the presence of cell-permeable and impermeable TG2 inhibitors while inhibition of TGFβ1 receptors blocked TG2 expression. This demonstrates the direct link between TG2 and TGFβ1 in CF. The presence of active cell surface TG2 correlated with an increase in the expression of EMT markers, associated with the CF mutant cells, which could be blocked by the presence of TG2 inhibitors. This was mimicked using the “addback” C38 cell and the primary human bronchial epithelial cell, HBEC, where an increase in TG2 expression and activity in the presence of TGFβ1 concurred with a change in cell morphology and an elevation in EMT marker expression. Conversely, a knockdown of TG2 in the CF mutant IB3 cells illustrated that an inhibition of TG2 blocks the increase in EMT marker expression as well as causing an increase in TEER measurement. This together with an increase in the migration profile of the CF mutant IB3 cell against the “add-back” C38 cell suggests that TG2 drives a mesenchymal phenotype in CF. The involvement of TG2 activated TGFβ1 in CF was further demonstrated with an elevation/inhibition of p- SMAD 2 and 3 activation in the presence of TGFβ1/TG2 cell-permeable/impermeable inhibitors respectively. The use of a comparative airway cell model where bronchial epithelial cells were cultured at the air liquid interface (ALI) confirmed the observations in submerged culture depicting the robustness of the model and reiterated the importance of TG2 in CF. Using a CFTR corrector combined with TG2 inhibitors, this study showed that the correction and stabilisation of the ΔF508 CFTR mutation in the mutant cell forged an increase in matured CFTR copies trafficking to the apical surface by circumventing proteosomal degradation. Thus the results presented here suggests that TG2 expression is elevated in the CFTR mutant bronchial cell via a TGFβ1 driven positive feedback cycle whereby activation of latent TGFβ1 by TG2 leads in turn to an elevation in its own expression by TGFβ1. This vicious cycle then drives EMT in CF ultimately leading to lung remodelling and fibrosis. Importantly, TG2 inhibition blocks TGFβ1 activation leading to an inhibition of EMT and further blocks the emerging fibrosis, thus stabilizing and supporting the maturation, trafficking and conductance of CFTR channels at the apical surface.

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14

Pasinetti, Nadia. "Wound healing signals mediated by Rho/ROCK activation in response to radiotherapy and consequences fot treatmeny of late damage within normal tissues." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00714360.

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Radiotherapy is the second most important treatment modality after surgery in the treatment of cancer. Recent technical advancements, such as intensity-modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT), combined with new targeted drugs have significant promise for therapeutic outcome. However radiation treatment could result in disabling normal tissue injury and in the development of progressive fibrosis in a subset of sensitive patients and in long-term cancer survivors. The main feature of tissue fibrosis is excessive accumulation of abnormal and cross-linked collagen mainly composed of fibrillar and immature extracellular matrix (ECM) components.The organs that can be affected by this phenomenon are liver, skin, intestine, kidneys and lungs. From a clinical point of view, fibrosis can be seen as an irreversible condition, without solution. We and others recently showed that beside the activation of the canonical TGF-β/Smad pathway, other intracellular signaling cascades including the Rho/ROCK pathway are switched on in fibrotic tissues. Interestingly, the Rho/ROCK pathway seems differentially activated in radiation-induced intestinal fibrosis, thereby providing a rationale for a specific, targeted anti-fibrotic strategy. Pharmacological inhibition of Rho using statins indeed prevent and even reverse intestinal radiation fibrosis.In our studies, we showed the role of Statin (Pravastatin e Simvastatin) and a specific inhibitor ROCK inhibitors (Y-27632) in a mice model of pulmonary induced-fibrosis obtained by a pharmacological approach (Bleomycin - BLM). Indeed, we developed a model of lung fibrosis by complete irradiation of chest and tested Pravastatin action. Confirmation of the involvement of Rho/ROCK/CTGF pathway in lung fibrosis are shown by immunohistochemistry: Pravastatin-treament normalized the expression of three markers: RhoB, TGF-RII and CTGF.Then, in models of radiation induced gut and lung fibrosis, we analysed, from a immunohistological point of view, the underlying mechanisms of the antifibrotic action of Pravastatin via MMP2-TIMP2 axis. Interestingly we found a different impact on fibrolysis when Pravastatin was administered preventively or curatively.Finally, in vitro, we investigate by zymography the expression of Gelatinases (MMP2 and MMP9) in primary lung fibroblasts cultures exposure at the different radiation and Pravastatin doses. Metalloproteases would appear to be in turn involved in pro-fibrolytic mechanisms induced by statin.The multiplicity of actors involved in the pathogenesis of fibrotic lesions explains why the definition of an effective therapeutic strategy is so complex.Researches in mechanistic processes of normal tissue damage paved the way for new therapeutic approaches. These new targets include reduction of vascular activation, inflammation and thrombosis and new molecular targets definition. Effective strategies are multiple on preclinical models, but numerous efforts have to be made to achieve the complicated goal of protection of normal tissues from the side effects of radiation therapy.

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15

Hamama, Saad. "Radiation-induced fibrosis : Characterization of the anti-fibrotic mechanisms displayed by pentoxifylline/vitamin E." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T071.

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La fibrose radio-induite est une complication sévère et tardive de la radiothérapie. Plusieurs études cliniques ont montré que la combinaison pentoxifylline-vitamine E est un traitement sûr et efficace contre la fibrose. Cependant, les mécanismes moléculaires de son efficacité restent inexplorés. Nous avons montré l’efficacité de la combinaison pentoxifylline-vitamine E dans l’entéropathie radique dans une faisabilité clinique. En parallèle, en utilisant un modèle unique, in vitro, de cellules musculaires lisses intestinales primaires isolées des personnes atteintes de l’entéropathie radique, nous avons montré une synergie entre la pentoxifylline et l’analogue hydrophile de vitamine E (trolox) qui permet à l’association d’inhiber l’expression de TGF-β1 au niveau de l’ARN messager et de la protéine. Cette action inhibitrice intervient au niveau transcriptionnel et conduit à une inhibition conséquente des cibles de la voie de signalisation TGF-β1/Smad (Col Iα1, FN1, PAI-1, CTGF), alors qu’elle semble sans effet sur la voie de signalisation Rho/ROCK. Pour la première fois, dans ces cellules issues de l’entéropathie radique, nous avons montré une surexpression de miR-210 ; microRNA induit par l’hypoxie. L’association pentoxifylline-trolox inverse la surexpression de miR-210 aussi bien dans les conditions normoxique que dans les conditions hypoxiques. L’implication de miR-210 dans l’entéropathie radique n’a pas été préalablement étudiée, néanmoins nous avons montré qu’un inhibiteur de miR-210 diminue l’expression de Col Iα1 dans ce modèle. L’effet anti-fibrosant exercé par l’association pentoxifylline-vitamine E est partiellement induit par l’inhibition de la cascade TGF-β1. L’inhibition de miR-210 est un deuxième mécanisme potentiel nécessitant d’autres investigations. Cette étude renforce les essais clinique antérieurs en montrant in vitro une synergie entre pentoxifylline et vitamine E et permettant de proposer cette association en première ligne thérapeutique dans la fibrose radio-induite. De plus, miR-210 est proposé comme une possible cible thérapeutique pour traiter la fibrose radio-induite
Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials as treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. We showed efficacy of Pentoxifylline-vitamin E combination in radiation-induced enteropathy in a small clinical study. In parallel, using a unique in vitro model of primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy we showed that pentoxifylline and the hydrophilic analogous of vitamin E (trolox) synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/Rock pathway. We have also demonstrated, for the first time, an overexpression of the hypoxia-induced microRNA miR-210 in the fibrotic cells. Pentoxifylline-trolox combination could reverse this miR-210 overexpression in normoxic and hypoxic conditions. While miR-210 has not been previously shown to be involved in radiation-induced enteropathy, we showed that miR-210 inhibitor could reduce mRNA expression of Col Iα1. The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. MiR-210 inhibition is another mechanism which needs further investigations. This study strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis. Also, it suggests miR-210 as a new potential therapeutic target for the treatment of this complication

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16

Dobson, Lee. "Glucose tolerance in cystic fibrosis." Thesis, University of Exeter, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403679.

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17

Hurley, Matthew. "Lung infection in cystic fibrosis." Thesis, University of Nottingham, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.716679.

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Cystic fibrosis (CF) is characterised by viscid secretions that, in the lungs, pre-dispose to infection. Many people with CF experience 'pulmonary exacerbations' accompanied by intermittent deteriorations in lung function. Pulmonary exacerbations are associated with a more rapid decline in lung health over time and are associated with infection. Early infection managed aggressively may be successfully eradicated. With successive infections and cumulative lung damage, chronic infection is established. Chronic infection leads to progressive decline in lung function with associated reductions in quality of life and increased treatment burden, morbidity and mortality. Naturally antibiotic-tolerant organisms that evolve resistance to commonly used antibiotics are problematic, in particular Pseudomonas aeruginosa. As is the case with other organisms that cause lung infection in those with CF, P. aeruginosa's antibiotic tolerance and ability to establish chronic infection is thought to be conferred through the biofilm mode of growth. The adaptability of the organism to pressures exerted by antibiotics and competition within the lung environment promote antibiotic resistance. New strategies effective in preventing and managing chronic infection are likely to yield improvement in survival and quality of life, however the development of such agents is yet to materialise.

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18

Downey, D. G. "Airways inflammation in cystic fibrosis." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269047.

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19

Evans, Katharine Sarah Emily. "Cystic Fibrosis and the eye." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/54848/.

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Cystic Fibrosis (CF) results from the defective function of CF Transmembrane Conductance Regulator (CFTR), an ion channel which facilitates epithelial chloride secretion. Previous observations of dry eye and abnormal visual function in CF subjects have been considered secondary manifestations due to associated vitamin A deficiency (VAD) and CF-related diabetes (CFRD). However, CFTR is fundamentally present in the corneal, conjunctival and retinal pigment epithelium and the corneal endothelium. The hypothesis for this thesis was that abnormal chloride secretion in CF causes reduced basal tear secretion and abnormal photoreceptor function: these investigations aimed to identify primary and secondary ocular manifestations of CF. Fluorescein tear break-up time was significantly reduced in adult CF subjects compared to healthy controls. Increased signs of ocular surface inflammation and higher tear feming grades were recorded in CF subjects, although differences failed to reach significance. Tear film stability was further reduced in CF adults with VAD suggesting the aetiology of dry eye appears to be a combination of primary and secondary manifestations of the disease. Visual function was essentially normal in CF juveniles but was adversely affected in CF adults compared to controls. Impaired distance and near visual acuity (DVA and NVA), contrast sensitivity (CS), dark adaptation (DA) and colour vision (CV) appeared to be a primary manifestation as differences were exaggerated in subjects with predicted increased levels of CFTR disruption and disease severity. These results provide support for the hypothesis and suggest normal rod and cone photoreceptor function are compromised by abnormal CFTR action. DVA, NVA, CS and DA were significantly affected by CFRD status and DA and CV were similarly reduced in VAD subjects. Therefore, abnormal visual function in CF is further modulated by secondary disease characteristics. These findings present the distinction between primary and secondary ocular manifestations of CF, which is novel to this investigation.

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20

Wright, Adam. "The macrophage in cystic fibrosis." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/8783.

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Background: Cystic fibrosis (CF) is caused by absent/defective CF transmembrane conductance regulator protein (CFTR). CF is characterized by thick airway mucus, chronic infection and neutrophil inflammation leading to respiratory failure. I analysed airway macrophages (MΦs) and their expression of pattern recognition receptors (PRRs) in CF, since these cells are crucial to airway immune defence and they can orchestrate inflammation. I also performed transcript analysis of CF monocyte-derived MΦs (MDMs). Methods: Sputum was induced in CF paediatric and adult cohorts. Phenotype and function of CF MΦ were determined by flow cytometry and compared to controls. Monocytes (>92% purity) were grown in vitro to generate MDMs (n=15). Transcripts encoding the entire human genome were analysed (n=5) and expression of individual genes were confirmed by RT-PCR. Results: In classical CF (n=10) there was an increase in the proportion of monocyte-like small MΦs (of total MΦ) compared to controls (n=10) (73 ± 18% and 16 ± 8%, respectively, p< 0.0001). In non-classical CF (n=4), with milder lung disease, small MΦs increased to 31 ± 20% (p>0.05). PRRs were absent on small MΦs from CF and control. In contrast, clear expression could be detected on large MΦs from control but not CF. In line with this, CF small MΦs showed a strongly reduced uptake of particles compared to controls. Microarray analysis of MDMs revealed α- and β-tryptase as being significantly higher under constitutive and stimulated conditions in CF compared to control. However, using RT-PCR, expression of α- and β-tryptase was similar between groups. Conclusions: The phenotype of small MΦs in CF suggests that these cells are newly recruited monocytes from blood. Low expression of PRRs on these cells in CF and their reduced uptake indicates a reduced capacity to clear inhaled particles, which may contribute to further damage in CF. Further to this I was unable to confirm any transcript differences between CF and control MDMs due to mutant CFTR.

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21

Rao, Satish Ramakrishna. "Blood monocytes in cystic fibrosis." Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/7345.

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Background: Neutrophilic inflammation causes lung damage in cystic fibrosis (CF). Recent data from animal models and other chronic pulmonary inflammatory conditions suggest that the monocytes/macrophages may be an important driver of airway inflammation. CF may be associated with increased airway levels of chemoattractants for monocytes and resulting expansion of CD14++ small macrophages. I sought to assess the levels of monocyte chemoattractants CCL2 and CX3CL1 in the blood and airways of CF patients, and expression of their respective receptors CCR2 and CX3CR1 on monocytes. In a pilot study, I sought evidence for expansion of airway CD14++ small macrophages. Methods: Blood was obtained from 32 CF patients and 25 healthy controls; and induced sputum (IS) from 24 CF patients and 17 healthy controls. Flow cytometry was used to determine expression of CCR2 and CX3CR1 on CD14++ and CD14+CD16+ blood monocytes and to characterise IS airway macrophages. CCL2 and CX3CL1 levels in blood and IS were determined by ELISA. Results: Absolute count of total monocytes and monocytes subpopulations was not different between CF and controls. Serum CCL2, but not CX3CL1, was increased in CF patients (p=0.006). Similarly, CF was associated with increased IS CCL2, but not CX3CL1 (190.6 vs. 77.3 pg/mL; p=0.029). CCR2 was expressed on CD14++ monocytes but not on CD14+CD16+ monocytes. Both CD14+CD16+ and CD14++ cells expressed CX3CR1 but the expression was higher in CD14+CD16+ cells compared to the CD14++ cells. There was no difference in expression of both chemokine receptors by either monocyte subpopulation between CF and controls. Small macrophages were significantly increased in CF airways (p=0.018). Conclusion: CCL2, but not CX3CL1 is increased in the airway and blood of CF patients. Blood monocytes from CF patients are phenotypically competent to respond to CCL2, since they express normal levels of CCR2. Preliminary results suggest an expansion of small macrophages in CF airways.

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22

Li, Shuo. "Murine gammaherpesvirus mediated splenic fibrosis." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/8156.

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Infection of IFNγ receptor knockout (IFNγ R-/-) mice with murine gammaherpesvirus-68 (MHV-68) results in fibrosis in the lung, spleen, liver and lymph nodes. In the spleen, pathology involves an increase in the number of latently infected B cells that corresponds with a Th2 biased immune response, in which germinal centres become walled off and fibrosis dominates the splenic architecture. Remarkably, the spleen recovers from this pathology, and the starting point for this process is a loss of latently infected B cells. The aim of this project is to gain further understanding of the control of MHV-68 latent infection in the absence of IFNγ response. This project investigates: (1) the mechanisms that result in the loss of splenocytes, in particular the reduction of latently infected B cells; (2) the dynamics of macrophages in the induction, expression and recovery of fibrosis. Several approaches were employed to examine the hypothesis that the massive cell loss in IFNγR-/- spleen is caused by apoptosis. However, there was no evidence for excessive apoptosis throughout the development of fibrosis. Moreover, RT-PCR analysis showed that there was no significant increase in expression of viral genes associated with lytic infection. Hence it is unlikely that viral reactivation and subsequent lytic infection occurs. These data suggest apoptosis and viral reactivation are not the main mechanisms that cause splenic cell loss. Furthermore, B cell subpopulations and cells that express viral ORF73 in IFNγR-/- mice were examined using a recombinant virus. The ORF73-expressing cells are mainly germinal centre B cells and memory B cells. These two subpopulations undergo a drastic decrease in numbers during fibrosis, whereas naïve B cells, which are less susceptible to infection, maintain a relatively stable population. Therefore, the significant reduction of latently infected B cells appears to be related to the removal of germinal center B cells and memory B cells. Macrophages induced by Th2 cytokines are considered to be pro-fibrotic, and they are reported to have the potential to differentiate into myofibroblasts. In order to determine the role played by macrophages in MHV-68 induced fibrosis, transgenic mice with eGFP constitutively expressed in macrophages and dendritic cells were used. A different pattern of macrophage distribution in IFNγR-/- mice was observed compared to that in wild type mice. Moreover, the number of splenic macrophages changed dramatically in the spleen at different stages of fibrosis. The possibility that alternatively activated macrophages differentiate into myofibroblasts was investigated by co-staining with α-SMA antibody. However, no evidence was found that macrophages are one of the origins of myofibroblasts. This suggests macrophages may play other roles in regulating fibrosis rather than contributing directly to the formation of fibrosis.

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23

O'Rawe, Angela Marie. "Energy balance in cystic fibrosis." Thesis, Queen's University Belfast, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261933.

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24

McCloskey, Margaret. "Energy balance in cystic fibrosis." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287209.

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25

Smith, David L. "Nocturnal hypoxaemia in cystic fibrosis." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296267.

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26

Corbett, Christopher. "Novel markers of liver fibrosis." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5603/.

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With chronic liver disease rising, the need to stage of liver disease and fibrosis accurately is paramount as it helps guide therapy and informs prognosis. Liver biopsy is a flawed gold standard, associated with morbidity and mortality. Application of simple non-invasive tests to assess fibrosis could provide a safe way of identifying patients in greatest need of intervention and of monitoring response to therapy. I have shown in this thesis that transient elastography is an excellent tool for ruling out significant fibrosis in patients with chronic liver disease. It is easy to learn and successful scanning correlates well with histological liver fibrosis. I have also shown that Use of APRI with a cut off of >1.5-2 and Fib-4 >3.25 can provide prognostic value for overall and liver-related mortality in patients with viral hepatitis. Finally I have assessed a range of potential new biomarkers showing that combining measuring serum levels of the chemokine CXCL10 and the endothelial adhesion receptor VAP-1 can increase the correlation strength with fibrosis stage. Using morphometric analysis of liver fibrosis I show that the same markers can be linked to quantitatively measured fibrosis, removing subjective bias and reducing inter and intra-operator variance in histological assessment.

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27

Hiscox, Rachel Joy. "The retina in cystic fibrosis." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/59738/.

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Cystic fibrosis (CF) is caused by defective function of CF Transmembrane Conductance Regulator (CFTR), an epithelial ion channel that facilitates chloride secretion. Previous research has identified impaired dark adaptation (DA) in CF, which has been attributed to concomitant vitamin A deficiency or CF-related diabetes (CFRD). However, CFTR has been localised to the retinal pigment epithelium (RPE) and it is proposed that abnormal DA could be a primary manifestation of CF. DA is similarly impaired in individuals with type 1 and 2 diabetes and is thought to be caused by retinal hypoxia as oxygen inhalation ameliorates abnormal thresholds. The aim of this thesis was to investigate DA during oxygen inhalation in CF subjects with and without CFRD to gain further insight about the aetiology of this abnormal DA. The work also aimed to examine retinal structure using optical coherence tomography (OCT) to determine the consequences of CFTR dysfunction at the RPE. Final DA thresholds were not impaired in CF subjects as a whole during the inhalation of air. However, when grouped according to diabetic status, CFRD subjects showed a significantly elevated final rod threshold which was ameliorated following oxygen inhalation. This suggests that the retina is hypoxic in CFRD subjects and that impaired DA in CF is secondary to CFRD rather than a primary manifestation of CFTR malfunction at the RPE. Contrary to the proposed hypothesis, retinal and RPE/photoreceptor layer thickness was significantly thinner in CF subjects. These results suggest that impaired CFTR function at the RPE does not directly affect retinal structure. · In conclusion, this is the first study to determine that retinal structural and functional abnormalities are not caused directly by CFTR dysfunction but are a secondary manifestation of the disease. Further research is necessary to understand the impact of these findings.

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28

McIlwaine, Patricia Margaret. "Airway clearance in cystic fibrosis." Thesis, Ulster University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625501.

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This thesis overviews and highlights a body of work performed at the BC Children's Hospital, Vancouver, Canada between 1986 and 2013, and involving travel to Belgium, Denmark and the United Kingdom. It is based on five articles published by McIlwaine on research and development in the use of various airway clearance techniques for the treatment of cystic fibrosis, namely: Autogenic Drainage; Positive Expiratory Pressure; Oscillating Positive Expiratory Pressure; and High Frequency Chest Wall Oscillation. The thesis comprises of seven chapters, including the introduction. Chapter 2 presents the physiological evidence and theories to support each technique. Chapter 3 describes various types of airway clearance studies based on the published studies submitted by McIlwaine and discusses barriers and challenges related to each study design. A clinical research pathway for future airway clearance studies is proposed. Chapter 4 examines the use of outcome measures for each stage of the pathway. Chapter 5 is based on the most recent published paper by McIlwaine, and offers an overview on how to optimise designing a multi-centre clinical airway clearance study, identifying challenges and barriers to performing such a study. The work presented in this thesis has contributed to research by furthering an understanding of the physiology upon which various airway clearance techniques are based, as well as providing guidance on the use of appropriate outcome measures. The published papers underlying the thesis have validated the airway clearance techniques of Autogenic Drainage and positive Expiratory Pressure and have in-validated the use of Oscillating PEP using Flutter and High Frequency Chest Wall Oscillation, in the treatment of cystic fibrosis. Outcomes of this work have lead to a change in clinical practice, in Europe and N. America, and have had a direct and positive effect in decreasing the burden of care in people living with cystic fibrosis.

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29

Ward, Andrew. "A cystic fibrosis infection monitor." Thesis, University of Strathclyde, 2015. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=26047.

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30

Abu, Helal Raghd. "Endothelial Cell CEACAM1 Regulates Fibrosis." Ohio University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1619725200062184.

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31

Abu, Helal Raghd. "Endothelial Cell CEACAM1 Regulates Fibrosis." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1619725200062184.

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32

Patel, Vimal. "Myocardial fibrosis in hypertrophic cardiomyopathy." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10046437/.

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Hypertrophic cardiomyopathy (HCM) is characterised by myocardial hypertrophy, fibrosis and abnormal vascular pathology and is usually caused by mutations in sarcomeric protein genes. Histological studies and in vivo imaging with cardiac magnetic resonance imaging (CMRI) have shown that myocardial fibrosis is an important entity that contributes to disease progression. However, little is known about the regulation of genes involved in collagen synthesis and metabolism, the pathways that contribute to the development of myocardial fibrosis and whether this is an early pathological process which ultimately leads to the development of the overt phenotype in genetic mutation carriers. Furthermore, the contribution of fibrosis on myocardial function has been poorly defined. In this thesis, I identified that myocardial genetic expression of collagen is upregulated in patients with HCM and this is paralleled by elevated levels of procollagen in plasma. The genetic expression of transforming growth factor beta (TGF-β) and its downstream mediator connective tissue growth factor was also enhanced in HCM and correlated with collagen I and III RNA levels, suggesting a central role of TGF-β in mediating fibrosis. Plasma markers of collagen synthesis and metabolism were also increased in sarcomeric mutation carriers without hypertrophy, suggesting that fibrosis may be an early process that contributes to the development of the overt phenotype. Plasma levels of procollagen I were higher in patients with non-sustained ventricular tachycardia and focal fibrosis identified by CMRI was associated with impaired systolic deformation. Diffuse fibrosis beyond that seen in healthy controls also correlated with a reduction in systolic function. Together, the findings of this thesis support the hypothesis that myocardial fibrosis is an active process in HCM that precedes clinical phenotype. Myocardial fibrosis is at least in part mediated by the TGF- β pathway and associated with impaired systolic performance and may contribute to arrhythmic risk in HCM.

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33

Vitko, Megan Sue. "Intestinal Dysfunction in Cystic Fibrosis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266.

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34

Bizzell, Laurie. "Maternal Stress and Cystic Fibrosis." Thesis, University of North Texas, 1996. https://digital.library.unt.edu/ark:/67531/metadc278693/.

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The purpose of the current study was to examine the relationship between parent and child factors for mothers of children diagnosed with cystic fibrosis to predict mother's psychological distress. Mothers were surveyed to identify measurement models in areas of Child and Parental characteristics and a Full Causal Model of Maternal distress. Factors related to Child Characteristics include general parental stressors and cystic fibrosis specific parental stressors. Factors related to Parental Characteristics include the mother's sense of parental competence and self-esteem. Additional factors related to the Full Causal Model include social support, major and minor life events, and demographics. Results were analyzed using LISREL IV structural equation modeling. Measurement model analysis found a good fit for the Child Characteristics model (Chi Square = 6.85, df = 4, JD = .144, Goodness of Fit Indices = .972) and Parental Characteristics model (Chi Square = 5.89, df = 3, p = .117, Goodness of Fit Indices = .971), but not for the full causal model of maternal distress (Chi Square = 114.98, df = 66, E = .000, Goodness of Fit Indices = .853)

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35

Putman, Melissa. "Cystic Fibrosis Related Bone Disease." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17613728.

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Over the past several decades, life expectancy for patients with cystic fibrosis (CF) has increased significantly. As patients live longer, other nonpulmonary co-morbidities related to CF have become increasingly prevalent, including CF-related bone disease. Because CF related bone disease has only recently emerged as a clinical problem, and the underlying bone alterations and pathogenesis of this condition have not been established. This thesis explores the underlying bone micro-architecture and strength alterations found in adults with CF using state-of-the-art bone imaging techniques and explores whether improvements in the treatment of patients with CF over the past 15 years has led to similar improvements in bone health.

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Zibadi, Sherma. "Metabolic Syndrome-Induced Cardiac Fibrosis." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195321.

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Recent studies support the association between metabolic syndrome (MetS), a cluster of cardiovascular risk factors, and diastolic dysfunction. Disproportionate collagen accumulation, particularly cross-linking of collagen, plays a key role in translating interstitial fibrosis into mechanical chamber stiffness and diastolic dysfunction. Characteristic changes in the expression and activity of myocardial lysyl oxidase (LOX), a matrix modifying enzyme that catalyzes cross-linked collagen, are unclear in MetS. We established a diet-induced MetS model to study diastolic dysfunction by treating male C57BL/6 mice a high-fat high-simple carbohydrate (HFHSC) diet for 6 months. Despite blunted gene expression of LOX isoforms, MetS mice demonstrated significant increase in the ratio of protein expression of mature to proenzyme LOX, enhanced LOX activity, and increased cardiac cross-linked collagen compared with controls. This fibrotic response coincided with marked increase in left ventricular end-diastolic pressure and stiffness and impaired diastolic filling pattern. Our data demonstrate that diet-induced MetS alters the remodeling enzyme LOX, thereby increasing the amount of crosslinking and inducing diastolic dysfunction.Furthermore we examined the role of T-lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice which are devoid of functional T-lymphocytes and C57BL/6 mice were treated with HFHSC diet for 12 months. Similar to male C67BL/6, female HFHSC-fed C57BL/6 mice demonstrated significant increase in maturation and catalytic activity of myocardial LOX, cross-linking, ventricular stiffness and diastolic dysfunction. Whereas induction of LOX protein was minimal in SCID mice compared with wild-type counterparts. Correspondingly fibrillar cross-linked collagen formation and diastolic dysfunction were less prominent in SCID mice. Our results suggest a potential role of T-lymphocytes in induction of myocardial stiffness and diastolic dysfunction through modulation of LOX-dependent collagen maturation.Moreover we studied the role of leptin, an adipokine over-produced in MetS with fibrotic effects in non-cardiac tissues, as a key mediator of profibrogenic responses in the heart by administrating leptin to C57BL/6 and leptin-deficient ob/ob mice. With exogenous leptin administration ob/ob mice displayed passive diastolic filling dysfunction that coincided with increase in myocardial collagen compared with ob/ob controls. Our findings suggest profibrotic effects of leptin in the heart, primarily through predominance of collagen synthesis over degradation.

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37

Dentini, Priscila. "Complexo Burkholderia cepacia em pacientes com fibrose cística em um Centro de Referência no Brasil = identificação, prevalência e importância clínica." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309992.

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Orientador: José Dirceu Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-16T17:48:38Z (GMT). No. of bitstreams: 1 Dentini_Priscila_M.pdf: 10675938 bytes, checksum: afc138751a1f11e6991384ca9bbee25c (MD5) Previous issue date: 2010
Resumo: Objetivos: Determinar a prevalência da colonização/infecção pelo Complexo Burkholderia cepacia (CBc) e os respectivos genomovares em pacientes com fibrose cística (FC) e comparar os indicadores clínicos, nutricionais, tomográficos e funcionais de gravidade da lesão pulmonar em dois grupos de pacientes: GI: pacientes colonizados/infectados pelo CBc e GII: pacientes sem colonização/infecção pelo CBc, com a finalidade de avaliar o impacto deste microrganismo na deterioração pulmonar. Métodos: Foi realizado um estudo clínico-laboratorial, prospectivo, com 222 pacientes com FC, acompanhados nos ambulatórios pediatria e adultos da UNICAMP. Os pacientes foram divididos em 2 grupos: GI (n=50) e GII (n=134). Os microrganismos foram identificados por meio de testes bioquímicos convencionais, pelo Vitek2®Compact, PCR do gene recA, e nested-PCR com primers espécie-específicos. O seqüenciamento do gene recA foi realizado para cepas com PCR inconclusivas. Os pacientes foram classificados pelo escore clínico de Schwachman e as medidas de peso/idade, estatura/idade e IMC/idade foram utilizadas para avaliar o estado nutricional. As alterações tomográficas foram classificadas pelo escore de Bhalla e a função pulmonar foi avaliada por espirometria. Os dados foram comparados entre os grupos com a finalidade de avaliar o impacto do CBc na lesão pulmonar. Resultados: A prevalência do CBc foi de 22,5% e dos genomovares: Bukholderia multivorans (30,0%), seguido de Burkholderia cepacia (24,0%), Burkholderia cenocepacia IIIA (10,0%), Burkholderia cenocepacia IIIB (2%) e Burkholderia vietnamiensis (2,0%). No grupo I, 26,0% dos pacientes estavam infectados, 18,0% apresentaram colonização transitória e 56,0% colonização intermitente pelo CBc. Não houve diferença estatística na média de pontos do escore de Schwachman (p=0,07), nem na classificação da gravidade (p=0,611), porém houve diferença nas variáveis: estado nutricional (p=0,020) e atividade geral (p=0,026). Houve diferença estatística na média de pontos do escore de Bhalla (p=0,04) e entre os parâmetros: gravidade da bronquiectasia (p=0,007), espessamento peribrônquico (p=0,013), extensão das bronquiectasias (p=0,010), generalidades da árvore bronquial (p=0,020). O teste de função pulmonar mostrou: CVF(%) (p=0,076), VEF1(%) (p=0,066), FEF25-75% no (p=0,312) e VEF1/CVF (p=0,312). Classificação dos distúrbios ventilatórios: DVO no GI=4,8% e GII=23,8%, DVR no GI e GII=9,5%, DVM no GI=19,0% e GII=1,6% e DVM com CVF reduzida no GI=47,6% e GII=30,2%. Na avaliação nutricional houve diferença significante entre as médias de peso(kg) e estatura(cm) (p=0,02). Conclusões: A prevalência do CBc em nosso centro é significativamente superior aos dados apresentados pela literatura nacional e internacional. A maior prevalência da Burkholderia multivorans difere da maioria dos estudos. Há a suspeita de que possa ter ocorrido infecção cruzada entre os pacientes ou que seja uma característica regional. Os escore de Shwachman, escore de Bhalla, espirometria e dados nutricionais mostraram que o CBc tem sério impacto na deterioração pulmonar e na piora clínica. Os métodos fenotípicos são úteis para a identificação presuntiva do CBc. O Vitek® apresentou boa acurácia na identificação do CBc, porém com alguns erros decorrentes de limitações do método/equipamento. O PCR, nested-PCR e seqüenciamento do gene recA apresentaram boa especificidade na identificação do CBc e dos genomovares, entretanto, ainda ocorrem algumas limitações, decorrentes da variedade genotípica, sendo necessária a utilização de métodos mais abrangentes, como o MSLT
Abstract: Objectives: Determine the Burkholderia cepacia complex (BCC) colonization/infection and genomovar prevalence in cystic fibrosis patients and compare the clinical, tomographic and functional severity indicators of lung injury in two groups of patients: GI - patients colonized or infected with BCC and GII - patients without BCC colonization or infection, with the aim of assessing the impact of this microorganism in pulmonary deterioration. Methods: A clinical-laboratory and prospective study was conducted with 222 CF patients seen in the CF outpatient (pediatrics and adults) in UNICAMP. Patients were divided into two groups: GI (n = 50) and GII (n = 134). Microorganisms were identified by conventional biochemical tests, Vitek2®Compact, recA-PCR and recA-nested-PCR with species-specific primers. The recA gene sequencing was performed for strains with inconclusive PCR reactions. Patients were classified by Schwachman's clinical score and measures of weight/age, height/age and BMI/age were used to assess nutritional status. The tomography changes were classified by Bhalla's score and lung function was assessed by spirometry. Data were compared between groups with the aim of assessing the CBC impact in lung injury. Results: The BCC prevalence was 22.5% and the most prevalent genomovars was: Bukholderia multivorans (30.0%), followed by Burkholderia cepacia (24.0%), Burkholderia cenocepacia IIIA (10.0%), Burkholderia cenocepacia IIIB (2%) and Burkholderia vietnamiensis (2.0%). In group I, 26.0% of patients were infected, 18.0% had transient colonization and 56.0% intermittent colonization by BCC. There was no statistical difference in the average point of Schwachman's score (p = 0.07) or in the severity classification (p = 0.611) but had differences in variables: nutritional status (p = 0.020) and general activity (p = 0.026). In the average point Bhalla's score was statistical difference (p = 0.04) and between the parameters: severity of bronchiectasis (p = 0.007), peribronchial thickening (p = 0.013), extent of bronchiectasis (p = 0.010), general the bronchial tree (p = 0.020). The pulmonary function test showed: FVC (%) (p = 0.076), FEV1 (%) (p = 0.066), FEF25-75% (p = 0.312) and FEV1/FVC (p = 0.312). Respiratory disorders classification: DVO in GI and GII = 4.8% = 23.8%, DVR in GI and GII = 9.5%, DVM in GI and GII = 19.0% = 1.6% and with DVM FVC decreased in GI and GII = 47.6% = 30.2%. Nutritional assessment was significant difference between the mean weight (kg) and height (cm) (p = 0.02.) CCoonncclluussiioonnss:: The BCC prevalence in our center is significantly higher than the dates provided by national and international literature. The increased Burkholderia multivorans prevalence differs from the most studies. It is suspected that may have been cross-infection between patients or is a regional characteristic. The Shwachman's and Bhalla score, spirometry and nutritional data showed that the BCC has serious impact on the deterioration and worsening pulmonary clinic. The phenotypic methods are useful for the presumptive BCC identification. The Vitek2®Compact showed good accuracy in BCC identification of, but with some errors due to limitations of the method/equipment. PCR, nested-PCR and recA sequencing showed good specificity in BCC genomovars identifying, however, there are still some limitations, stemming from different genotype, being necessary to use more comprehensive methods, such as the MSLT
Mestrado
Saude da Criança e do Adolescente
Mestre em Saude da Criança e do Adolescente

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38

Meziani, Lydia. "Study of Interaction Between the Inflammatory Response and Radiation-Induced Fibrosis." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T041.

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La fibrose radio-induite (FRI) est une complication tardive de la radiothérapie souvent associée à une réponse inflammatoire chronique et à un infiltrat de macrophages. Aujourd’hui, les macrophages sont pressentis comme des médiateurs cellulaires important dans le processus de fibrose mais leur rôle n’a jamais été étudié dans le contexte de la FRI. Dans une précédente étude nous avions montré que l’irradiation (IR) induit une polarisation M1 des macrophages cardiaques après irradiation de souris ApoE-/- et est associée un score de fibrose élevé, ce qui suggérait que la polarisation des macrophages pourrait contribuer à la fibrogénèse radio-induite. Afin de valider cette hypothèse, nous avons cherché à caractériser le rôle des macrophages dans la FRI en utilisant un modèle classique de fibrose pulmonaire chez la souris C57Bl/6 induit après IR thoracique à 16Gy. Nous avons caractérisé les phénotypes et la fonction des macrophages alvéolaires (MA) et interstitiels (MI). Durant la phase précoce, les résultats montrent une déplétion des MA accompagnée de la sécrétion de CXCL1, MCP-1 et de MCSF. Cette déplétion est suivie d’une repopulation suite au recrutement et à la prolifération des monocytes/macrophages d’origine médullaire. La nouvelle population de MA présente une polarisation hybride accompagnée d’une augmentation simultanée de la sécrétion de cytokines Th1 et Th2. Durant la phase tardive les MI présentent une polarisation de type M2 accompagnée d’une diminution des cytokines Th1 et d’une augmentation de cytokines Th2 dans le lysat tissulaire. Nous avons ensuite cherché à caractériser la contribution des MA hybrides vs MI M2 dans le processus de fibrose. Nous avons montré que contrairement au MA hybrides, les MI M2 étaient capables d’induire l’activation des fibroblastes in vitro et l’expression de TGF-β1. De plus, la déplétion des MA hybrides avec une administration intranasale de clodronate exacerbe la FRI et induit l’augmentation de l’infiltrat de MI M2. Ensuite, nous nous somme interrogés à la contribution du processus de fibrose dans la polarisation des macrophages. Après 24h de coculture entre fibroblastes irradiés et macrophages pulmonaires non irradiés, une sécrétion de cytokines telles que M-CSF et TIMP-1 qui pourraient stimuler l’activation des fibroblastes est observée. De plus, l’inhibition de la FRI avec de la pravastatine montre que l’inhibition de la fibrose est accompagnée d’une augmentation des MI M1 et d’une diminution des MI M2 dans le poumon. En résumé, nos résultats montrent une contribution opposée des Macrophages Alvéolaires et des Macrophages Interstitiels dans le processus de fibrose radio-induite ainsi qu’une contribution du processus de fibrose dans le type d’activation des Macrophages interstitiels formant ainsi une boucle d’activation fibrogénique chronique
Radiation-induced fibrosis (RIF) is a delayed complication of radiotherapy often associated with chronic inflammatory process and macrophage infiltration. Nowadays, macrophages are suggested to be important cellular contributors to fibrogenic process, but their implication in the context of RIF has never been investigated. In a previous study we have shown that irradiation (IR) induced the polarization of cardiac macrophages into M1 in ApoE-/- mice and was associated with a high fibrosis score in ApoE-/- mice, suggesting that macrophage polarization could drive tissue sensitivity to ionizing radiation. This observation prompted us to investigate the role of macrophages in RIF using a classical experimental model of lung fibrosis developed in C57Bl/6 mice after 16Gy thorax-IR. We profiled both alveolar macrophages (AM) and interstitial macrophages (IM). During the acute phase we found AM depletion associated with CXCL1, MCP-1 and M-CSF secretion, followed by a repopulation phase mediated by recruitment and proliferation of monocytes/macrophages from the bone marrow. Interestingly, the newly recruited AM exhibited a yet never described hybrid polarization (M1/M2), associated with the up-regulation of both Th1 and Th2 cytokines. At delayed times points, IM were M2-polarized and associated with downregulation of Th1 cytokines and upregulation of Th2 cytokines in tissue lysates. These results suggest a differential contribution of hybrid AM vs M2 IM to fibrogenesis. Interestingly, in contrast to activated hybrid AM, activated M2 IM were able to induce fibroblast activation in vitro mediated by an enhanced TGF-β1 expression. Therefore, specific depletion of hybrid AM using intranasal administration of clodrosome increased RIF score and enhanced M2 IM infiltration. We next evaluated if the fibrogenic process can in turn affect macrophage polarization. Interestingly, after coculture of irradiated fibroblast with non-irradiated pulmonary macrophages, secretion of cytokines such as M-CSF and TIMP-1, which can stimulate macrophage activation, was observed. Furthermore, RIF inhibition using pravastatin treatment showed that fibrosis inhibition was associated with a decrease in M2 IM accompanied by an increase in M1 IM, but had no effect on polarization of AM. These present study shows a dual and opposite contribution of alevolar versus intertitial macrophages in RIF and the contribution of the fibrogenic process to IM polarization, resulting thereby in a chronical fibrogenic loop

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Fernandes, Flávia Ferreira. "ELF (Enhanced Liver Fibrosis) como marcador não invasivo de fibrose hepáticana hepatite C crônica." Universidade do Estado do Rio de Janeiro, 2014. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8773.

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A fibrose hepática é o aspecto mais relevante e o mais importante determinante de morbimortalidade na hepatite C crônica (HCC). Historicamente, a biópsia hepática é o método de referência para avaliação da fibrose causada pela HCC, apesar de apresentar limitações. O estudo de marcadores não invasivos, que possam obviar a necessidade da biópsia, é uma área de constante interesse na hepatologia. Idealmente, a avaliação da fibrose hepática deveria ser acurada, simples, prontamente disponível, de baixo custo e informar sobre o prognóstico da patologia. Os marcadores não invasivos mais estudados são a elastografia hepática transitória (EHT) e os laboratoriais. A EHT já foi extensamente validada na HCC e está inserida na rotina de avaliação destes pacientes. Dentre os laboratoriais, existem diversos testes em continua experimentação e, até o momento, nenhum foi integrado à prática clínica no Brasil, embora já aplicados rotineiramente em outros países. O Enhanced Liver Fibrosis (ELF), um teste que dosa no soro ácido hialurônico, pró-peptídeo amino-terminal do colágeno tipo III e inibidor tissular da metaloproteinase 1, tem se mostrado bastante eficaz na detecção de fibrose hepática significativa e de cirrose na HCC. Neste estudo o ELF teve o seu desempenho avaliado em relação a biópsia hepática e demonstrou apresentar boa acurácia na detecção tanto de fibrose significativa quanto de cirrose. Na comparação com a EHT apresentou acurácia semelhante para estes mesmos desfechos, com significância estatística. No entanto, foi observada uma superestimação da fibrose com a utilização dos pontos de corte propostos pelo fabricante. Este achado está em acordo com a literatura, onde não há consenso sobre o melhor ponto de corte a ser empregado na prática clínica. Com a ampliação da casuística foi possível propor novos pontos de corte, através da análise clássica, com a biópsia hepática como padrão ouro. O resultado obtido vai ao encontro do observado por outros autores. Em seguida, os novos pontos de corte do ELF foram reavaliados sem que a biópsia hepática fosse a referência, através da análise de classes latentes. Mais uma vez o ELF apresentou bom desempenho, inclusive com melhora de suas sensibilidade e especificidade em comparação com a análise clássica, onde a biópsia hepática é a referência. Assim sendo, é possível concluir que o ELF é um bom marcador não invasivo de fibrose hepática. No entanto, para detecção de fibrose significativa e cirrose, deve ser considerada a aplicação na prática clínica dos novos pontos de corte aqui propostos.
Liver fibrosis is the most relevant issue concerning chronic hepatitis C (CHC) and determines its prognosis. Historically, liver biopsy has been the reference method for evaluating fibrosis related to CHC, though it presents many drawbacks. There is a continuing interest in the development of non invasive markers capable of replacing liver biopsy. The ideal surrogate for fibrosis evaluation should be accurate, simple, low cost and yield prognostic information. So far, the most well known non invasive methods are transient hepatic elastography (TE) and laboratory panels. TE has already been extensively validated and is integrated in patients routine. There is plenty of laboratory panels in continuing evaluation and some are already integrated in daily practice abroad. In Brasil, until the present moment, it is not a reality. Enhanced Liver Fibrosis (ELF) panel comprises the serum concentration of hyaluronic acid, tissue inhibitor of matrix metalloproteinases-1, and aminoterminal propeptide of type III procollagen and has demonstrated good performance in detecting significant fibrosis and cirrhosis in CHC patients. In the present study ELF had its performance evaluated against liver biopsy and obtained satisfactory accuracy in detecting significant fibrosis and cirrhosis. In comparison to TE no statistically significant diference was observed, for the same endpoints mentioned before. However, the application of manufacturers cutoff points produced overestimation of fibrosis stages. These findings are in accordance with other authors results, in that there is no consensus so far on the most adequate cutoff points for main clinical end points. Enlarging the data permited calculating new cutoff points, through the classical statistical approach, using liver biopsy as the gold standard. The results once more matched those published in literature. Following this, the ELF new cutoff points were evaluated in a statistical modeling where there are no gold standards, the latent classes analysis. Besides showing a satisfactory performance, in this new approach, ELF experimented an improvement in sensitivity and specificity, if compared with the classical analisys, with liver biopsy as reference. ELF panel has a good performance as a noninvasive fibrosis marker. However, new cutoff points need to be applied to improve its performance for the discrimination of different stages of fibrosis in CHC patients.

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40

Durham, Dixie Lea. "Survey of adult cystic fibrosis patients and parents of cystic fibrosis patients on nutrition education." [Boise, Idaho] : Boise State University, 2009. http://scholarworks.boisestate.edu/td/8/.

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Kaarteenaho-Wiik, R. (Riitta). "Tenascin expression and distribution in pulmonary and pleural fibrotic disorders." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514253051.

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Abstract Fibrotic pulmonary and pleural disorders represent a group of intrathoracic disorders with different etiologies and prognoses. A prominent part of both pulmonary and pleural fibrotic disorders remains etiologically unknown. An essential feature for all these disorders is an increase and disarray of many extracellular matrix proteins which take part in the remodeling of the fibrotic tissue. Further, the injury in pulmonary as well as in pleural fibrosis occurs often at the border between the epithelial or mesothelial and the mesenchymal cells breaking the epithelial basement membrane. Tenascin is an oligomeric matrix glycoprotein of the extracellular matrix. The best known isoforms are tenascin -C, -X, -R, -Y and -W. Tenascin-C is synthesized during embryonic development, expressed in a variety of tumors, being absent or scantily expressed in most adult tissues. The function of tenascin-C is still unclear. In lung, tenascin-C has been shown to be expressed in fetal lung during branching morphogenesis, benign and malignant lung tumors, idiopathic pulmonary fibrosis, sarcoidosis and asthma. The aim of the present study was to study tenascin-C (later called tenascin) expression in various types of pulmonary fibrosis such as usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), sarcoidosis and extrinsic allergic alveolitis as well as in fibrotic and inflammatory disorders of the pleura of different etiologies. Further, the aims were to compare the accumulation of tenascin with the prognosis in UIP, to confirm the immunohistochemical findings in UIP by Western blotting and immunoelectron miscroscopic (immuno-EM) studies, to investigate which cells synthesize tenascin in UIP and in pleural fibrosis by mRNA in situ hybridization, and to determine whether epithelial lining fluid (ELF) and serum tenascin concentration are increased in patients with UIP, sarcoidosis and extrinsic allergic alveolitis. Tenascin was shown to be increased by immunohistochemical studies in all types of pulmonary and pleural fibrotic disorders included in the study. In UIP, increased tenascin expression was associated with a shortened survival time of the patients. In immuno-EM, labeling for tenascin was seen within type II pneumocytes. UIP cases showed reactivity for a polypeptide of Mr = 200 000 by Western blotting. Myofibroblasts and type II pneumocytes were mainly shown to synthesize tenascin in UIP. Also in pleural fibrosis myofibroblasts, and in addition possibly mesothelial cells, were observed to be responsible for its synthesis. ELF and serum tenascin concentrations were increased in UIP, sarcoidosis and extrinsic allergic alveolitis. In conclusion, tenascin expression is increased in pulmonary and pleural fibrotic disorders, especially in newly formed fibrosis. In UIP, tenascin is actively synthesized at the sites of recent epithelial injury, suggesting that it plays an important role in the fibrogenesis in the lung.

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42

Liu, Yi-Chia. "Understanding chronic inflammatory diseases in the human lung : the cystic fibrosis and idiopathic pulmonary fibrosis paradigms." Thesis, University of Nottingham, 2014. http://eprints.nottingham.ac.uk/27807/.

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The chronic infection of the cystic fibrosis (CF) lung with Pseudomonas aeruginosa strongly correlates with critical outcomes. Pseudomonas alkyl-quinolone signal (PQS) is a diffusible cell-density dependent signal controlling the production of virulence determinants. The PQS amount in the CF lung was proportionate to P. aeruginosa colonisation and PQS molecules have been demonstrated to inhibit pro-inflammatory signalling. However, how PQS influence the recognition of P. aeruginosa by the human lung is unknown. The contribution of PQS to the interaction of P. aeruginosa with human bronchial epithelial cells (HBECs) was characterised using a PQS-deficient mutant ΔpqsA in comparison with its isogenic wild type (WT). Although ΔpqsA appeared attenuated, the pathogenesis of WT and ΔpqsA upon infection of HBEC did not differ in bacterial growth, actin and junctional protein degradation, and pro-inflammatory activation. Despite PQS being highly secreted by a CF isolate LESB58, preliminary data showed that LESB58 was less cytotoxic than the laboratory WT. Our results suggest that PQS does not alter P. aeruginosa pathogenicity on HBECs. Idiopathic pulmonary fibrosis (IPF) is characterised with heterogeneous pathological patterns caused by scarring leading to irreversible destruction of lung architecture. Emerging evidence suggests that dysregulated immunological events could cause the failure of tissue-healing. Systemic immune responses of patients with IPF and age- and sex-matched healthy donors were determined by quantifying cytokines produced by peripheral blood mononuclear cells (PBMCs) upon an array of stimuli. The results showed that PBMCs in patients with IPF were less likely to produce IL-17A, IL-10 and IL-13 than healthy controls (OR 0.14-0.3, 95% CI 0.003-0.03). Patients with lower levels of cytokines had a four to six-fold increased risk of death (HR 4.31-6.13, 95% CI 0.0052-0.0176). This study contributes to a better understanding of the role of PQS in P. aeruginosa pathogenesis and identified cytokine production as a novel biomarker in IPF.

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43

DaSilva, Santos Iara Karlla. "Impacto de la inflamación y fibrosis en la función del injerto renal." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666855.

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A pesar de los grandes avances en el campo del trasplante renal (TR), los resultados a largo plazo aún no son óptimos. Varios estudios han demostrado que diversos factores como la inflamación precoz y/o la presencia de fibrosis intersticial (FI) están asociados a un peor pronóstico del injerto, pero todavía se trata de un tema controvertido. En este estudio analizamos el estado inflamatorio (Banff, macrófagos CD68+, fenotipos de macrófagos M1-M2) y la expresión génica de múltiples factores relacionados con la inflamación y FI (TGF-β1, metaloproteinasas, proteínas de matriz extracelular, entre otros) en injertos procedentes de donantes cadáver (DC) y los comparamos con un grupo control de donantes vivos (DV). Así mismo analizamos la potencial asociación de estos factores, ya desde antes de la implantación, con diversas variables clínicas y con la función renal a medio-largo plazo. Entre otros hallazgos, confirmamos que los órganos procedentes de DC presentan un mayor infiltrado intersticial de macrófagos CD68+ y describimos que tanto la expresión génica de varias proteínas pro-inflamatorias como pro-fibróticas se encuentran significativamente incrementadas en los DC incluso antes de la implantación. También observamos un aumento en la expresión génica de proteínas que promueven la infiltración leucocitaria, especialmente macrófagos, en el tejido (MCP-1, ICAM-1), así como de mediadores de inflamación como TNFα, IL1β. También se observó un aumento en la expresión génica de receptores de membrana de los macrófagos que les confiere el fenotipo inflamatorio (M1) así como el antinflamatorio (M2). En los DC también se observó un aumento significativo de los precursores y mediadores de FI. Es de destacar que muchos de estos parámetros (inflamatorios y pro-fibróticos) se asociaron a la función renal estimada (MDRD) en distintos tiempos de seguimiento. El análisis multivariante (regresión lineal múltiple) mostró que tanto la función retrasada del injerto como la expresión génica de TGF-β1 a los cuatro meses fueron predictores independientes de la función del injerto del último control (media 5.8 1.0 años). En conclusión, confirmamos la estrecha interconexión entre inflamación y fibrosis especialmente en el TR de DC, que ésta se inicia ya antes de la implantación y persiste post-TR y que estos factores muy precoces (potencialmente tratables) pueden determinar el pronóstico del injerto a largo plazo.
Despite great achievements in the field of renal transplantation (RT), long-term results are still not optimal. Several studies have shown that various factors such as early inflammation and/or the presence of interstitial fibrosis (IF) are associated with a worse graft prognosis, but this issue is still controversial and far from being resolved. In this study, we analyzed the inflammatory state (Banff, CD68 + macrophages, M1-M2 phenotypes, among others) and the gene expression of multiple factors related to both inflammation and IF (TGF-β1, metalloproteinases, extracellular matrix proteins, among others) in grafts from cadaveric donors (CD) and they were compared with a control group from living donors (LD). We also analyzed the potential association of all these factors with several clinical variables with medium and/or long-term renal function. Among other findings, we confirm that organs from CD have a greater CD68+ macrophage infiltration and we describe that the expression of several proinflammatory and and profibrotic molecules is significantly increased in CD even before grafting. We also observed an increased gene expression of proteins related to graft leukocyte infiltration, mainly macrophages, such as MCP-1 or ICAM-1, as well as of inflammatory mediators such as TNFα or IL1β. We also observed an increased gene expression of macrophage membrane cell receptors related to their inflammatory (M1) or anti-inflammatory (M2) phenotype. Finally, we described a significant increase of IF precursors and mediators in CD. It is noteworthy that multiple parameters (both inflammatory and profibrotic) were associated with the estimated glomerular filtration rate (MDRD) at different times. Multiple regression analysis revealed that delayed renal function as well as graft TGF-β1 gene expression four months after RT were independent predictors of the last renal function control during follow-up (5.8 1.0 years). In conclusion, we confirm the existence of an especially close interconnection between inflammation and fibrosis, especially in the CD RT setting, starting before engraftment and progressing after RT, and that these very early (potentially treatable) factors may already devise its long-term graft prognosis.

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44

Pat, Betty Kila. "Signal transduction pathways in renal fibrosis /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17739.pdf.

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45

Ball, Lindsay Clare. "Cystic fibrosis and vitamin D supplementation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2010. https://www.mhsl.uab.edu/dt/2010m/ball.pdf.

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46

Andersson, Charlotte. "Towards Pharmacological Treatment of Cystic Fibrosis." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2634.

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S-nitrosogluthatione is an endogenous substance, present at decreased levels in the lungs of CF patients and was recently found to induce mature CFTR in airway epithelial CF cell lines. We show that S-nitrosoglutathione in physiological concentrations increases the presence of ΔF508 CFTR in the cell membrane and induces cAMP dependent chloride transport in cystic fibrosis airway epithelial cells. The properties of S-nitrosoglutathione include other potential benefits for the CF patient and make this agent an interesting candidate for pharmacological treatment of CF that needs to be further evaluated.

Genistein was found to increase the chloride efflux in both normal and ΔF508 cells without stimulation of cAMP elevating agents and without prior treatment with phenylbutyrate. Genistein, in concentrations close to those that can be detected in plasma after a high soy diet, could induce chloride efflux in cells with the ΔF508 CFTR mutation and its possible use in the treatment of CF should therefore be further investigated.

Studies on nasal epithelial cells from CF patients showed cAMP dependent chloride efflux in some of the patients with severe genotypes. This may complicate in vitro evaluation of clinical treatment of these patients. The presence of cAMP dependent chloride transport did not necessarily lead to a milder phenotype. Other factors than CFTR may influence the clinical development of the disease.

Cystic fibrosis (CF) is the most common monogenetic disease among Caucasians. A defective cAMP regulated chloride channel (cystic fibrosis transmembrane conductance regulator, CFTR) in epithelial cells leads to viscous mucus, bacterial infections, inflammation and tissue damage in the lungs that cause death in 95% of the cystic fibrosis patients. There is no cure for the disease although existing treatment has dramatically prolonged the life expectancy. The aim of this thesis was to study pharmacological agents for their ability to restore the cellular deficiency in CF airway epithelial cells. X-ray microanalysis, MQAE fluorescence and immunocytochemistry were used to evaluate the effects.

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47

Renzoni, Elisabetta Augusta. "Fibroblast gene expression in pulmonary fibrosis." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490948.

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Background: Idiopathic pulmonary fibrosis (IPF) has a median survival since diagnosis of2-3 years. Interstitial lung disease associated with systemic sclerosis (SSc-ILD) is characterised by a better survival than IPF. Lung fibroblasts are the main cell type responsible for the excessive extracellular matrix synthesis in lung fibrosis. The pathogenesis offibrosis in both conditions is largely unknown, and it is unclear to what extent it differs between the two. Hypothesis: The gene expression profile of fibroblasts from IPF and SSc-ILD differs from control lung fibroblasts; significant differences between IPF and SSc-ILD fibroblasts could explain the worse survival ofIPF patients. The study of gene profiles in response to pro-fibrotic cytokines transforming growth factor beta (TGFbeta) and endothelin-l (ET-1), could allow insights into their role in fibrotic lung diseases. Methods: The global gene expression profile oflung fibroblasts isolated from IPF, SSc-ILD and control lungs was assessed by using Affymetrix oligonucleotide microarrays. After an exploratory set performed using U95v2 arrays, a second, larger set was performed using the more extensive U133A2 arrays. Response to TGFbeta was evaluated in three fibroblasts lines from each group (IPF, SSc-ILD and controls) ofthe first set. Response to ET-l was evaluated in control fibroblasts alone. To evaluate the role played by ET-1 signalling, gene profiles offibroblasts treated/untreated with dual endothelin receptor antagonist Bosentan were also evaluated. Results: Significant differences in the gene expression patterns between fibrotic and control fibroblasts were observed, particularly in the second set. The pattern ofgene expression did not differ between IPF and SSc-ILD fibroblasts, although changes compared to controls tended to be more extreme in the IPF group. The response to TGFbeta did not differ between fibrotic fibroblasts and controls. A striking similarity to the ET-l induced gene profile was observed in the profile ofIPF and SSc-ILD fibroblasts. The gene expression patterns ofboth SSc-ILD and IPF fibroblasts became more similar to that ofcontrol fibroblasts after treatment with Bosentan. Conclusions: The gene expression profile ofIPF and SSc-ILD lung fibroblasts differs from that of controls. ET-l signalling appears to playa significant role in the observed changes. Lung fibroblasts appear to participate in both fibrotic conditions through similar pathways ofresponse. Differences between the two conditions are probably due to events leading to fibroblast recruitment and activation, rather than to differences in their response pattern.

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48

Dunlevy, Fiona Kathleen Carol. "Protease-antiprotease imbalance in cystic fibrosis." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491992.

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Affects over 8000 patients In the UK. Persistent neutrophilic inflammation is associated with high levels of airway NE. DX-890 is a smallprotein inhibitor ofNE developed by Dyax, USA for use in CF. This project investigated the ex-vivo effects ofDX-890 on human sputum, neutrophils and epithelial cells, to help determine the potential ofDX-890 as a drug for CF. The Ki ofDX-890 was measured to be 11.12 pM. ICso values measured in pure NE and CF sol were similar, demonstrating that DX-890 retained activity in CF sol. Thickened dehydrated CF mucus may prevent access ofDX-890 to NE and reduce efficacy ill vivo. It was hypothesised that, by reducing stickiness of sputum with DNase or surfactant, DX-890 activity would be enhanced. DX-890 inhibited significantly more NE when sputum was pre-treated with surfactant ill vitro. DX-890 reduced release of active NE from fMLP-activated neutrophils and it was found that DX-890 also inhibits NE inside the neutrophil. DX-890 significantly reduced transmigration of neutrophils across a monolayer ofepithelial cells in response to fMLP, implicating NE activity in the process of transmigration. Nasal epithelial cells from CF and non-CF participants were grown in a monolayer and release of the proinflammatory mediator IL-8 was measured. DX-890 prevented NE induced IL-8 release and also IL-8 release induced by CF sol. In conclusion, inhibition ofNE with DX-890 may reduce airway inflammation by minimising production of IL-8 from epithelial cells, and release of active NE from neutrophils. DX-890 efficacy in whole sputum may be enhanced by co-treatment with surfactant. Used in conjunction with current CF therapies such as antibiotics and physiotherapy, DX-890 may help prevent lung damage and prolong life by reducing airway

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49

Govan, John R. W. "Pseudomonas, alginate biosynthesis and cystic fibrosis." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/28137.

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50

Winbanks, Catherine, and winbanks@unimelb edu au. "Novel Aspects of Renal Tubulointerstitial Fibrosis." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080617.143850.

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Tubulointerstitial fibrosis is the key histological predictor of the progression of declining renal function and the final common pathway of progressive kidney disease, regardless of aetiology. Despite its significance, there are currently no treatments available to abrogate this process and those that suffer with this burden eventually succumb to renal failure. Tubulointerstitial fibrosis is largely mediated by fibroblasts and myofibroblasts present in the interstitium. In response to injury, activated fibroblasts differentiate into myofibroblasts which serves as a histological hallmark of fibrosis. Myofibroblasts are characterised as the key contributors to interstitial volume and their presence ultimately leads to loss of renal function. The pathological entities leading to fibrosis inextricably depend on complex signalling pathways. Whilst many of the well-known growth factors that exert effects on renal fibroblasts (such as FGF, EGF and PDGF) involve the activation of receptor tyrosine kinases, the intracellular signalling events dictating the response of fibroblasts remain undefined. The kinase mTOR, responsible for integrating stress and amino acids and controlling cell growth, is increasingly recognised for its ability to integrate growth factor signals mediated through the upstream serine/threonine kinase PI3K. A number of recent studies have highlighted the role of PI3K and mTOR in the regulation of key events relevant to fibrosis, serving as a basis for Chapter 3: The role of PI3K and mTOR in the regulation of fibroblast proliferation and collagen synthesis, and the first part of Chapter 5: The role of PI3K and mTOR in the regulation of myofibroblast differentiation. These studies have identified a key role for PI3K and mTOR in the regulation of fibroblast proliferation, differentiation and collagen synthesis. The work described within has also attempted to examine the derivation of myofibroblasts via EMT. EMT is a process that is integral to embryogenesis and may act as an important source of myofibroblasts during fibrosis. This process is examined in Chapter 4: Development and validation of an ex vivo model of EMT. This model aims to better represent the in vivo environment and has also been used to identify novel regulators involved in EMT being utilised in the second part of Chapter 5: The role of PI3K and mTOR in EMT. Although cytokines and growth factors are thought to be chiefly responsible for tubulointerstitial fibrosis, we now know that serine proteases of the coagulation cascade may also play roles in renal disease. However, unlike their role in glomerular diseases, the role of coagulation in tubulointerstitial fibrosis is less well-known. The work described in Chapter 6: Constituents of the coagulation cascade are spatially and functionally related to experimental tubulointerstitial fibrosis has examined temporal and spatial in vivo relationships of coagulation factors and markers of fibrosis that aid our understanding of mechanisms of fibrosis. The aim of this thesis was to examine those facets of renal fibroblast function that are most devastating to renal function and culminate in an expansion of the renal interstitium during fibrosis. This work hopes to provide useful information to aid the understanding of the multifaceted mechanisms involved in renal tubulointerstitial fibrosis.

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