Mechanisms of the noxious inflammatory cycle in cystic fibrosis.
Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-kappaB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRDeltaF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-kappaB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes leading to the intrinsic inflammatory response in cystic fibrosis.
Rottner
Mathilde
M
1INSERM U 770; Université Paris-Sud 11, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. mathilde.rottner@hemato-ulp.u-strasbg.fr
Freyssinet
Jean-Marie
JM
Martínez
M Carmen
MC
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D002518:Ceramides; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009569:Nitric Oxide; D005978:Glutathione; D002118:Calcium