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-κB 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 (CFTRΔF508), 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-κB 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

Mitochondrial Alterations and Oxidative Stress in Cystic Fibrosis

Cystic fibrosis (CF) is the most frequent autosomal recessive disease and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the deletion in the phenylalanine 508 site (ΔF508) of the CFTR gene, the study of its function as chloride channel occupied most investigations. Now, we know that CFTR is also involved in the GSH and HCO3− transport, and its function could regulate the mitochondrial function and ROS production. In this way, the notion of the CFTR as a simple chloride channel has begun to change toward a more complex function as molecular hub that integrates different cellular signals. There is a growing body of evidence that shows mitochondrial dysfunctions and increased oxidative stress in CF. Here, we review the mitochondrial defects induced by the altered function of the CFTR in CF, focusing on oxidative stress and inflammation as targets for therapy.Fil: Valdivieso, Ángel Gabriel. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

Biochemical and molecular genetics of cystic fibrosis

Cystic fibrosis (CF) is the most common severe recessive genetic disorder in the Caucasian population. In 1938, D. H. Anderson provided the first comprehensive description of the disease and also introduced the name “cystic fibrosis of the pancreas.” Patients with CF suffer from excessive mucus accumulation resulting in severe clinical consequences in the respiratory, gastrointestinal, and genitourinary tracts (see Table I). All these symptoms are consistent with defects of exocrine glands, as suggested by S. Farber in 1945; he called the disease “mucoviscidosis,” a name still popular in some parts of continental Europe. CF patients also have elevated electrolyte levels in their sweat, an observation which, first described by di Sant’Agnese et al. (1953), became the hallmark for CF diagnosis.link_to_subscribed_fulltex