The emerging potential of autophagy-based therapies in the treatment of cystic fibrosis lung infections

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a channel that normally transports anions across epithelial cell membranes. The most common manifestation of CF is buildup of mucus in the airways and bacterial colonization of the lower respiratory tract, accompanied by chronic inflammation. Antibiotics are used to control CF-associated opportunistic infections, but lengthy antibiotic treatment risks the emergence of multiple-drug resistant (MDR) strains. New antimicrobial strategies are needed to prevent and treat infections in these high-risk individuals. Autophagy contributes to the control of a variety of microbial infections. For this reason, the recent discovery of functional impairment of autophagy in CF provides a new basis for understanding susceptibility to severe infections. Here, we review the role of autophagy in host defense against CF-associated bacterial and fungal pathogens, and survey pharmacologic approaches to restore normal autophagy function in these individuals. Autophagy restoration therapy may improve pathogen clearance and mitigate lung inflammation in CF airways.

Autophagy mediates oral submucous fibrosis

“…Autophagy is crucially involved in collagen release in OSF (28). In the present study, CQ inhibits the release of collagen in fibroblasts, indicating that the inhibition of autophagy may be effective in acute and chronic fibrotic diseases.…”

Elevated Mirc1/Mir17-92 cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages

“…15 Our data support the notion that the pathobiology of CF is multi-factorial, including functional impairment of autophagy in macrophages, as indicated by increased susceptibility to specific bacterial infections and inflammation. 39 Macrophages expressing mutant F508del-CFTR on both alleles inherently exert reduced autophagy activity, which is associated with exacerbated inflammatory responses. 10,11,19,40 In this regard, autophagy controls bacterial infection and IL-1b production in macrophages.…”

“…Therefore, alternative approaches to improve autophagy in CF are needed. 39,49 Despite the rapidly growing literature describing defective autophagy in CF, the underlying mechanisms remain to be fully elucidated. To characterize the impaired autophagy activity and inherently reduced expression of autophagy proteins observed in CF macrophages, we examined the expression of several Mirs predicted to target autophagy.…”

“…48,51 Improved autophagy activity may be a result of the release of sequestered essential autophagy proteins, such as ATG7, from SQSTM1/p62 collections within F508del aggregates. 10,18,19,[39][40][41] The disassembly of these aggregates would allow for the autophagy molecules to traffic and localize to the phagophore membrane, and also permit folded F508del-CFTR protein to reach the plasma membrane and facilitate chloride transport. This mechanism was suggested by the Luciani group and ours.…”

“…This mechanism was suggested by the Luciani group and ours. 10,19,39 Another potential regulatory element of autophagy is the existence of 2 paralogs of the cluster, Mir106a-363 and Mir106b-25. Each paralog shares high sequence similarity with one another and intersects the predicted targets.…”