Discordance in cathepsin B and cystatin C expressions in bronchoalveolar fluids between murine bleomycin-induced fibrosis and human idiopathic fibrosis

International audienceAbstractThe activity of cysteine cathepsin B increased markedly in lung homogenates and in bronchoalveolar lavage fluids (BALF) of the mouse model of bleomycin-induced lung fibrosis after 14 days of challenge. In contrast the level of the cysteine cathepsin inhibitor cystatin C was unaffected in BALF of wild-type and cathepsin B-deficient mice. Therefore, murine cystatin C is not a reliable marker of fibrosis during bleomycin-induced lung fibrosis. Current data are in sharp contrast to previous analysis carried on human BALF from patients with idiopathic pulmonary fibrosis, for which the level of cathepsin B remained unchanged while cystatin C was significantly increased

Comorbidities of COPD

International audienceBy 2020, chronic obstructive pulmonary disease (COPD) will be the third cause of mortality. Extrapulmonary comorbidities influence the prognosis of patients with COPD. Tobacco smoking is a common risk factor for many comorbidities, including coronary heart disease, heart failure and lung cancer. Comorbidities such as pulmonary artery disease and malnutrition are directly caused by COPD, whereas others, such as systemic venous thromboembolism, anxiety, depression, osteoporosis, obesity, metabolic syndrome, diabetes, sleep disturbance and anaemia, have no evident physiopathological relationship with COPD. The common ground between most of these extrapulmonary manifestations is chronic systemic inflammation. All of these diseases potentiate the morbidity of COPD, leading to increased hospitalisations and healthcare costs. They can frequently cause death, independently of respiratory failure. Comorbidities make the management of COPD difficult and need to be evaluated and treated adequately. Extrapulmonary comorbidities are common in COPD and influence prognosis; we propose an exhaustive comorbidities revie

Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis

Membrane-bound proteinase 3 (PR3(m)) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3(m) triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3(m) and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefevre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3(m) expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3(m) on PLS neutrophils, whereas the total amount of PR3(m) on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34(+) hematopoietic stem cell model. Human CD34(+) hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3(m), cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised

Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Patients atteints d'un carcinome broncho-pulmonaire non à petites cellules, avec mutation du récepteur à l'EGF (étude rétrospective sur la plateforme d'Orléans-Tours)

TOURS-BU Médecine (372612103) / SudocSudocFranceF

ALTERATIONS DE LA FONCTION DIAPHRAGMATIQUE LORS DE L'INSUFFISANCE RENALE CHRONIQUE CHEZ LE RAT

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Interaction entre les cellules épithéliales et les fibroblastes dans la réparation alvéolaire (application à la fibrose pulmonaire)

La fibrose pulmonaire idiopathique (FPI) est une maladie associant des lésions de l'épithélium alvéolaire et un retard de réparation. L'hepatocyte growth factor (HGF) et le keratinocyte growth factor (KGF) sont des facteurs de croissance pour l'épithélium qui protègent de la fibrose dans différents modèles animaux. Nous avons comparé in vitro la production d'HGF et de KGF par des fibroblastes pulmonaires provenant de patients atteints de FPI et de témoins. Nos résultats montrent que les fibroblastes de FPI ont 1/ un défaut de production d'HGF lié à un défaut de sécrétion de PGE2 ; 2/ une faible capacité d'activation de l'HGF liée à une faible expression de son activateur l'HGFA et une forte expression de ses inhibiteurs HAI-1 et HAI-2 ; 3/ une faible sécrétion de KGF en réponse à l'IL-1b liée à un défaut d'expression et d'activation de c-Jun et de JNK. L'insuffisance de " bons " médiateurs favorisant la réparation de l'épithélium pourrait intervenir dans la physiopathologie de la FPIIdiopathic pulmonary fibrosis (IPF) is a lung disease associated with alveolar epithelial injury and delayed repair. Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are growth factors for alveolar epithelial cells that protect from pulmonary fibrosis in animal models. We evaluated in vitro the regulation of HGF and KGF production by human lung fibroblasts from patients with IPF and from controls. Our results demonstrate that IPF fibroblasts have 1/ a defect in HGF production linked to a defect in PGE2 secretion, 2/ a reduced capacity to activate pro-HGF through a reduced expression of its activator (HGFA) and an increased expression of its inhibitors HAI-1 and HAI-2, and 3/ a dysregulation of KGF secretion through the weak response to IL-1b associated with a defect of expression and activation of c-Jun and JNK. In conclusion, the failure to generate "good" mediators that promote repair and prevent fibrosis could play a significant role in the pathophysiology of IPFPARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Insuffisance respiratoire aiguë chez le patient porteur d'un cancer broncho-pulmonaire dans un service de pneumologie

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Facteurs pronostiques des pneumopathies sévères à l'amiodarone

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Évaluation de la morbi-mortalité dans les exacerbations aiguës de fibrose pulmonaire idiopathique

TOURS-BU Médecine (372612103) / SudocSudocFranceF