Dissertationen zum Thema „Respiratory parameters of lung“

Background: la spondilite anchilosante (SA) è una patologia infiammatoria sistemica cronica ad evoluzione progressiva ed anchilosante che colpisce principalmente le articolazioni sacro-iliache e lo scheletro assiale. Sono frequenti manifestazioni extra-articolari a livello polmonare, con quadri respiratori restrittivi e ridotta capacità funzionale. Il trattamento convenzionale prevede esercizi di mantenimento del ROM e allungamento muscolare. Ad oggi non sono presenti studi a sufficienza sul miglioramento della funzione polmonare e della capacità di esercizio in questi pazienti. Obiettivo: verificare l’efficacia della fisioterapia respiratoria rispetto all’usual care in termini di funzionalità polmonare e capacità funzionale nei pazienti con SA. Metodi: la ricerca è stata condotta tra marzo 2020 e ottobre 2020 attraverso le seguenti banche dati biomediche: PubMed, The Cochrane Library, PEDro. Sono stati applicati i seguenti criteri di inclusione, senza limiti temporali: RCT in lingua italiana o inglese e con punteggio ≥ 5 secondo la PEDro Scale, che trattano l’efficacia della fisioterapia respiratoria nella SA rispetto al trattamento convenzionale, in termini di outcome funzionali e respiratori. Risultati: Sono stati inclusi sei RCT. Le misure di outcome erano: mobilità spinale, capacità aerobica, capacità funzionale, capacità di esercizio, funzionalità polmonare, forza dei muscoli respiratori e attività della malattia. Conclusioni: sia la fisioterapia respiratoria che l’usual care risultano efficaci nella mobilità spinale, capacità funzionale e attività di malattia. La fisioterapia respiratoria determina benefici ulteriori soprattutto nella capacità aerobica e di esercizio, ed in misura minore in termini di espansione toracica, funzionalità polmonare e forza dei muscoli respiratori. Un programma di fisioterapia respiratoria associato al trattamento convenzionale ha effetti positivi nella riabilitazione della SA. Sono necessari ulteriori studi a riguardo.

Stroke is a major public health problem and stroke patients suffer much mortality and morbidity due to chest infections, especially in the acute period. Chest infections are associated with respiratory muscle weakness and poor cough. We studied ischaemic hemispheric stroke patients within two weeks of their first-ever stroke to investigate their respiratory physiology, volitional and non-volitional respiratory muscle strength and voluntary and reflex cough function. -- Patients were weak on voluntary but not involuntary tests of expiratory muscle function. They were also impaired on tests of both voluntary and reflex cough. The data we collected suggests that impairment may be due in part to ineffective coordination of the complex cough manoeuvre, following cerebral ischaemia. -- To further investigate the underlying reasons for impaired cough flow we studied functional residual capacity (FRC) in a group of stroke patients with mild impairments. In the semi-recumbent position patients’ FRC was significantly lowered, compared with healthy controls even in these acute patients little residual disability. The low FRC was strongly associated with low cough inspired volume and low cough inspired volume was associated with poor cough flow. -- Transcranial magnetic stimulation was used to investigate the corticomotor projection to the abdominal muscles. We also designed a cough training protocol to be tried initially in the lab, to see if there is an effect of cough training on corticomotor excitability. This was a feasibility study in two patients; we make recommendations to increase the training duration to ten minutes and suggest how TMS could be used to assess the effect of training on corticomotor excitability. If an effect is shown in the lab across a number of patients, the training regimen could then be tried over longer periods in a clinical trial.

Lung cancer is the most commonly diagnosed cancer and the most common cause of cancer related death worldwide. Population-based lung cancer screening programmes have been initiated in the USA and could soon be implemented in other countries. The overarching purpose of this thesis was to explore the emotional impact of lung cancer screening. The research was conducted as part of a clinical trial that was investigating the effectiveness of a blood autoantibody test, EarlyCDT®-Lung, in identifying individuals at the risk of lung cancer. A systematic review was conducted that aimed to identify factors associated with the emotional impact of screening for lung cancer. Participants with indeterminate test results, current smokers and females were more likely to experience negative non-specific and specific emotional outcomes. In addition to highlighting several key factors associated with higher levels of emotional distress following screening, factors that warranted further research were also identified. Such factors included age, education level, marital status, ethnic origin, and perceived risk of developing lung cancer. Finally, important methodological and theoretical limitations in the literature were identified. One key methodological limitation was that no studies measured positive emotional outcomes. A longitudinal study was conducted exploring the impact of lung cancer screening on positive affect, negative affect, lung cancer worry and distress specific to screening for lung cancer. Participants from each of the EarlyCDT®-positive, EarlyCDT®-negative, and control groups completed questionnaires containing emotional outcome measures at pre-randomisation and then at one, three, six and 12 months post randomisation. Scores for each outcome measure were described by groups over time and multilevel regression modelling was used to compare scores over time within and between groups. Results were reassuring as screening was found to have no clinically important impact on positive affect, negative affect, frequency of lung cancer worry or impact of lung cancer worry on mood and ability to perform daily activities. Although screening specific distress in the EarlyCDT®-positive group was significantly higher than that of the EarlyCDT®-negative group, it did reduce over time. Statistically significant and clinically important increases in the proportion of participants reporting anxiety about the results of future tests/treatments were identified. As a result of this finding, a further study was carried out to identify factors that could influence an individual’s level of anxiety about the results of future tests/treatment. Participants more at risk of reporting anxiety about the results of future tests/treatment were younger participants, non-white participants, current smokers and participants who did not own or have a mortgage on their home. Psychological variables associated with increased anxiety were: higher general anxiety scores, higher depression scores, higher negative affect scores, participants who reported that they were upset when they thought about their risk of lung cancer, participants who were worried about getting lung cancer, and those who reported the highest impact of lung cancer worry on mood and ability to perform daily activities. The final chapter of this thesis presents the results of a randomised controlled trial embedded within the emotional outcomes study (described above), which evaluated the effect of timing of monetary incentives (£5 voucher sent with questionnaire vs. £5 voucher sent on receipt of questionnaire) on the following outcomes: study participation rates, questionnaire response rates over time, the number of reminders sent and the completeness of returned questionnaires over time. Previous research had found that monetary incentives were useful in increasing response rates in clinical trials. Results from this trial extended the evidence base by showing that the timing of monetary incentives makes no difference to the above outcomes. In each chapter the findings of this thesis are discussed in terms of their contribution to knowledge. Recommendations for future research and clinical practice are also made within each chapter.

The aim of this thesis was to examine the effects of exercise on gas mixing in the lung during exercise. There were four major stages. Firstly, the existing equipment used with resting subjects was applied to the exercising subject and was found to be inappropriate. Secondly, an in-line system of measuring flow and gas concentration was devised. Thirdly this system was validated with the aid of a physical model and resting subjects. Finally, nitrogen wash-out data were collected from 24 subjects at rest and during progressive exercise at three standard exercise intensities. The dynamic response characteristics of the bag-in-box spirometer at high breathing frequencies (50 min-1) were such that tidal volume was underestimated by almost 50%. The box was too small and its response too a linear for adequate correction factors to be applied. The in-line system, based on a linear relationship between flow and several argon, oxygen, carbon dioxide and nitrogen mixtures ( r = + 0.99, p < 0.01 , Y = 0.2687 FAr + 0.995 ), measured tidal volumes reliably ( CV < 1% ) when expired flow was maintained at 35° C. Thirty-six wash-outs of a 2.4 litre bell jar produced a mean value of 2.461 litres ( SD. 0.034, CV. 1.4% ). The capacity of the in-line system to measure gas mixing efficiency reliably was tested on resting subjects ( six trials each on two days ). Mean values were 76.7% ( SD. 7-5% ) and 76.8% ( SD 4.7% ); mean CV for all trials was 8%. Progressive exercise resulted in significant reduction in lung volume as measured by recovered nitrogen; there was evidence that at the greatest exercise intensity all the nitrogen was not recovered. Decreased diffusion time as a result of greater respiratory frequency may have been responsible. The significantly greater tidal volumes and respiratory frequencies observed on exercise resulted in bigger minute volumes. Both series and alveolar deadspaces increased, but the greater minute volume more than compensated for the growing dead spaces, and so the inspired volume available for mixing was increased. Ventilatory and gas mixing efficiency improved significantly as exercise progressed, but the greatest improvement occurred at the first power output of 50W; thereafter, there was very little change in gas mixing efficiency in spite of three-fold increase in ventilation. It is possible that gas mixing efficiency functions optimally at FRC and that, unlike some other physiological measures, there is little reserve capacity. However, the possibility of gas mixing deficiencies at maximal exercise leading to a ventilatory limit to maximal oxygen uptake remains, and this issue still needs to be investigated.

Of the 800,000 suicides recorded globally every year, over a third are due to pesticide ingestion, the majority of which occur in rural Asia with organophosphorus (OP) compounds. These anticholinesterase pesticides cause an acute cholinergic syndrome characterised by decreased consciousness, excessive airway secretions and respiratory failure. A combination of these clinical features is the most common cause of death. Up to 30% of OP pesticide poisoned patients are admitted to the Intensive Care Unit (ICU) for tracheal intubation and lung ventilation, but up to half die. It is not understood why the case fatality for intubated poisoned patients is so high, but one hypothesis is that the patients, when unconscious, aspirate their stomach contents (including the OP and the solvent present in its agricultural formulation) causing a toxic lung injury which contributes to the observed high mortality. In this PhD, I aimed to characterise the lung injury caused by OP pesticide self-poisoning through both indirect (ingestion) and direct (aspiration) means. To achieve this, I analysed data from previous toxicological minipig work and designed and conducted a specific minipig pulmonary aspiration study which was complemented by an experimental OP poisoning ex vivo lung perfusion model and human data from pesticide poisoned patients in Sri Lanka. I first investigated the pulmonary pathophysiology resulting from orogastric administration of OP pesticide without aspiration. Analysis of my group’s Gottingen minipig in vivo work demonstrated that orogastric placement of agricultural OP (dimethoate EC40) produced lung injury via exposure to blood-borne pesticide. Pathological lung changes consisted of alveolar and interstitial oedema, pulmonary haemorrhage and modest neutrophilia with increased concentrations of protein, IL-6 and IL-8 when compared with controls, but with low concentrations of TNF-α and IL-10 in bronchoalveolar lavage fluid (BALF). In a second study, OP poisoned minipigs had increased concentrations of BALF protein, neutrophils, IL-8 and CRP six hours after orogastric poisoning when compared with their baseline values. Electron microscopy images of both studies demonstrated damage to the alveolar capillary membrane secondary to systemic OP poisoning. Prior to conducting the main pulmonary aspiration study in minipigs, there was considerable refinement of the processes involved through use of: (i) pilot aspiration and dose ranging studies; (ii) the development of a specific pulmonary histopathological scoring system; and (iii) employment of modern human anaesthetic equipment and intensive care patient management protocols. After this period of model development, an in vivo 48 hour study using Gottingen minipigs (n=26) was conducted to investigate the pulmonary pathophysiology in animals given either sham bronchoscopy (sham control) or 0.5 mL/kg of: saline (saline control), porcine gastric juice [GJ], OP (dimethoate EC40) + GJ [OP+GJ], or solvent (cyclohexanone) + GJ [Solv+GJ] into the right lung under bronchoscopic guidance. The results showed that in a minipig model OP and GJ placed into one lung created a direct (right) and indirect (left) lung injury significantly different to controls, and in some respects worse than GJ alone 48 hours after poisoning. The direct lung injury caused by OP+GJ was characterised by significantly worse pathology (p=0.0003) in terms of: pulmonary neutrophilia, alveolar haemorrhage, necrosis, oedema and fibrin deposition, when compared with sham controls at 48 hours. Lungs injured directly with OP+GJ also had significantly higher concentrations of BALF neutrophils (p≤0.01), protein (p≤0.05), IL-6 (p≤0.01), IL-8 (p≤0.01) and CRP (p≤0.05) at 24 hours, and BALF protein (p≤ 0.01), and CRP (p≤ 0.05) when compared with sham controls at 48 hours. The BALF from OP+GJ minipigs at 48 hours also had higher numbers of aerobic bacteria than other groups, suggesting the development of pneumonia could be a source of additional lung injury. Lung damage might also have resulted from a reduction in the surfactant component responsible for the lowering of alveolar surface tension. Direct lung injury with OP+GJ caused a proportional reduction of beneficial pulmonary surfactant phosphatidylcholine (PC) species 16:0/16:0 [29(±4) % vs. 38(±4) %] when compared with sham controls at 48 hours. Unlike the other groups, OP+GJ (direct and indirectly-injured) lungs had type 2 alveolar cell ultrastructural morphological differences in the lamellar bodies that stored the surfactant. The lamellar bodies were more numerous and more dense in the OP+GJ lungs compared with other groups and could signify a failure of surfactant release or some other pathology pertinent to OP aspiration lung injury. Computed tomography analysis showed that direct lung injury with OP+GJ caused significantly more lung tissue to be poorly or non-aerated [77 (±13) % ; p≤0.0001 when compared with sham] as opposed to 62 (±27) % in GJ, 53(±13)% in sham and 47(±0.2)% in saline control animals by 47.5 hours and was mainly due to pulmonary haemorrhage and oedema fluid. The key differences between aspiration of OP+GJ versus GJ alone was that the majority of inflammatory markers (e.g. BALF protein, IL-6 and CRP) appeared to increase from 24-48 hours in OP+GJ treated animals, but decreased in GJ pigs, possibly signifying resolution. Treatment with GJ alone produced less severe histopathological damage, bacterial BALF numbers and percentage of poorly and non-aerated lung tissue. Importantly, there was less evidence of indirect lung injury within the GJ pigs when compared with animals treated with OP+GJ. Solvent placed into the lung seemed to offer some form of protection from the effects of GJ aspiration. This was dramatically demonstrated by the histopathology scores, proportional percentage of beneficial phosphatidylcholine (PC) species 16:0/16:0 and the percentage of poorly and non-aerated lung tissue all approaching control animal levels by 48 hours in minipigs that had Solv+GJ placed in the directly-injured (right) lung. Further evidence of benefit was provided by statistically significant reductions (p≤ 0.05) in BALF concentrations of IL-8, IL-6 and CRP in minipigs which had aspirated Solv+GJ when compared with OP+GJ and/or GJ minipig groups at 24 hours. The pathophysiology of aspirated OP+GJ was also investigated in a pilot ovine ex vivo lung perfusion (EVLP) model (n=4). Lungs directly-injured with OP+GJ had higher concentrations of total protein (4300 mg/L vs. 350 mg/L) with a proportional reduction of beneficial pulmonary surfactant phosphatidylcholine species 16:0/16:0 (27% vs.34%) when compared with control lungs. Analysis of toll-like receptor (TLR) lung tissue expression in the OP+GJ directly and indirectly-injured lungs indicated that inflammatory mechanisms might also involve upregulation of TLR 3 and 5, unlike other lung injuries e.g. those induced with lipopolysaccharide, which typically upregulates TLR 2 and 4. To compare OP-induced lung injury in humans and the minipigs, a small feasibility study was conducted in the ICUs of the University of Peradeniya hospital, Sri Lanka. Unfortunately, ethics review and recruitment proved more difficult than expected and we failed to recruit to target. We did however find raised BALF concentrations of IL-6, IL-8 and CRP and low concentrations of TNF, IL-1β, IL-10 in intubated OP poisoned patients at 24 hours when compared with controls. We also found that two plasma micro-RNA biomarkers thought to be involved in inflammation and lung injury, MiR-21 and MiR-146a, had significantly reduced expression in OP-poisoned patients with aspiration compared to non-intubated control patients from the UK (p=0.008 and p=0.0083 respectively). The work from this thesis has allowed the characterisation of both indirect and direct lung injuries caused by OP pesticide ingestion and aspiration. The minipig model showed that at 48 hours the lung injury created by aspiration of OP+GJ appeared more severe than GJ alone, but the addition of the solvent cyclohexanone seemed protective and even beneficial in the context of GJ aspiration. The cytokine expression profiles from both the human and minipig work, combined with the preliminary TLR lung tissue analysis from the EVLP model, suggest that OP+GJ aspiration is unlike normal GJ aspiration and classic ARDS.
Increased concentrations of aerobic bacteria in the minipig OP+GJ lungs at 48 hours and evidence of suppression of plasma miR-21 and miR-146a in OP poisoned patients could be linked, and may involve cholinergic immune system modulation. These molecular mechanisms need to be investigated further in both in vitro and in vivo models. These discoveries indicate the complex nature of the pulmonary injury that occurs after OP pesticide poisoning, and suggests that damage is not caused by gastric contents alone. Preliminary findings indicate that aspiration of OP+GJ could create favourable conditions for the development of aspiration or ventilator-associated pneumonia but this would need confirmation in larger clinical studies. The potential roles of micro RNA as a biomarker of OP poisoning and lung injury, and solvent as a therapy for aspiration should be explored in further pre-clinical studies.

Airway pressure release ventilation (APRV) is a promising, unconventional mode of ventilation for the treatment of various respiratory diseases, including acute respiratory distress syndrome (ARDS). However, despite increasing global use and reported advantages of APRV over other modes, definitive conclusions cannot be drawn due to several concerns. First, the major confusion between APRV and other, similar modes, such as bi-phasic positive airway pressure (BIPAP). Second, clinical and methodological heterogeneity among published studies of APRV are understandably extensive, which contributes to outcome variability. Third, the absence of consensus on a standard protocol with clear rationale for the settings. This thesis provides an overview of the spectrum of ventilator settings that may be designated as APRV, summarises the research and clinical use status of APRV, exemplifies the need to clarify the characteristics that comprise the mode, and to assure reports of APRV use, from case reports through RCTs, including adequate data for a proper assessment. It encourages continued publication of observational as well as experimental clinical trial data, and discusses the feasibility of analysis strategies that may expand the information available from small patient samples. It also presents an unpublished, comprehensive, multifaceted clinical practice protocol (Al-ahmad protocol) for the use of APRV. Using the Al-ahmad protocol, four studies were conducted on non-spontaneously breathing patients who had ARDS (arising from a variety of pathologies). One study used a validated physiological simulator called integrated cardiopulmonary models (ICPMs) while the other three, were prospective cohort observational studies on real patients. The first study evaluated patients’ responses to changes in inspiratory pressure during conventional ventilation (CV) and APRV modes, using ICPMs vs. a real patient. The second study compared partial pressure of carbon dioxide (PaCO2) at any given ventilatory minute ventilation (MV) during CV and APRV. The third study aimed to identify proper configurations to optimise PaCO2 on patients with diverse pulmonary pathologies including restrictive (e.g. ARDS) and obstructive (e.g. chronic obstructive pulmonary disease) when using APRV. The fourth study compared oxygenation and haemodynamic status during CV and APRV. Results from ICPMs appeared to be analogous for both modes except for the significant difference in MV and tidal volume observed in the simulated vs. real APRV patients. We found in our clinical studies that compared to conventional modes, APRV was associated with significantly lower PaCO2 at significantly lower levels of MV, better oxygenation, and haemodynamic status.

Background: Accurate and appropriate spirometry reference values allow for early detection of respiratory illness and perform an important role in monitoring lung health. There is, in general, a scarcity of data from Africa, and the Global Lung Initiative (GLI) has published global reference equations but models did not include data from African studies. The aim of this study was to investigate lung function in a group of healthy South African females and the applicability of the GLI reference equations. Methodology: Maternal lung function testing was undertaken at 6 to 10 weeks post-partum as part of a birth cohort study, the Drakenstein Child Health Study. Pre- and post-bronchodilator spirometry was performed according to a standardised protocol and correlated with clinical information. Bronchodilator response was assessed by repeating spirometry 15 minutes after administration of inhaled 400mcg salbutamol. Results: A total of 462 women were included, mean age 17 years (range 18- 42 years). The GLI reference equations fitted the observed lung function results well for the group of mothers who did not self-report smoking or asthma. There were 64 (14%) mothers with an abnormal Forced Expiratory Volume in 1 Second (FEV 1) result, 60 (13%) mothers with an abnormal Forced Vital Capacity (FVC), and 35 (8%) mothers with an abnormal FEV 1 /FVC ratio. There were 22 (5%) mothers who had reversible FEV 1; the rate of undiagnosed reversibility was 4% of the cohort. High body mass index was associated with a higher risk for poor FVC and FEV 1 /FVC lung function, OR 1.40 (CI: 1.01, 1.65) and OR 1.25 (CI 1.10, 1.95) respectively. Mothers with a higher socio-economic status had better FEV 1 with the adjusted SES OR 0.65 (CI 0.36, 1.08). Conclusions: There was a high prevalence of abnormal lung function in this cohort of South African adult females and a number of cases of undiagnosed reversibility. Spirometry testing is important to diagnose lung disease in South African communities. The GLI's reference equations were appropriate and applicable for a cohort of South African adult women.

Systemic inflammation is associated with impaired lung function. Inflammation is part of asthma and chronic obstructive pulmonary disease (COPD), but the local and systemic inflammatory pattern differs. The overall aim was to evaluate systemic inflammatory markers in obstructive lung diseases and more specifically: To determine if CRP is related to respiratory symptoms, asthma, atopy and bronchial responsiveness (paper I), in a population sample from three countries (paper I and II); to evaluate if CRP is related to COPD, lung function and rate of lung function decline (paper II); to investigate the association of serum MMP-9 and TIMP-1 with lung function in a cross-sectional population based study (paper III); and finally, to study possible gender differences in the longitudinal association between CRP and lung function in a prospective population based study (paper IV). In the first study we reported that CRP was related to non-allergic asthma but not allergic asthma, and that CRP was related to respiratory symptoms such as wheeze, nocturnal cough and breathlessness after effort, but not associated with atopy or bronchial responsiveness. In the second study we found that COPD was more common in subjects in the highest CRP quartiles and higher CRP levels were associated with lower FEV1 values in both men and women, but the negative association between CRP and FEV1 was larger in men than women. The FEV1 decline was larger in men with high CRP levels, whereas no such association was found for women. In the third study we reported that lower FEV1 was associated with higher levels of MMP-9, TIMP-1 and their ratio MMP-9/TIMP-1. After stratification for gender this association was significant in men but not women. In the fourth study we found that CRP levels were associated with change in both FEV1 and FVC in men but not women. This association was found for both baseline CRP and change in CRP, confirming a stronger association between systemic inflammation and lung function decline in men than women. In conclusion, systemic inflammation is associated with non-allergic asthma but not allergic asthma. Our findings of a stronger association between the systemic inflammation and lung function impairment in men, but not women, may indicate a gender difference in the mechanisms of lung function decline.

Respiratory motion is a major factor contributing to errors and uncertainties in Radiotherapy (RT) treatment of lung tumours. Knowledge of this motion may improve the planning and delivery of RT treatment for lung cancer patients. This thesis develops and evaluates methods of building patient specific respiratory motion models. These relate the internal motion to respiratory parameters derived from an external surrogate signal that can be measured during data acquisition and treatment delivery. The models offer a number of advantages over current methods of imaging and analysing respiratory motion, in particular their ability to account for variations in the respiratory motion. Computer Tomography (CT) data is acquired over several respiratory cycles to sample some of the variation in the respiratory motion. B-spline registrations are used to recover the motion and deformation from the CT data. The models are then constructed by fitting functions that relate the registration results to the respiratory parameters. This thesis describes the CT data and respiratory parameters that have been used to construct the motion models. It details the registrations protocols used and evaluates their results. The initial models presented in the thesis relate the registration results to a single parameter, the phase of the respiratory cycle, and average out any variation in the respiratory motion. The later models relate the registration results to two respiratory parameters, with the intention of modelling some of the variation. A number of different functions are assessed for both the single and two parameter models. The results show that the models can predict the respiratory motion in the CT data very accurately (mean error < 1.4 mm). This thesis also discusses some of the uses of the motion models in RT and, in particular, explores the use of the motion models for 'tracking' respiratory motion while delivering intensity modulated RT.

Respiratory muscle dysfunction is a clinical condition that may be present in both respiratory and non-respiratory diseases. This impairment of muscle function can have a negative effect on clinical outcomes, contributing to a further worsening of the patient’s clinical condition. This doctoral thesis has been directed by the ‘Rehabilitation Research Group’ (RERG) in collaboration with the Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer Group (Lung Cancer and Muscle Research Group) of the Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) in Barcelona. Muscle dysfunction has been a priority area of research in these groups from different perspectives: exercise and muscle training in the RERG, Physiopathology and Molecular Biology in the Lung Cancer and Muscle Research Group. The large number of published studies in journals with high impact factor endorses the quality and leadership of these research groups. Up to then, research on RMT had focused on patients with chronic obstructive pulmonary disease, but had been scarcely addressed in other conditions. In the last 5 years, the RERG has aimed to study the effects of RMT in other respiratory diseases (bronchiectasis, lung cancer) and in non-respiratory diseases. The study of respiratory muscle dysfunction in stroke patients has made it possible to start an increasing collaboration with neurorehabilitation researchers, in which RMT plays a role in the management of patients with dysphagia.
La disfunción muscular respiratoria es una condición clínica que puede estar presente tanto en las enfermedades respiratorias como no respiratorias. Este deterioro de la función muscular puede tener un efecto negativo en los resultados clínicos, lo que contribuye a un mayor empeoramiento de la condición clínica del paciente. Esta tesis doctoral ha sido dirigida por el "Grupo de Investigación en Rehabilitación" (RERG) en colaboración con el Grupo de Investigación de Enfermedades Respiratorias Crónicas y Cáncer de Pulmón (Grupo de Investigación de Cáncer de Pulmón y Músculo) del Instituto Hospital del Mar de Investigaciones Mèdiques (IMIM) en Barcelona. La disfunción muscular ha sido un área prioritaria de investigación en estos grupos desde diferentes perspectivas: ejercicio y entrenamiento muscular en el RERG, Fisiopatología y Biología Molecular en el Cáncer de Pulmón y el Grupo de Investigación Muscular. El gran número de estudios publicados en revistas con alto factor de impacto refuerza la calidad y liderazgo de estos grupos de investigación. Hasta entonces, la investigación sobre RMT se había centrado en los pacientes con enfermedad pulmonar obstructiva crónica, pero apenas se había abordado en otras condiciones. En los últimos 5 años, el RERG se ha propuesto estudiar los efectos de la RMT en otras enfermedades respiratorias (bronquiectasias, cáncer de pulmón) y en enfermedades no respiratorias. El estudio de la disfunción de los músculos respiratorios en los pacientes con ictus ha permitido iniciar una creciente colaboración con los investigadores de neurorehabilitación, en los que RMT desempeña un papel en el tratamiento de los pacientes con disfagia.

Background Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive airway diseases with a substantial burden in terms of morbidity, mortality and costs. Smoking is the single most important risk factor for COPD, and is associated with incident asthma. It is important to know if the prevalence of asthma and COPD is increasing or decreasing in the population in order to effectively allocate health care resources. The definitions of these diseases have varied over time which makes it difficult to measure changes in prevalence. The preferred method is to estimate the prevalence with the same procedures and definitions based on cross-sectional population samples with identical age distributions in the same geographical area at different time points. Measurements of lung function (spirometry) are required to diagnose COPD, and spirometry is used to evaluate disease severity and progress of both asthma and COPD, where observed values are compared to reference values. The most commonly used reference values in Sweden are published during the mid 1980s, and there are few evaluations of how appropriate they are today based on Swedish population samples. The aim of the thesis was to estimate trends in the prevalence of asthma and COPD in relation to smoking habits, and to evaluate and estimate reference values for spirometry. Methods The project was based on population-based samples of adults from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Postal questionnaires were sent to large cohorts, recruited in 1992 (n=4851, 20-69 years), 1996 (n=7420, 20-74 years) and 2006 (n=6165, 20-69 years), respectively. The questionnaire included questions on respiratory symptoms and diseases, their comorbidities and several possible risk factors including smoking habits. Structured interviews and spirometry were performed in random samples of the responders to the 1992 and 2006 surveys, of which n=660 (in 1994) and n=623 (in 2009) were within identical age-spans (23-72 years). The trend in asthma prevalence was estimated by comparing the postal questionnaire surveys in 1996 and 2006, and the trend in COPD prevalence was estimated by comparing the samples participating in dynamic spirometry in 1994 and 2009, respectively. The prevalence of COPD was estimated based on two different definitions of COPD. Commonly used reference values for spirometry were evaluated based on randomly sampled healthy non-smokers defined in clinical examinations of participants in the 2006 postal questionnaire (n=501). The main focus of the evaluation was the global lung function initiative (GLI) reference values published in 2012, for which Z-scores and percent of predicted values were analysed. New sex-specific reference values for spirometry were estimated by linear regression, with age and height as predictors. These new OLIN reference values were also evaluated on a sample of healthy non-smokers identified in the population-based West Sweden Asthma Study. Results Although the prevalence of smoking decreased from 27.4% to 19.1%, p<0.001, between 1996 and 2006, the prevalence of physician-diagnosed asthma increased from 9.4% to 11.6%, p<0.001. The prevalence of symptoms common in asthma such as recurrent wheeze did not change significantly between the surveys or tended to decrease, while bronchitis symptoms such as cough and sputum production decreased significantly. The evaluation of the GLI reference values showed that the predicted values were significantly lower compared to the observed values in Norrbotten, which makes the percent of predicted too high. This was especially true for FVC percent predicted with a mean of 106%. In general, the deviations were more pronounced among women. New OLIN reference values valid for the Norrbotten sample were modelled and showed a high external validity when applied on the sample from western Sweden. The prevalence of moderate to severe COPD decreased substantially over the 15-year period between 1994 and 2009, regardless of definition. Conclusions In parallel with substantially decreased smoking habits in the population between 1996 and 2006, the prevalence of several airway symptoms decreased while the prevalence of physician-diagnosed asthma increased. These results suggest increased diagnostic activity for asthma, but may also suggest that the asthma prevalence has continued to increase. In contrast to asthma, the prevalence of COPD tended to decrease and moderate to severe COPD decreased substantially. The continuous decrease in smoking in Sweden during several decades prior to the study period is most likely contributing to these results. The evaluation of reference values showed that the GLI reference values were lower than the observed spirometric values in the population, especially for women, why the new up-to date reference values may be of importance for disease evaluation in epidemiology and in the health care as well.

Background: Positive expiratory pressure (PEP) and continuous positive airway pressure (CPAP) are two forms of resistance breathing used in spontaneously breathing patients. With a threshold resistor or a flow resistor, both PEP and CPAP provide a positive (elevated) pressure level during the expiratory phase. With PEP, inspiratory pressure is negative, i.e. lower than ambient air pressure, as during a normal inspiration, but with CPAP, the inspiratory pressure is positive, i.e. higher than ambient air pressure. Methods: This thesis is based on four separate studies in which four different breathing devices, a PEP-bottle (threshold resistor device), a PEP-mask (flow resistor device), a threshold resistor CPAP and a flow resistor device were investigated. Paper I, II and III are based on studies in healthy volunteers. Paper IV is a bench study performed in a hypobaric chamber. Paper I examined differences between two PEP devices, the PEP-bottle and the PEP-mask. Paper II evaluated the performance of a flow resistor CPAP device, (Boussignac CPAP). Paper III investigated the effect of two PEP-devices, a PEP-bottle and a PEP-mask and two CPAP devices, a threshold resistor CPAP and a flow resistor CPAP, on inspiratory capacity (IC). In paper IV, the effect of changes in ambient pressure on preset CPAP levels in two different CPAP devices was compared. Results: With the PEP bottle, both expiration and inspiration began with a zero-flow period during which airway pressure changed rapidly. With the PEP-mask, the zero-flow period was very short and the change in airway pressure almost non-existent (paper I). During normal breathing with the Boussignac CPAP, changes in airway pressure were never large enough to reduce airway pressure below zero. During forced breathing, as airflow increased, both the drop in inspiratory airway pressure and the increase in expiratory airway pressure were potentiated (paper II). IC decreased significantly with three of the breathing devices, the PEP-mask and the two CPAP devices (paper III). With the threshold resistor CPAP, measured pressure levels were close to the preset CPAP level. With the flow resistor CPAP, as the altitude increased CPAP produced pressure levels increased (paper IV). Conclusion: The effect on airway pressure, airflow, IC and the effect of changes in ambient air pressure differ between different kinds of resistance breathing devices. These differences in device performance should be taken into consideration when choosing the optimal resistance breathing device for each patient.

Respiratory gating in lung PET imaging to compensate for respiratory motion artifacts is a current research issue with broad potential impact on quantitation, diagnosis and clinical management of lung tumors. However, PET images collected at discrete bins can be significantly affected by noise as there are lower activity counts in each gated bin unless the total PET acquisition time is prolonged, so that gating methods should be combined with imaging-based motion correction and registration methods. The aim of this study was to develop and validate a fast and practical solution to the problem of respiratory motion for the detection and accurate quantitation of lung tumors in PET images. This included: (1) developing a computer-assisted algorithm for PET/CT images that automatically segments lung regions in CT images, identifies and localizes lung tumors of PET images; (2) developing and comparing different registration algorithms which processes all the information within the entire respiratory cycle and integrate all the tumor in different gated bins into a single reference bin. Four registration/integration algorithms: Centroid Based, Intensity Based, Rigid Body and Optical Flow registration were compared as well as two registration schemes: Direct Scheme and Successive Scheme. Validation was demonstrated by conducting experiments with the computerized 4D NCAT phantom and with a dynamic lung-chest phantom imaged using a GE PET/CT System. Iterations were conducted on different size simulated tumors and different noise levels. Static tumors without respiratory motion were used as gold standard; quantitative results were compared with respect to tumor activity concentration, cross-correlation coefficient, relative noise level and computation time. Comparing the results of the tumors before and after correction, the tumor activity values and tumor volumes were closer to the static tumors (gold standard). Higher correlation values and lower noise were also achieved after applying the correction algorithms. With this method the compromise between short PET scan time and reduced image noise can be achieved, while quantification and clinical analysis become fast and precise.

The maintenance of the airway/respiratory epithelium during adult homeostasis and repair and its construction during embryonic development require tightly regulated cell fate decisions. This regulation takes the form of complex transcription factor and signalling cascades, much of which are unknown, particularly in human lung development. Multiciliogenesis describes the process of specification/differentiation of airway epithelial progenitors/stem cells into mature multiciliated cells (MCCs). Here, I have identified 2 novel transcription factors, Fank1 and Jazf1 which form part of the transcription factor cascade regulating multiciliogenesis in adult and embryonic mouse tracheas. Mouse tracheal epithelium is representative of epithelium lining the entire human airway and it is possible that we will also be able to extrapolate these findings to the human airway. It is not until we fully understand the regulation of multiciliogenesis that it will be possible to look at ways of pushing basal cells towards a MCC fate for purposes of cell replacement therapy, for example in patients with mucociliary disease. As well as exploring cell fate decisions in the mouse upper airway epithelium using embryonic tracheal explants and mouse tracheal epithelial cell (MTEC) cultures, I have also explored the regulation of cell fate decisions in distal human lung epithelium at the pseudoglandular stage of development. At this stage SOX9+ distal tip cells are self-renewing and multipotent and give rise to SOX2+ stalk descendents, which differentiate into airway epithelium. The regulation of SOX9+ lung tip cell multipotency and migration of SOX2+ stalk descendents during human lung development is poorly understood. I have compared human tip (SOX9+) versus stalk (SOX2+) transcriptomes using gene ontology (GO), which has highlighted some key signalling pathways enriched in tip cells which could be important in maintaining distal tip cell multipotency. These pathways have been utilised in optimising conditions for propagating self-renewing tip-derived organoids. These organoids have the potential to be differentiated into bronchiolar and alveolar fates and as such are an invaluable research tool for studying human lung epithelial development, whilst minimising the use of human embryos and its associated ethical implications. I have also performed human tip versus mouse tip transcriptome GO analysis which highlights that although there are many similarities, there are also differences between human and mouse lung epithelium development, emphasising the need for research on human tissue.

Background: The United Kingdom (UK) has poor lung cancer survival rates compared to other countries, and this is partly explained by differences in early mortality. In order to diagnose lung cancer at an earlier stage in the UK there is a pressing need to understand the management process from the recognition of symptoms by people with lung cancer, through the initial interactions with primary care to the referral to secondary care and the choice of the subsequent treatment plan. Objectives: The aim of this thesis is to use mixed methods to identify some of the factors which may affect the diagnosis and prognosis in patients with lung cancer in the United Kingdom across the whole patient pathway. Methods: Prospectively collected clinical data were used in conjunction with qualitative methodology. Primary care records were obtained from The Health Improvement Network, alongside data from the National Lung Cancer Audit (NLCA), linked to Hospital Episode Statistics and Office for National Statistics datasets. Case-control and cohort studies were conducted using multivariable logistic regression to look at independent associations with early mortality, likelihood of receiving surgery and place of death. Survival analyses were performed using Kaplan Meier curves and Cox regression and validation studies used area under the receiver operating curves (AUC). The Framework approach was used to identify themes and sub-themes arising from focus group interviews. Results: Mixed methods were used to look at barriers to early diagnosis and attitudes towards lung cancer screening in a high risk population. A number of key practical and emotional barriers which may impact on screening uptake were identified, alongside the issue of smoking stigma and blame. Primary care data were used to look at predictors of early (0-90 day) mortality in the UK. Thirty per cent of patients with lung cancer died within 90 days of diagnosis. Increasing age, male sex, socioeconomic deprivation, rural versus urban location and current smoking were all independently associated with early death. Patients who had poorer prognosis did interact with primary care before diagnosis, suggesting missed opportunities to identify them earlier. NLCA data linked to organisational audit data highlighted inequities between Trusts, in particular with regards to variability in the workload of specialists and differences in access to diagnostic and therapeutic modalities. On site access to positron emission computed tomography, stereotactic ablative radiotherapy and video-assisted thoracoscopic lobectomy were independently associated with increased likelihood of receiving surgery for lung cancer. Records for patient who developed brain metastases following radical surgical treatment for lung cancer were reviewed. Those with more advanced disease stage, younger age and adenocarcinoma sub-type were more likely to develop metastases and modelling suggested that 71% may have been visible pre-operatively had magnetic resonance imaging of the brain been performed as part of the staging process. An internal and external validation was performed to assess the ability of two risk scoring systems to predict 90 day post-operative mortality. AUC values for internal and external validation of the NLCA score and validation of Thoracoscore were 0.68 (95% CI 0.63-0.72), 0.60 (95% CI 0.56-0.65) and 0.60 (95% CI 0.54-0.66) respectively. Post-hoc analysis was performed using NLCA records on 15554 surgical patients to derive summary tables for 30 and 90 day mortality, stratified by procedure type, age and performance status. Linked NLCA data were used to look at place of death from lung cancer. Thirty-five per cent of patients with lung cancer die in acute hospital beds, with male sex, old age (≥ 85 years), socioeconomic deprivation, WHO performance status 4 at diagnosis and emergency route to diagnosis all independently associated with increased likelihood of death in this setting. There is marked geographical variation in place of death, particularly with regard to provision of hospice services. Conclusions: The studies described in this thesis use prospectively collected data to provide a snapshot of different aspects of the lung cancer patient journey which may impact on prognosis, alongside qualitative methodology to try to determine reasons for diagnostic delay and attitudes towards screening programmes. There remain some important clinical questions about lung cancer care and outcomes which need to be looked at to provide a greater understanding of where the inequities in the lung cancer patient pathway in the UK lie and to try to address modifiable factors with an aim to improve outcomes.

The work described within this thesis was conducted at the University of Nottingham between April 2011 and March 2014. Due to the inter-disciplinary nature of this work it was undertaken by the author in conjunction with the other scientists in the Translational Imaging group at the Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham and collaborators in both the Pulmonary Biology group, University of Nottingham and the Respiratory Pharmacology group, Imperial College London. Pulmonary hyperpolarized (hp) noble gas magnetic resonance imaging (MRI) has seen increasing development and utility over the past two decades. However the application of this relatively new pulmonary imaging modality to small animal models is technically challenging. Ex vivo lung models have allowed for the investigation of functional respiratory measurements in small animals but have yet to be utilized with hp noble gas MRI. The ex vivo lung model presented within this work allowed for the study of pulmonary physiology using hp 129Xe and hp 83Kr MR imaging in intact lungs from both healthy rodents and rat models of respiratory disease. Novel hp 129Xe imaging protocols were developed to provide measurements of functional respiratory parameters and to gather information of regional gas distribution in healthy excised rodent lungs. Furthermore the developed 129Xe methodology was used to study regional responses in an ex vivo model of human asthma after intravenous deliveries of increasing quantities of the bronchoconstricting agent methacholine. The ex vivo model provided the platform to develop the novel lung imaging technique of hp 83Kr surface quadrupolar relaxation (SQUARE) MRI with this new methodology used to study an excised rat model of emphysema potentially providing the first application for this quadrupolar noble gas isotope in the field of respiratory medicine.

Inhaled drug delivery is currently the gold standard for treating many respiratory diseases. However, improved treatments are needed for lung diseases like Cystic Fibrosis (CF) and Acute Respiratory Distress Syndrome (ARDS), where mucus or fluid build-up in the lung limits ventilation and, thus, delivery of inhaled drugs. Delivery is most needed in the diseased or damaged regions of the lung, but if an area is not ventilated, inhaled drug will simply not reach it. To overcome this, this research proposes delivering drugs to the lungs within a perfluorocarbon (PFC) liquid. The lungs will be filled with a reverse emulsion containing a disperse phase of aqueous drugs within the bulk PFC and then ventilated. The PFC functions as both a respiratory medium, providing gas exchange, and as a delivery vehicle, providing a more uniform deposition of drugs. After treatment, the highly volatile PFCs are exhaled, returning the patient to normal respiration. This technique improves upon current therapies as follows. First, drugs are delivered directly to where they are needed, yielding higher concentrations in the lung and lower systemic concentrations. Second, PFCs are ideal for washing out lung exudate and mucus. The low surface tension and high density of PFC allows it to easily penetrate plugged or collapsed alveoli, detach infected mucus from the airway walls, and force these fluids to the top of the lungs where they can then be removed via suction. Mucus and exudate removal should allow drugs to penetrate previously plugged airways during emulsion delivery and subsequent treatment with inhaled therapies. Thus, drug delivery via emulsion would be used as a pre-treatment to enhance inhaled or systemic drug therapy. Third, PFC’s anti-inflammatory properties help return to normal lung function. This research examines two applications of this technology: delivery of antibiotics to combat respiratory infections (antibacterial perfluorocarbon ventilation, APV) or delivery of growth factors to enhance alveolar repair (perfluorocarbon emulsions for alveolar repair, PEAR). This work represents an in-depth analysis of the emulsions used during APV and PEAR. Initial efforts evaluated emulsion efficacy under in vitro setting that better simulated lung in vivo antibiotic delivery. The subsequent studies utilized an in vivo rat model of bacterial respiratory infection to validate the effects of emulsion on pharmacokinetics and to assess APVs potential treatment benefits. Lastly, in vitro methods of cellular response assessed the utility of delivering growth factors in PEAR. Significant advancements were made in optimizing the emulsion as a viable means of pulmonary drug delivery. Final efforts resulted in a promising emulsion formulation that overcame the quick transport of tobramycin away from the lung and successfully reduced pulmonary bacterial load in vivo. In vitro applications of PEAR showed the emulsions posed a significant barrier to the availability and, thus, the biological effect of lysophosphatidic acid growth factors. Further in vivo work is required to improve APV’s efficacy over conventional treatments and to determine PEAR’s feasibility and efficacy in promoting lung repair.

Asthma is the most common chronic disease in children and the effects of air pollution exposure on asthma and respiratory health in children have been a growing concern over recent decades. Although a number of epidemiological studies have been carried out in this field, these have produced conflicting results. The aim of this study was to assess the effects of long term exposure to nitrogen dioxide (NO2) and particulate matter (PM10) on asthma prevalence and lung function in children. To achieve this, a novel exposure model was developed and evaluated, which allowed retrospective exposure assessment of children participating in a population based birth cohort study – the Manchester Asthma and Allergy Study (MAAS). MAAS is a prospective birth cohort study comprising 1185 children specifically designed to study asthma and allergies. Clinical follow up took place at ages 3, 5, 8 and 11 years. At each follow up parents completed questionnaires on asthma diagnosis and symptoms and children underwent skin prick tests for common allergens. Children’s specific airways resistance (sRaw, at ages 3, 5, 8, 11) and forced expiratory volume in one second (FEV1, at ages 5, 8, 11) were measured. At ages 5 and 11 years FEV1 was measured at baseline and after bronchodilator treatment. The exposure model developed during this study incorporated outdoor and indoor air pollution, spatio-temporal variation in air pollution and time-activity patterns of children. The model was based on the concept of microenvironmental exposure. It modelled personal exposure based on PM10 and NO2 concentrations in children’s home, school and journey microenvironments (MEs) and the length of time they spend in these MEs. Land use regression (LUR) models were used to model PM10 and NO2 concentrations in outdoor MEs. These LUR models were specifically developed for the Greater Manchester area. A novel method was used to develop the LUR models, which used the output from an air dispersion model as dependent variables in the regression analysis. Furthermore, a novel approach was used to obtain annual concentration of PM10 and NO2 from 1996 to 2010, which involved the recalibration of the LUR models for each year. A mass balance model and indoor to outdoor ratios were used to model concentrations in indoor MEs. The performance of the exposure model was evaluated through a personal monitoring study in schoolchildren attending a local secondary school. Children wore personal NO2 monitors for two consecutive days in four seasons. Parental questionnaires and time-activity diaries were used to obtain information for the exposure model and to model NO2 exposure for the same time period. The results showed good agreement between monitored and modelled NO2 concentrations (Normalised mean bias factor=-0.04). Multiple linear regression and generalised estimating equations (GEE) were used to assess the cross-sectional and longitudinal effect of modelled exposure on sRaw and FEV1 (as % predicted). Multiple logistic regression and GEE were used to assess the effect of modelled exposure on the prevalence of asthma and current wheeze.The longitudinal analyses showed significant associations between PM10 and NO2 exposure and % predicted FEV1 (PM10: B=-1.37, p=0.019; NO2: B=-0.83, p=0.003), but no association with sRaw (PM10: B=0.009, p=0.37; NO2: B=-0.007, p=0.16). The cross-sectional analyses showed no association between pollutant exposure during the summer or winter prior to age 11 and any of the lung function measures (p>0.05). Long term PM10 or NO2 exposure were not associated with asthma or current wheeze (p>0.05).This study developed and evaluated a novel air pollution exposure model for epidemiological research. The results of this study suggest a negative impact of long term exposure to NO2 and PM10 on growth in FEV1 during primary school age. However, no evidence of an association between long term exposure to NO2 and PM10 and childhood asthma was found.

Background: Cotton workers are highly exposed to organic dust. Inhalation of cotton based particulate has been associated with various respiratory symptoms and impaired lung function. This study investigates the respiratory health profile of textile mill workers in Nepal in relation to dust and endotoxin exposure. Methods: This study was conducted in four sectors (garment, carpet, weaving and recycling) of the textile industry in Kathmandu, Nepal. A total of 938 individuals completed a health questionnaire and performed spirometry. A subset of 384 workers performed cross-shift spirometry. Personal exposure to inhalable dust and airborne endotoxin was measured during a full-shift for a 114 workers. Results: Geometric mean concentrations of personal exposure to cotton dust and endotoxin were 0.81 mg/m3 and 2160 EU/m3 respectively. Overall prevalence of persistent cough, persistent phlegm, wheeze, breathlessness and chest tightness were 8.5%, 12.5%, 3.2%, 6.5%and 3.6% respectively. Symptoms were most common among the recyclers and less in the garment sector. Exposure to inhalable dust significantly predicted the symptoms of persistent cough and chest tightness. Significant cross-shift reduction in FEV1, FVC, and FEF25_75 were measured in the textile workers (p<0.001 for all); reductions being greater in the recyclers (-143 ml) and smallest in the garment workers (-38 ml) (p=0.012). Cross-shift reduction in FEV1 was significantly predicated by exposure to inhalable dust. Exposure to endotoxin did not correlate with any of the respiratory symptoms nor to lung function. Conclusion: The measured association between exposure to inhalable dust and reporting of respiratory symptoms and lung function suggests that despite high levels of endotoxin exposures, inhalable dust is the driver for these effects and attention should turn to what might be the toxic component in this dust other than endotoxin.

Asthma is characterised by airway remodelling and an increase in airway resistance. A greater understanding of the mechanisms involved in airway inflammation and airway hyper-responsiveness (AHR) may highlight therapeutic opportunities for asthma. This study initially aimed to optimise the preparation of precision cut lung slices (PCLS) in mouse and pig to investigate the influence of calcium (Ca2+) homeostasis on airway smooth muscle (ASM) contraction as a prelude to human studies. The PCLS technique was then applied to a murine model of allergic airway disease to explore the inflammatory process and pathogenesis of airway hyper-reactivity in sensitised mice. Initial experiments using murine and porcine airways validated the PCLS model and demonstrated the significance of release and refilling of Ca2+ from internal stores to induce and maintain an airway contraction. Results also highlight interesting species differences in agonist sensitivity, with the porcine system sharing similar pharmacology to human airways. Using a murine model of allergic airway disease, agonist induced contractile responses in peripheral airways were measured in vitro using the PCLS technique. BALB/c mice underwent initial sensitisation by intraperitoneal administration of ovalbumin, receiving a 3 day challenge with aerosolised OVA l% (vlv), for varying periods of up to 3 weeks for acute, mid-chronic and chronic sensitisation protocols. To investigate the influence of the inflammatory environment, naive murine lung slices were incubated with selected inflammatory mediators. OVA sensitisation led to progressive structural remodelling and AHR to methacholine (MCh) challenge. However, this hyperresponsiveness was decreased 48 hours post lung removal. Of the inflammatory mediators selected for lung slice incubation, IL-33 significantly increased AHR to MCh. IL-33 is a proinflammatory cytokine with transcriptional repressor properties, playing a role in initiating the TH2 inflammatory response. In lung slices prepared from IL-33 receptor (ST2) KO mice IL-33 was unable to sensitise the contractile response. These data suggest the inflammatory environment promotes AHR and disassociates this airway sensitivity from structural remodelling. These data suggest a key role for IL-33 in mediating AHR in this murine model. Investigation of the mechanisms involved in airway hyper-reactivity revealed mRNA expression of IL-33 and the IL-33 receptor (ST2) in soluble and membrane bound forms were significantly increased in the mid-chronic and chronic ovalbumin sensitised murine lung tissue. Further quantitative analysis in human lung showed expression of IL-33 in epithelial and ASM cells. The human ST2 receptor (also known as IL-IRL-l) was expressed in mast cells. Together these results suggest IL-33 is a sensor of tissue damage; indirectly inducing AHR through further inflammatory cell activation to target ASM. This study demonstrates IL-33's role as an inflammatory marker of asthma and suggests a novel therapeutic intervention by targeting of the ST2 receptor.

A barrier to assessing the effectiveness of respiratory physiotherapy has been insufficient accurate, reliable and sensitive outcome measures. Lung sounds provide useful, specific information for assessing and monitoring respiratory patients. However, standard auscultation techniques are too subjective to allow them to be used as an outcome measure. In this research, Computer Aided Lung Sound Analysis (CALSA) was used to assess whether adventitious lung sounds’ characteristics could be quantified clinically and used as a new objective, non-invasive, bedside clinical outcome measure for physiotherapy alveolar recruitment and airway clearance techniques. Two experimental studies were conducted incorporating ‘before-and-after’ and ‘repeated measures’ components. Fifty four participants with productive lung disorders (cystic fibrosis and bronchiectasis) were recruited from out-patient clinics. Demographic, anthropometric, lung function, oxygen saturation, breathlessness and lung sound data were collected at baseline and after a single intervention (selfintervention in the first study and intervention applied by a physiotherapist in the second study). The intra-subject reliability of crackle frequency (f) within each session was found to be ‘good’ to ‘excellent’, estimated by the Analysis of Variance, Intraclass Correlation Coefficient, Smallest Real Difference and Bland and Altman 95% limits of agreement. Crackle initial deflection width (IDW) and crackle two cycles deflection width (2CD) were reliable over short time periods. The f of crackles increased in the majority of participants post interventions. Agreement on the number (N) and timing (T) of crackles between CALSA and a physiotherapist‘s auscultatory findings was found to be poor in anterior chest sites, but higher in posterior sites. Conclusion: the use of CALSA to identify the type and f of adventitious lung sounds collected clinically is feasible; crackle IDW and 2CD are both reliable measures but crackle 2CD is more consistent; crackle f was more responsive than the N or T of crackles per breathing cycle to the interventions. In future, CALSA may provide an objective and responsive tool for assessing and monitoring respiratory interventions in clinical settings.

In this paper, old as well as new technological findings to decrease premature infant mortality are reviewed. This paper discusses fetal development throughout pregnancy from conception to full-term status as well as fetal lung development specifically from conception until full-term status. Several ideas to rapidly develop and mature fetal lungs are discussed such as mothers ingesting artificial surfactant supplements, either independently or coupled with antenatal corticosteroids, as well as intra-amniotic instillation prior to 28 weeks gestational. Drawbacks regarding these two are mentioned as well such as the fetus’s lungs not being mature enough to use the artificial surfactant leading into the idea of researching ways to rapidly develop fetal lungs, either week-by-week or stage-by-stage. Lastly, if the baby is born pre-maturely and is severely underdeveloped, research is currently being done on an artificial womb that the baby can be placed in to simulate a uterus where the fetus can develop on a normal timeline as he or she would in the mother’s womb.

Objetivo de nuestro estudio fue evaluar la capacidad diagnóstica de la ecografía pulmonar en el diagnóstico del Síndrome del Distrés Respiratorio (SDR), así como en el seguimiento de la respuesta al tratamiento. La ecografía pulmonar se comparó con los rayos X como método estándar de diagnóstico y seguimiento de pacientes con SDR. La escala radiográfica de cuatro grados se comparó con perfiles de ultrasonido de tres grados. El segundo objetivo era hacer un cálculo de las dosis recibidas debido a la radiografía de tórax en niños incluidos en el estudio. También se compararon los hallazgos radiológicos con los datos clínicos y de laboratorio de los pacientes. El estudio prospectivo incluyó 150 neonatos con diferentes edades gestacionales (