Дисертації з теми "Dysfonction chronique de l'allogreffe"
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Dao, Myriam. "Le blocage du récepteur cannabinoïde de type 1 : une nouvelle piste thérapeutique dans la maladie rénale chronique." Electronic Thesis or Diss., Sorbonne université, 2021. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2021SORUS389.pdf.
Some studies suggest that the cannabinoid receptor type 1 (CB1R) inhibition could be a new therapeutic toolbox in chronic kidney disease (CKD), especially in metabolic nephropathies. We aimed that CB1R promotes renal fibrogenesis, regardless of its cause. Its inhibition, genetic or pharmacological, could protect the kidney against the progression of CKD. We supported our hypothesis by a threefold approach: translational, experimental in mice and in vitro with culture cells of proximal tubular epithelial cells and myofibroblasts. Whereas CB1R expression was low in normal kidney grafts, it was highly expressed during chronic allograft dysfunction, especially in tubular cells. CB1R expression significantly increased early on after transplantation and correlated with renal fibrosis at M3. In vitro, we found that rimonabant, a CB1R antagonist, blunted collagen synthesis by tubular cells. We performed an experimental mouse model of CKD induced by ischemia-reperfusion (I/R-CKD). In this model, the global genetic or pharmacological inhibition of CB1R prevented CKD and significantly reduced interstitial fibrosis. In vitro, pharmacological inhibition of CB1R reduced collagen synthesis by myofibroblasts. Unexpectedly, the deletion of CB1R restricted to renal tubular cells worsened CKD in I/R-CKD. The protective effect of the global inhibition of CB1R is therefore probably mediated by a predominant effect on myofibroblasts.Thus, we demonstrated that the pharmacological blockade of CB1R could be a new therapeutic toolbox in CKD, regardless of its origin
Brugat, Thibaut. "Dysfonction télomérique dans les cellules résistantes de leucémie lymphocytaire chronique (LLC)." Paris 5, 2010. http://www.theses.fr/2010PA05P602.
CLL is a highly heterogeneous disease and remains incurable. The biological researches have identified the mean telomere length (protective ends of chromosome) as a new prognostic factor because the malignant cells of the progressive form of the disease have shorter telomeres than the indolent form. In parallel it has been demonstrated in our lab that leukemic cells from CLL patients may be resistant (CLL-R) or sensitive (CLL-S) in vitro to DNA damage (DSB) induced apoptosis. This difference seems to be correlated with their sensitivity to first-line treatment and is associated with deregulation of the non homologous end-joining system (NHEJ). The objective of this study was to know if the telomeric dysfunction is associated to a resistance to DSB and to better caracterise this dysfunction in CLL cells. The results show that the mean telomere length is twofold shorter in the CLL-R as compared to CLL-S and that this shortening is associated with an altered telomere structure which may limit the action of elongation systems. We also demonstrated that the presence of short telomeres in CLL-R cells is accompanied by i) a shortening of the telomeric single-stranded portion, ii) telomeres recognition by factors implicated in DSB signalling and repair by the NHEJ system, and iii) a loss of telomeric sequences associated with chromosomal abnormalities which are hallmarks of poor prognosis. Altogether, these results suggest that telomere dysfunction is not only a biological characteristic of the progressive form of CLL but may also be responsible for its development and /or its appearance
Amabile, Nicolas. "Microparticules endothéliales circulantes et dysfonction endothéliale in vivo." Paris 7, 2010. http://www.theses.fr/2010PA077268.
Microparticles (MPs) are shed membrane vesicles released by different cells after activation or apoptosis. This work investigates the relationships between circulating endothelial microparticles (EMPs) levels and endothelial fonction in different clinical situations in human beings. We first showed a strong relationship between EMPs levels, arterial stiffness and flow-mediated dilation (FMD) in end-stage renal failure disease (ESRF) patients. Moreover, the EMPs that were isolated ex vivo from these patients' plasma experimentally induced an endothelial dysfunction by reducing nitric oxide synthesis. Furthermore, we showed an inverse relationship between EMPs levels and value of shear stress applied to these ESRF patients' endothelium. Then, we studied subjects with pulmonary hypertension (PH): we found an increase in EMPs levels compared to normal controls and a strong correlation between CD31+/41-, CD 144+ EMPs levels and several hemodynamic parameters of disease severity. We also investigated the impact of an acute tobacco second hand smoke exposure on healthy volunteers endothelium: this acute endothelial injury induced a quick and sustained increased in EMPs levels, associated with a transient decrease in FMD values, that were subsequently followed by an increase in the number of circulating endothelial progenitor cells. Finally, we focused on the prognostic value of EMPs levels on clinical outcome: we found that elevated values of CD62e+ EMPs predicted poor outcome in PH patients, whereas increased levels of CD31+/41- EMPs were associated with increased incidence major cardiovascular events in ESRF subjects
D'Amours, Martin. "Interactions des facteurs endothéliaux dans la dysfonction endothéliale en insuffisance rénale chronique." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24559/24559.pdf.
Souweine, Jean Sébastien. "Dysfonction musculaire en hémodialyse : de la sarcopénie à la myopathie urémique." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT040.
Muscle dysfunction, a common feature in chronic haemodialysis patients, is associated with an increased risk of mortality independently of the disease severity, like sarcopenia in elderly patients. Despite similarities between the two situations, muscle dysfunction in chronic haemodialysis patients must be distinguished from sarcopenia. Some molecular abnomalities observed, such as the transition from slow to fast-fibre in muscle, appear to be different from those described during aging. This thesis comprises four studies which aim to identify and characterize the muscle dysfunction in chronic haemodialysis patients. In the first study, we developed a reliable and reproducible tool allowing the measurement of quadriceps muscle strength at the bedside. The second one showed that clinical and biological factors associated with a decrease in muscle strength were different from those associated with a decrease in muscle mass. In this study we were also able to identify patients with a decrease in muscle strength without a decrease in muscle mass, which characterizes dynapenic patients. The prognosis of these patients was studied in the third study. The risk of death was similar in these patients compared to sarcopenic patients, even though dynapenic patients were younger with fewer comorbidities.. This work also showed that muscle strength is a better prognosis marker than muscle mass. Finally, in the fourth study, we showed in hemodialysis patients on the waiting list for a kidney transplant, that a true renal insufficiency-induced myopathy with specific histological characteristics could exist. These characteristics are compatible with the decrease in endurance observed in this population. Thus, starting from the universally recognized clinical criterion of muscle mass, we have evolved towards the exploration of strength and endurance. Finally, this work provides some elements that confirm the existence of muscle abnormalities specific to chronic renal failure
Hazzan, Marc. "Dysfonction chronique du greffon en transplantation rénale : stratégies immunosuppressives et approche anti-inflammatoire expérimentale." Lille 2, 2006. http://www.theses.fr/2006LIL2S016.
Chronic allograft dysfunction (CAD) is a chronic inflammatory state inside the graft, causally related to immunological and non immunological injuries. Despite significant improvements in immunosuppressive regimens that led to better results in the short term, CAD remains a major cause of late graft lost in renal transplantation. The clinical part of this work was to evaluate the efficiency and safety of mycophenolate mofetil (MMF) in a strategy of cyclosporine (CsA) withdrawal, for the prevention of acute rejection and nephrotoxicity of calcineurin inhibitors, two of the strongest risk factors for CAD. In a retrospective study we compared azathioprine to mycophenolate mofetil associated with CsA: MMF+CsA reduced the incidence of acute rejection and weakened the deleterious consequences of acute rejection, resulting in significantly increased 3-year graft survival rates in patients who had experienced one or more acute rejection episodes during the first 6 months post graft. In a randomized, open-labelled study to evaluate early (3 months) withdrawal of CsA under MMF and prednisone in low immunological risk recipients, we demonstrated a significant improvement of the renal function at 1 and 2 years after CsA discontinuation. However, a higher proportion of the recipients withdrawn from CsA experienced acute rejection, as compared with patients withdrawn from MMF and maintained under CsA and prednisone. Pharmacokinetics of MMF and borderline histological changes in the 3-month graft biopsy were identified as 2 independent predictors of acute rejection after CsA withdrawal. The 1-year systematic graft biopsy revealed that a significant number of patients withdrawn from CsA developed peritubular C4d deposits, independently of the occurrence of early acute rejection episodes. However, neither 1-year Chronic Allograft Damage Index nor 2-year graft function were suggestive of a progression towards chronic rejection in these patients. Further follow-up as well as specific investigations (e. G. HLA antibodies) are needed to clarify this result, which questions the prognostic value of C4d deposits on protocol biopsies in stable patients. Because both immunological and non immunological injuries contribute to a chronic inflammatory process, we evaluated the impact of different anti-inflammatory and/or immunomudulatory drugs on the progression of CAD. Pentoxifylline, statins, and PPAR (Peroxisome Proliferator-Activated Receptors) agonists were tested because of their known pleiotropic effects and their safety in clinical practice. In a murine model of skin allograft, neither pentoxifylline nor statins modified the course of chronic rejection in this model. The PPAR ligand fenofibrate paradoxically exacerbated fibrosis in allogeneic and syngeneic skin grafts when administrated immediately after the graft. These data suggest that activation of PPAR, which is transiently expressed after a cutaneous lesion, may interfere with wound healing in this model. Prevention of CAD can partly rely on early modifications of the immunosuppressive regimen to avoid long term nephrotoxicity of calcineurin inhibitors, but this strategy carries a significant risk of acute rejection, and CsA elimination cannot be recommended for all patients. This risk can be minimized in carefully selected recipients according to the early events post graft, pharmacokinetics of the immunosuppressive drugs, and histological results at 3 months. However, the nephrotoxicity of calcineurin inhibitors is only one among multiple factors involved in the chronic inflammatory process leading to CAD. Non-specific anti-inflammatory treatment in association with immunosuppressive drugs could slow down progression of graft failure. An experimental approach can help to select active molecules before initiating clinical trials that will require high numbers of patients and a prolonged follow-up
Durand, Maxim. "Etude de la régulation lymphocytaire T dans deux modèles de transplantation rénale et pulmonaire." Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1001/document.
Transplantation is nowadays systematically associated with the administration of immunosuppressive treatments inhibiting the allo-immune response toward the graft to prevent the rejection by the recipient's immune system. However, these heavy treatments have several deleterious effects and are not able to control longterm chronic rejection development. Thus, the objective of this PhD work, based on two distinct clinical situations, is part of two priority axes of transplant research: (1) identify early predictive markers of long-term lung allograft dysfunction and (2) decipher the mechanisms involved in the acceptance of kidney allograft in operational tolerance. We first investigated the mechanisms of graft acceptance in kidney transplanted patients with a functional graft in the absence of immunosuppressive therapy. We identified in these patients a greater proportion of circulating memory regulatory T lymphocytes, with an increased ability to degrade extracellular ATP, a pro-inflammatory mediator, and favour a protolerogenic environment. Thus, this mechanism, not efficient in stable patients under treatments, could participate in the inhibition of the allo-immune response leading to maintaining a functional kidney graft in the absence of immunosuppression. In a second time, we interested in the prediction of chronic rejection occurrence in lung transplanted patients. We report that the early posttransplant regulatory T lymphocyte profile is modified in patients who will develop chronic rejection in the 3 years. Thus, monitoring this predictive biomarker could allow a better identification of patients at risk of rejection
Delample, Delphine. "La dysfonction musculaire périphérique dans la bronchopneumopathie chronique obstructive : mécanismes cellulaires et implication du stress oxydant." Montpellier 1, 2008. http://www.theses.fr/2008MON1T032.
D'Amours, Martin. "Dysfonction endothéliale et insuffisance rénale chronique, rôle de l'angiotensine II, de l'endothéline-1 et du monoxyde d'azote." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0025/MQ38061.pdf.
Pain, Mallory. "Un nouveau biomarqueur de la dysfonction chronique du greffon pulmonaire : du modèle in vitro à la cohorte COLT." Nantes, 2014. http://archive.bu.univ-nantes.fr/pollux/show.action?id=7a8ee065-2a60-42d6-b914-3806664fe12b.
Chronic lung allograft dysfunction (CLAD) is the major limitation to lung transplantation, with the most common phenotype being bronchiolitis obliterans (BO). BO is characterized by an irreversible airflow obstruction after an aberrant airway remodeling process. Bronchial epithelial cells (BEC) seem to play a key role in this process through epithelial to mesenchymal transition (EMT). The aim of this study was to 1) set up an in vitro model of allogeneic co-culture 2) test the impact of allogeneic context on EMT 3) identify new predictive biomarkers of BO. I have developed a new in vitro co-culture model between BEC and allogeneic activated T cells and/or monocytes. Detection of CCL2, CCL3, CCL4 and CXCL-10 in culture supernatants shows the relevance of the model. I have demonstrated that immune cells in synergywith TGF-ß favors MMP-9 secretion. Furthermore, I have demonstrated the role of CCL2/CCR2 in this secretion, suggesting CCR2 as a potentiel therapeutic target. Finally, thanks to COLT cohort, I have validated plasma MMP-9 as a predictive biomarker of BO. This new in vitro model suggests the implication of allogenicity in EMT during epithelium remodeling by the induction of MMP and propose a link between CCL2 and MMP-9. It appears as a relevant tool for biomarker discovery as presented here with MMP9. Plasmatic MMP-9 maybe a valuable biomarker for BO
Martin, Laurent. "Contribution à l'étude du rôle des anticorps dans le développement de la néphropathie chronique de l'allogreffe après transplantation rénale : analyse in situ." Dijon, 2004. http://www.theses.fr/2004DIJOMU04.
Lacasse, Miriam. "Dysfonction cardiaque autonome dans la maladie pulmonaire obstructive chronique : récupération de la fréquence cardiaque après un exercice: facteur prédictif de mortalité dans la maladie pulmonaire obstructive chronique." Thesis, Université Laval, 2005. http://www.theses.ulaval.ca/2005/22579/22579.pdf.
Background. A delayed heart rate recovery (HRR = peak exercise heart rate (HR) – HR at 1-minute recovery) reflects cardiac autonomic dysfunction, which is associated with a poor prognosis. Purpose. To compare HRR between patients with chronic obstructive pulmonary disease (COPD) and controls; to compare survival in patients with COPD according to HRR; to evaluate survival influence of HRR modification following pulmonary rehabilitation. Methods and results. HRR was compared between 147 COPD patients and 25 controls (11±9 vs 19±9 beats, p<0.0001). In patients with COPD, abnormal HRR (≤14 beats) was associated with a 5.12 mortality hazard ratio (CI 95% [1.54-17.00]). After pulmonary rehabilitation (n=77), persistent abnormal HRR represented a higher mortality risk (8.12; CI 95% [2.12-31.02]). Conclusions. HRR is decreased in COPD and, when abnormal, is linked with decreased survival. Persistent abnormal HRR after rehabilitation is associated with a poor prognosis.
Mezni, Imen. "Évaluation d'un marqueur précoce de la dysfonction chronique du greffon rénal : la PCR urinaire de l'ARNm de la Vimentine." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS088.
Chronic graft dysfunction is the major cause for end-stage renal failure after renal transplantation, both through immune and non-immune mechanisms. When the renal tubular epithelium undergoes epithelial phenotypic changes (EPC), reminiscent of epithelial mesenchymal transition (EMT), and associated with interstitial fibrosis and tubular atrophy, the prognosis is poor with a diminution of renal function and graft loss. In this prospective study. We studied the renal epithelial phenotype by immunohistochemistry and measured mRNA in urine of vimentin, CD45, GAPDH and uroplakin 1a by RT-PCR. We compared grafts from living donors and those from deceased donors. We evaluated the diagnostic performance of RT-PCR on urine for the diagnosis of epithelial phenotypic changes in transplant patients, with renal biopsy surveillance at 3 months and a biopsy on particular indication. We have shown that the EMT score on renal biopsy surveillance and the evolution of graft renal function were better in the patients from living donors than in those from cadaveric donors. The value of the mRNA of vimentin and CD45 relative to the uroplakin is correlated with the score in vimentin immunostaining in routine biopsies. These biomarkers could be used as a noninvasive tool to monitor the renal graft fibrogenesis. This test could be used for early detection of fibrotic diseases of the kidney transplant. In an independant study, the transcriptome in urine was analyzed, and it was found that normalization of mRNA with uroplakin mRNA was useful, and that EPC were associated with immune and inflammatory profiles
Mezni, Imen. "Évaluation d'un marqueur précoce de la dysfonction chronique du greffon rénal : la PCR urinaire de l'ARNm de la Vimentine." Electronic Thesis or Diss., Sorbonne université, 2018. http://www.theses.fr/2018SORUS088.
Chronic graft dysfunction is the major cause for end-stage renal failure after renal transplantation, both through immune and non-immune mechanisms. When the renal tubular epithelium undergoes epithelial phenotypic changes (EPC), reminiscent of epithelial mesenchymal transition (EMT), and associated with interstitial fibrosis and tubular atrophy, the prognosis is poor with a diminution of renal function and graft loss. In this prospective study. We studied the renal epithelial phenotype by immunohistochemistry and measured mRNA in urine of vimentin, CD45, GAPDH and uroplakin 1a by RT-PCR. We compared grafts from living donors and those from deceased donors. We evaluated the diagnostic performance of RT-PCR on urine for the diagnosis of epithelial phenotypic changes in transplant patients, with renal biopsy surveillance at 3 months and a biopsy on particular indication. We have shown that the EMT score on renal biopsy surveillance and the evolution of graft renal function were better in the patients from living donors than in those from cadaveric donors. The value of the mRNA of vimentin and CD45 relative to the uroplakin is correlated with the score in vimentin immunostaining in routine biopsies. These biomarkers could be used as a noninvasive tool to monitor the renal graft fibrogenesis. This test could be used for early detection of fibrotic diseases of the kidney transplant. In an independant study, the transcriptome in urine was analyzed, and it was found that normalization of mRNA with uroplakin mRNA was useful, and that EPC were associated with immune and inflammatory profiles
Koechlin, Christelle. "Stress oxydant et dysfonction musculaire périphérique dans la bronchopneumopathie chronique obstructive : réalité biologique, physiopathologique et relations avec la maladie respiratoire." Montpellier 1, 2004. http://www.theses.fr/2004MON1T010.
Kremer, Hélène. "Dysfonctions vasculaire et musculaire, aiguë et chronique. Quelle place pour la modulation pharmacologique du stress oxydant ?" Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ135.
The aim of this work was to study the arterial and muscular dysfunctions in two rodent models of acute and chronic injuries, then the evaluation of pharmacological evaluation of oxidative stress on vascular abnormalities induced in these models.In the acute model, a mouse endotoxic shock, human serum albumin administration improved survival, endothelial dysfunction and reduced vascular hyporeactivity thanks to its concentration-dependant , anti-oxidative and anti-inflammatory properties, leading to a decrease of inductible NOS expression and an qualitative and quantitative increase of endothelial NOS.In the chronic model, rat’s administration of ciclopsorine and everolimus induced an endothelial dysfunction characterized by alterations of both NO and EDHF pathways and associated with an in situ oxidative stress. In the cardiac muscle, an increase of reactive oxygen species and a decrease of right ventricle mitochondrial respiratory chain complexes activities was observed only with everolimus. The preventive administration of polyphenols markedly increased the blunted EDHF component, but not the NO component, of the cyclosporine-induced endothelial dysfunction by reducing NADPH oxidase over expression and oxidative vascular stress. Finally, oxidative stress is a common entity, implicated in genesis of vascular and muscular dysfunctions. Its modulation by human albumin or polyphenols administration improves respectively arterial hyporeactivity of endotoxinic shock and endothelial dysfunction in our two models
Lecru, Lola. "Les récepteurs cannabinoïdes : une nouvelle cible thérapeutique de la fibrogenèse rénale." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T088.
Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. In the present study, we show that the cannabinoid 1 receptor (CB1) may be a new pathway in renal fibrogenesis, independently of its involvement in metabolic disease. We found that CB1 expression was highly expressed in kidney biopsies of patients suffering from IgA nephropathy, diabetes, and acute interstitial nephritis. We also used an experimental model of renal fibrosis, the unilateral ureteral-obstruction model, in mice. Both genetic and pharmacological invalidation of CB1 induced a profound reduction in renal fibrosis, showing its prominent role in renal fibrosis. Cannabinoid receptor 2 is also involved in renal fibrogenesis but does not potentialize the role of CB1. CB1 expression is drastically increased in myofibroblasts upon TGFß-1 stimulation. The decrease in renal fibrosis during CB1 invalidation is explained by a direct action on myofibroblasts: CB1 blockade reduced collagen expression in vitro. In addition, CB1 also modulates the macrophage infiltrate responsible for renal fibrosis in unilateral ureteral obstruction through a decrease in MCP1 synthesis, a major chemoattractant cytokine. Our study strongly suggests a major role for CB1 in the activation of myofibroblasts, which are the main effector cells in renal fibrogenesis, and suggests that CB1 may represent a major new target for treating chronic kidney disease
Varin, Rémi. "Dysfonction endothéliale et insuffisance cardiaque : effets d'un traitement chronique par un inhibiteur de l'enzyme de conversion et-ou d'un exercice physique." Rouen, 2001. http://www.theses.fr/2001ROUEA001.
Merindol, Descazeaud Virginie de. "Modifications du cytosquelette des cellules tubulaires proximales rénales par les inhibiteurs de la calcineurine : rôle dans la dysfonction chronique du greffon." Limoges, 2011. https://aurore.unilim.fr/theses/nxfile/default/7207b0d4-b329-4a71-ae05-5575092c0b83/blobholder:0/2011LIMO310I.pdf.
Cyclosporine and tacrolimus are calcineurin inhibitors widely used in the prevention of transplanted organ rejection. The use of calcineurin inhibitors has greatly improved graft survival in transplant allograft recipients but long term treatment has led to the recognition of some major and limiting side effects, including nephrotoxicity, that contribute to chronic allograft dysfunction and lead to end-stage renal disease by inducing phenotypic changes of renal cells and abnormal function. The aim of this work was to identify the effects of calcineurin inhibitors exposure on the cytoskeleton organization of proximal tubular cells and the consequences of such modificationS on cell’s phenotype. We demonstrate here that, independently of the NFAT pathway, exposure to cyclosporine provokes a strong rearrangement of the actin cytoskeleton and a specific inhibition of the fibrinolytic system in renal proximal tubular cells. For the first time in kidney cells, we also identify cofilin pathway as a potential target of cyclosporine effect. On the other hand, exposure to tacrolimus does not reproduce the effects of cyclosporine on the cytoskeleton organization. This work provide new fields of investigation to further understand the mechanisms implicated in the deterioration of proximal tubular cells structure after kidney transplantation and the contribution of calcineurin inhibitors
Lambert, Virginie. "Thérapie cellulaire par progéniteurs cardiaques issus de cellules souches embryonnaires dans un modèle porcin de dysfonction ventriculaire droite par surcharge chronique." Paris 5, 2009. http://www.theses.fr/2009PA05P639.
The long term prognosis of some congenital heart diseases may be impaired related to severe right ventricular (RV) dysfunction and conventional therapies give poor results. Cell therapy may be an alternative therapeutic approach. The aims of this study were 1/ to create an experimental model of RV dysfunction secondary to chronic overload as observed in congenital heart diseases, 2/ to apply on this failed RV a cell therapy using cardiac progenitors derived from human embryonic stem cells. We have characterized in a large animal a model of RV dysfunction secondary to a combined chronic overload using a surgical procedure reproducing the RV outflow tract diseases as observed after repair in tetralogy of Fallot. After 4 months, we have observed the various aspects of RV dysfunction: hemodynamic with an impairment of myocardial contractility, electrophysiological with an increasing of duration of both QRS and action potential and histological with a myocardial remodelling at the first stage. In this model of RV dysfunction, we have applied cell therapy and injected into multiple sites of RV myocardium cardiac progenitors derived from human embryonic stem cells. We have observed an improvement of myocardial contractility and a stabilization of the deleterious effects of the chronic overload on cardiac function. No ventricular arrhythmia occurred and no teratoma was detected. This first attempt of cell therapy using cardiac progenitors is encouraging and may be an interesting innovative approach to treat RV dysfunction secondary to chronic overload
Gouzi, Fares. "Impact de l'inactivité physique et du réentrainement dans la dysfonction musculaire périphérique complexe de la BPCO : au delà du déconditionnement ?" Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON1T033/document.
Chronic diseases are one of the medical challenges of the 21st century. The chronic obstructive pulmonary disease is paradigmatic of this type of diseases, because of its heterogeneity, and its systemic repercussions. The peripheral muscle dysfunction constitutes a key-repercussion in COPD. However, the links between this muscle dysfunction and the pulmonary impairment remain poorly understood.The physical activity reduction has been the first link proposed. However, the magnitude of structural muscle remodeling in COPD differs to the one of deconditioned sedentary subjects (though, this could be the consequence of greater and older inactivity in COPD), and other factors like the oxidative stress have been incriminated. The peripheral muscle dysfunction in COPD patients has never been directly compared to the one of healthy subjects of the same physical activity level, and is limited by the heterogeneity of the muscle dysfunction in COPD patients. Last, the exercise training has never shown similar muscle response in COPD patients as compared to healthy sedentary subjects. The aim of this PhD Thesis was to understand the exact contribution the physical inactivity and the exercise training in the heterogeneous peripheral muscle, dysfunction in COPD patients.First, we observed that the lifetime physical activity was not greater in COPD patients as compared to lifetime sedentary healthy subjects. In another hand, we showed phenotypes of peripheral muscle dysfunction in COPD patients. However, and whatever the phenotype considered, there was significantly more ultra-structural damage in COPD patients vs. healthy sedentary subjects. Last, a similar exercise training program did not induce similar functional, histo-morphological and angiogenic muscle responses in COPD patients vs. healthy sedentary subjects.Altogether, our work challenges the classical paradigm of the COPD spiral of decline and open doors to research on other specific pathways of the field of muscle dysfunction in COPD in order to optimize the pulmonary rehabilitation
Meziri, Faycal. "Influence de l'érythropoïétine recombinante humaine sur les fonctions cardiovasculaire et rénale chez le rat présentant une dysfonction endothéliale : effets des interactions avec l'exercice chronique." Phd thesis, Université d'Avignon, 2011. http://tel.archives-ouvertes.fr/tel-00919398.
Meziri, Fayçal. "Influence de l'érythropoïétine recombinante humaine sur les fonctions cardiovasculaire et rénale chez le rat présentant une dysfonction endothéliale : effets des interactions avec l'exercice chronique." Thesis, Avignon, 2011. http://www.theses.fr/2011AVIG0707/document.
The chronic administration of rHuEPO can engender side effects. An increase of the hematocritinduced by rHuEPO, by increasing the erythrocytosis, the blood viscosity and the shear stress onvascular surface, can be responsible of arterial high blood pressure and arterial thrombosis. Thepresence of a normal endothelial function and nitric oxide (NO) can counter the noxious effectsof rHuEPO. On these bases, we studied the cardiovascular effects of a chronic administration ofrHuEPO in various frames: within doping field, to trained rats with L-NAME-induced NOdependentendothelial dysfunction and within the framework of a treatment, to chronic kidneydisease (CKD) rats developing endothelial dysfunction caused by the "5/6 nephrectomy". In ourdoped rats, we observed an important mortality (51%). A severe arterial high blood pressuredeveloped in these rats (> 220 mmHg) associated with an impairment of the NO-dependentvasorelaxation (< 60 %). CKD rats also showed an increase in blood pressure and an endothelialdysfunction, in response to acetylcholine in the aorta and in response to a rise in flow in perfusedmesenteric artery. These parameters were improved by exercise. Kidney sections stained withSirius red showed marked fibrosis in CKD rats. Fibrosis, creatinine and albumin were decreasedby exercise alone but were increased in rats from the CKD + EPO + Ex group. NAD(P)H oxidaseactivity and the expression of Nox4, p67phox, and MAPK erk1/2 were increased in CKDrats. Exercise or rHuEPO prevented these increases. However, the NAD(P)H oxidase activityand the expression of MAPK erk1/2 remained high in the kidney of rats from the CKD+EPO+Exgroup. Our data suggest that exercise alone has a protective effect against vascular and renaldysfunction and renal fibrosis. These protective effects are linked to the downregulation of theNADPH oxidase activity and MAPK erk1/2 signaling pathways. However, exercise combinedwith rHuEPO treatment has deleterious effects on kidney structure and function in CKDrats. These adverse effects appear to be related to the stimulation of NADPH oxidase and MAPKerk1/2 signaling pathways. Despite the cardiovascular and renal protective effects of physicaltraining, these results highlight the potentially damaging renal function and structure bycombining exercise with rHuEPO therapy in renal failure. In conclusion, we can say that therHuEPO affects seriously cardiovascular function in trained rat with endothelial dysfunction. Thisrisk being fatal, many sportsmen, looking to increase their performance, put their life in danger.Moreover, having noticed the deleterious effects in the kidney by combining exercise andrHuEPO therapy under experimental conditions on a model of renal failure, we suggest a clinicalinvestigation to verify the transposition of our results to patients with renal failure
Jourde-Chiche, Noémie. "Rôle des toxines urémiques dans le déséquilibre lésion/régénération de l'endothélium." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22956.
Chronic kidney disease (CKD) is associated with dramatically increased cardio-vascular morbidity and mortality. Not only do traditional risk factors explain this accelerated atherosclerosis, but also chronic inflammation, oxidative stress and endothelial dysfunction. Uremic toxins are solutes accumulating in serum and tissues of CKD patients. Among them, protein-bound uremic toxins are poorly removed by haemodialysis (HD), and have shown deleterious effects on cultured endothelial cells (HUVEC). We showed that indoxyl suphate (IS), a protein-bound toxin, induces reactive oxygen species production in HUVEC, through activation of NAD(P)H oxidase, and intracellular glutathione depletion. This induction of oxidative stress was observed for concentrations of IS found in CKD patients. CKD patients exhibit high levels of endothelial microparticles (EMP), a marker of endothelial lesion, and low levels of endothelial progenitor cells (EPC), originating from bone marrow and implied in endothelial repair. We asked whetehr uremic toxins could play a role in this imbalance. In HD patients, we showed that the number of CD34+/CD133+ EPC was inversely correlated with the serum levels of two uremic toxins, indole-3-acetic acid (IAA, a protein-bound uremic toxin close to IS) and ß2microglobulin. In vitro, IAA induced apoptosis of CD133+ cells, unless erythropoietin was added to the medium. Uremic serum induced EPC apoptosis. Although endothelial progenitor cell number was reduced in CKD patients compared to healthy controls, it was positively correlated with two markers of vascular lesion : the number of EMP in serum, and the pulse wave velocity reflecting arterial stifness. This suggests that EPC can be mobilized in the circulation upon vessel injury, in spite of uremic toxicity, and maybe thanks to erythropoietin treatment in HD patients. In conclusion, uremic toxins induce endothelial dysfunction, assessed by increased endothelial oxidative stress and shedding of EMP, and reduce regeneration capacities of endothelium. They are probably key actors in cardio-vascular risk of CKD patients
Abdellaoui, Aldjia. "La dysfonction musculaire du patient Broncho-pneumopathie Chronique Obstructive : à propos de quelques mécanismes impliqués dans l’amélioration de la fonction musculaire induite par les programmes de réentrainement." Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON1T001.
We are no longer allowed to consider COPD as a simple respiratory disease but rather as a systemic disease. Among the systemic effects, muscle dysfunction appears to be a key factor in the pathogenesis of COPD because it strongly influences how the disease will progress. However, the exact origin of muscle dysfunction is still unknown. It is acknowledged that during COPD exacerbations muscle dysfunction is worsened and that, in the absence of post-exacerbation muscle training, recovery is slow and partial. Thus, the objectives of this thesis were first to try to understand the cellular mechanisms involved in the peripheral muscle dysfunction in patients with stable and unstable (after exacerbations) COPD and, then, to assess different programs of physical training to improve muscle function in such patients.Concerning the identification of the mechanisms underlying peripheral muscle dysfunction, we found that protein oxidation, particularly mitochondrial protein oxidation, is higher in the quadriceps of patients with stable COPD than in control subjects. In addition, we have shown that COPD exacerbations are associated with increased muscle oxidative damage of mitochondrial and contractile proteins that is correlated with the level of muscle dysfunction. We then assessed a training protocol using neuromuscular electrostimulation for patients during COPD exacerbation and a training program of moderate intensity (ventilatory threshold) for clinically stable patients. Our results indicate that the two training programs prevent oxidative stress and improve muscle function in COPD patients. However, mitochondrial adaptation is limited in patients with stable COPD compared with controls. In conclusion, our results show that contractile and mitochondrial proteins are the target of increased oxidative stress particularly during COPD exacerbation. However, training programs tailored to the severity of muscle dysfunction can prevent further oxidative damage and contribute to improving muscle function. Our findings might help improving the choice of training programs for patients with COPD
Preterre, David. "Développement d'un modèle in vitro d'exposition chronique aux forces de cisaillement pariétal sur primocultures de cellules endothéliales coronaires de rat pour l'évaluation de la dysfonction endothéliale in vitro." Rouen, 2004. http://www.theses.fr/2004ROUES018.
Vascular endothelium role in cardiovascular diseases has gained more and more interest for a few years. Being considered just as a barrier, research gave it many properties which became the foundations of cardiovascular homeostasis. As endothelium may interact with its micro-environment, in vitro studies are not easy since endothelial cells are grown under non-physiological conditions. Development of an in vitro model which could simulate and modulate independently physical, chemical and physiological parameters of endothelium micro-environment appears to be necessary for the in vitro studies relevance. The "Roller" system allows study in a chronic and independent fashion those parameters. As recent studies pointed out the crucial role of oxidative status of endothelial cells into the outcome of physio-pathological events, we have been interested in endothelial oxidative status cellular responses when exposed to various micro-environmental conditions. Our results show that shear stress increase induces transient oxidative stress as well as long-term anti-oxidant enzymatic systems; chronic decrease in shear stress seems to induce an imbalance in endothelial cell oxidative state. Hypoxia did not induce reactive oxygen species production but modulates flow-induced oxidative stress and enhances NO bioavailability. Angiotensin II showed a dominant anti-oxidant effect mediated by AT2 receptors and pro-inflammatory and pro-oxidant TNF alpha effects were stronger when cells had undergone chronic flow decrease. Then, it appears that micro-environment strongly affects endothelial cell in culture and their response to exogenous stresses. Hypoxia role and mechanism at the tissue level remains to be assessed with co-culture systems (cardiomyocytes/endothelial cells). Furthermore, AT2 receptor presence at the coronary level could lead to novel research in terms of therapeutical strategies. To conclude, this model allows fine and chronic evaluation of endothelium interaction with its environment. Dynamic culture concept appears to be uncircumventable for development of studies which could offer an alternative to animal experimentation
Cabibel, Vincent. "Mécanismes physiopathologiques de l’altération de la commande motrice dans la bronchopneumopathie chronique obstructive." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONT4004.
Chronic obstructive pulmonary disease (COPD) is a respiratory pathology associated with several repercussions. The muscle weakness, characterized by a reduction of the muscle strength (30% on average, compared to healthy individuals) without any fatigue, is a major repercussion of the disease. Strength production relies on two physiological processes: the nervous system ability to activate the muscles and the capacity of the muscles to perform a contraction. Both these processes are impaired in COPD. However, while the muscles alterations are well documented, the mechanisms involved in the production of a non-optimal motor command are not fully understood. The aim of this thesis was therefore to identify the mechanisms involved in the motor command alteration in COPD patients. Our work confirmed the existence of a reduced motor command in COPD, compared to healthy subjects. The application of neuromodulation in patients failed to increase cortical excitability and motor command, and consequently to determine whether latent motor networks exists in COPD. We then demonstrated that the connectivity was altered between the brain hemispheres in COPD and that the ipsilateral motor areas activation was preserved in patients during force generation. Finally, we observed that psychoactive medications, prescribed to manage anxiety and depression, we highly prevalent in COPD. The consumption of these medications was associated with reduced excitability and increased inhibition at the cortical level and with an altered motor command. However, the absence of repercussion on strength suggests the existence of a compensatory mechanism
Pascal, Laurent. "Les dilemmes de l'allogreffe de sang placentaire explorés au travers de deux alternatives thérapeutiques : le sérum anti-lymphocytaire in vivo, l'interleukine-7 in vitro." Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S064/document.
The placental blood graft provides access to indications for hematopoietic stem cell transplantation (CSH) in the absence of availability of a compatible unrelated donor
Alexandre, François. "Implication du système nerveux central dans la faiblesse musculaire périphérique du patient atteint de broncho-pneumopathie chronique obstructive." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONT4003/document.
Peripheral muscle weakness, as defined by a reduced voluntary strength outside any state of neuromuscular fatigue, is a common complication of chronic obstructive pulmonary disease (COPD). Maximal voluntary strength is determined by both peripheral muscle properties (i.e. muscle volume and architecture, contractile quality) and the nervous system's ability to activate the muscle maximally. In COPD, many studies highlighted the paradoxical existence of maximal voluntary strength loss without any peripheral muscle impairment, and without a clearly identified voluntary activation deficit. However, patients with COPD exhibited several nervous system alterations compatible with a reduced maximal voluntary activation capacity. The aim of this thesis was to test the nervous system implication in COPD muscle weakness and to determine the involved mechanisms. As major results, we found a reduced cortical activity in COPD during maximal and sub-maximal voluntary contractions. Furthermore, we reported reduced motor cortex excitability and voluntary activation deficit, specifically in patients with muscle weakness. These results are in accordance with an involvement of cortical alterations in COPD muscle weakness. Then, we indentified a potential origin for cortical alterations: O2 desaturation during non-rapid eye movement (NREM) sleep. This hypothesis has been corroborated by the observation of a reduced voluntary activation in patients with NREM sleep desaturation. However, no significant repercussion could have been observed on maximal voluntary strength in these patients, suggesting a compensatory mechanism.Our results are an important step forward in understanding the COPD muscle weakness that was classically attributed to loss of muscle mass only. The involvement of the central nervous system in COPD muscle weakness also brings about new patient care opportunities via tailored approaches, in order to fight against muscle weakness and its deleterious consequences on a patient's life
Morand, Jessica. "Dysfonction cardiovasculaire et arythmies ventriculaires de l’ischémie-reperfusion : effets délétères de l’hypoxie intermittente et protecteurs de la supplémentation en zinc." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV015/document.
Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Intermittent hypoxia (IH), one of the major consequences of apneas, leads to oxidative stress, activation of HIF-1 (hypoxia inducible factor 1) and endothelin (ET-1) expression, all known to play an important role in the cardiovascular consequences of OSA.First, we have demonstrated that IH increases the incidence of ischemia-related lethal ventricular arrhythmias. Among the potential mechanisms involved, spectral analysis of heart rate and blood pressure variability and catecholamine assay, showed a sympathetic activation in animals exposed to IH. IH was also responsible for alterations in ventricular repolarisation (increased QTc and Tpeak-Tend intervals) and dispersion of the transmural gradient (increased endocardial action potential duration). These alterations were associated with increased expression of endocardial LTCC and TRPC calcium channels.The second part of the thesis aimed at investigating zinc homeostasis in response to the oxidative stress induced by ischemia-reperfusion (IR) or IH as well as the beneficial effects of zinc supplementation in this context. We observed that IR and IH induced a decrease in myocardial and plasma zinc concentrations, respectively. We also highlighted the protective effects of zinc supplementation during reperfusion against the ventricular arrhythmias and myocardial dysfunction induced by IR. Zinc administration during reperfusion also abolished the increase in infarct size induced by chronic IH exposure.Finally, we investigated the effects of zinc depletion in endothelial cells exposed to TPEN, a specific zinc chelator. We observed that TPEN induced a nuclear translocation of HIF-1α and an increase in ET-1 secretion with a resulting increase in endothelial cell migration. Thus, zinc depletion appears to promote activation of the HIF-1-ET-1 axis, known for its deleterious effects upon IH.In summary, chronic IH exposure enhances ventricular arrhythmias and increases infarct size upon myocardial I/R. Sympathetic activation, oxidative stress and alterations of zinc homeostasis appear to be contributing factors. Pharmacological targeting of these alterations should be performed in order to confirm their role as well as to potentially prevent the deleterious cardiovascular consequences of IH and OSA
Debigaré, Richard. "La dysfonction musculaire périphérique dans la maladie pulmonaire obstructive chronique /." 2002. http://proquest.umi.com/pqdweb?did=765056291&sid=18&Fmt=2&clientId=9268&RQT=309&VName=PQD.
Duchesneau, Nathalie. "Dysfonction du réseau veineux en insuffisance rénale expérimentale /." 1997. http://proquest.umi.com/pqdweb?did=738271111&sid=12&Fmt=2&clientId=9268&RQT=309&VName=PQD.
Nyam, Elsa. "Rôle de l’urée dans la dysfonction de la cellule bêta-pancréatique au cours de l’insuffisance rénale chronique." Thèse, 2016. http://hdl.handle.net/1866/16248.
Chronic kidney disease (CKD) is defined as a glomerular filtration defect and is associated with many disorders. Impaired glucose homeostasis is one of them. Glucose homeostasis is maintained in part by insulin, which is the hormone secreted by the pancreatic beta cells from the islets of Langerhans in response to glucose. The preservation of beta cell function is essential to maintain glucose homeostasis. It has been demonstrated that insulin secretion is altered during CKD; however, the underlying mechanisms remain unknown. In CKD, chronic accumulation of uremic toxins could contribute to beta cell dysfunction. Urea is a major uremic toxin and its toxicity has been recently reported in many tissues. The purpose of this master project was to ascertain the role of urea in pancreatic beta cell dysfunction during CKD. We have demonstrated that exposure of mouse islets to pathological concentrations of urea leads to diminution of insulin secretion via an increase in oxidative stress and O-glycosylation. This defect is due to disturbed intracellular glucose metabolism. Among others, we have observed a reduction in glycolysis associated with a decrease in the activity of phosphofructokinase-1. These results demonstrate a direct toxic effect of urea on insulin secretion and contribute to a better understanding of mechanisms of pancreatic beta cell dysfunction during CKD.
Borel, Jean Christian. "Effets cliniques, biologiques et aspects techniques de la ventilation non invasive." Phd thesis, 2008. http://tel.archives-ouvertes.fr/tel-00413011.
Nous avons montré que des patients affectés d'un syndrome obésité-hypoventilation (SOH) avaient une fonction endothéliale plus sévèrement altérée et une inflammation systémique plus importante que les patients obèses simples. La PaCO2 était corrélée à la dysfonction endothéliale (Borel et coll, manuscrit en préparation). Nous avons observé que la proportion d'hypoventilation en sommeil paradoxal, chez les sujets SOH, était associée à une réponse ventilatoire au CO2 abaissée et une somnolence diurne excessive. Pour la première fois, nous avons constaté que la ventilation non invasive nocturne améliorait la vigilance diurne objective (Chouri-Pontarollo et coll, Chest 2007). Nous menons actuellement la première étude randomisée du traitement des patients porteurs d'un SOH par VNI versus observation pendant un mois. L'analyse intermédiaire montrait qu'un mois de VNI nocturne chez les patients SOH améliorait la PaCO2 diurne, la capacité pulmonaire totale, la structure du sommeil, cependant aucun paramètre cardiovasculaire et métabolique n'était modifié.
Chez des patients insuffisants respiratoires chroniques pariéto-restrictifs, la VNI utilisée au cours d'un exercice aigu, augmentait la ventilation et améliorait la tolérance à l'effort (Borel et coll, Resp Med 2008). Chez ces mêmes patients, un réentrainement à l'effort sous VNI n'apportait pas de bénéfices additionnels par rapport à un réentrainement en ventilation spontanée sauf chez les patients les plus sévères. Ces derniers, amélioraient leur périmètre de marche et leur qualité de vie. Leur fatigue en particulier était améliorée s'ils s'étaient réentraînés sous VNI (Borel et coll, Am Journal of physical med and rehab, 2008, soumis).
Enfin, nous avons analysé l'impact des fuites intentionnelles des masques de VNI sur la performance des appareils de VNI bi-pressionnels. L'augmentation des fuites intentionnelles diminuait les capacités des appareils à atteindre et maintenir la pression de consigne. Ceci pouvait conduire à une diminution du volume délivré au patient, en particulier pour des fuites intentionnelles supérieures à 40 L.min-1 à 14 cm H2O de pression (Borel et al, Chest, sous presse).
Conclusion : L'hypoventilation alvéolaire chronique peut-être considéré comme un déterminant physiopathologique de la dysfonction endothéliale, de l'inflammation, de la somnolence, et de l'intolérance à l'effort. La VNI, utilisée au cours des efforts, permet d'améliorer les capacités d'exercice et la qualité de vie des patients insuffisants respiratoires restrictifs les plus sévères. Malgré les limites technologiques des appareils de VNI bi-pressionnels utilisés actuellement, la VNI corrige l'hypoventilation alvéolaire des patients SOH, cependant les effets sur l'inflammation, la dysfonction endothéliale restent incertains à cours et long terme chez ces sujets obèses.