Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Abstract

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.

Atypical Activation of the Unfolded Protein Response in Cystic Fibrosis Airway Cells Contributes to p38 MAPK-Mediated Innate Immune Responses

“…Nevertheless, the literature contains conflicting results concerning the presence of ER stress in CF and the potential contribution of ER stress to CF inflammatory disease. Several studies report that DF508, the mutation found in 70% of all CF patients, is retained within the ER, leading to upregulation of protein degradation and ER stress markers indicative of unbalanced ER homeostasis (15,42,(48)(49)(50)(51). More specifically, Martino et al (52,53) showed that XBP-1s is overexpressed in CF cells and the inflammatory responses in CF cells were dependent upon the action of this TF.…”

Rescue of Dysfunctional Autophagy Attenuates Hyperinflammatory Responses from Cystic Fibrosis Cells

“…To link these events to inflammation, we propose a model in which ER stress, a known component of CF-associated inflammation (2,14), acts as an intermediary between autophagosome accumulation and the inflammatory responses of CF cells (Fig. 5).…”

“…In the airways, the classic CF phenotype is characterized by the accumulation of thickened mucus and predisposition to bacterial colonization of the lower respiratory tract. Colonization of the CF lung by Pseudomonas aeruginosa and other pathogens induces robust and sustained neutrophil-mediated inflammation that is disproportionately exaggerated relative to the bacterial load (2). Although there is debate over whether inflammation in the CF lung is primary (i.e., caused by CFTR mutations) or secondary to chronic infection (3,4), inflammation remains the single most significant contributor to disease progression, and its control is crucial for improving patient outcomes (5).…”

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

“…The ability of the antioxidant curcumin to rescue DF508-CFTR localization in cell lines (88) suggests that oxidants might be responsible for the cytoplasmic mislocalization of CFTR observed in alcoholic, idiopathic and autoimmune pancreatitis (81). Of interest, the CFTR channel also transports the antioxidants GSH (30,121) and thiocyanate (174).…”

“…Cystic fibrosis, usually due to severe mutation in both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causes an accelerated non-calcific form of chronic pancreatitis that begins in utero: oxidative stress and inflammation are now regarded as integral features of the disease, driven by unfolded CFTR via the ER stress-UPR system (121,177). This is not the position depicted in Figure 1, which instead seeks to understand the increased frequency of CFTR mutation(s), with or without mutation in SPINK1, among patients with idiopathic chronic pancreatitis (97), especially the tropical variant (102).…”