Proteases, cystic fibrosis and the epithelial sodium channel (ENaC)

Abstract

Proteases perform a diverse array of biological functions. From simple peptide digestion for nutrient absorption to complex signaling cascades, proteases are found in organisms from prokaryotes to humans. In the human airway, proteases are associated with the regulation of the airway surface liquid layer, tissue remodeling, host defense and pathogenic infection and inflammation. A number of proteases are released in the airways under both physiological and pathophysiological states by both the host and invading pathogens. In airway diseases such as cystic fibrosis, proteases have been shown to be associated with increased morbidity and airway disease progression. In this review, we focus on the regulation of proteases and discuss specifically those proteases found in human airways. Attention then shifts to the epithelial sodium channel (ENaC), which is regulated by proteolytic cleavage and that is considered to be an important component of cystic fibrosis disease. Finally, we discuss bacterial proteases, in particular, those of the most prevalent bacterial pathogen found in cystic fibrosis, Pseudomonas aeruginosa.

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

“…#P Ͻ 0.05 vs. complete 5% HDE. 12,23,30,38). In light of the identification of protease activity in a variety of environmental allergens and irritants, it is not surprising that CAFO dust extract was found to contain potentially harmful proteolytic activity as well.…”

Targeting ion channels in cystic fibrosis

“…These studies led to the hypothesis that CFTR has a dual function as anion channel and regulator of ENaC, and provided an explanation how normal airway cells can switch from ENaC-mediated absorption to CFTR-mediated secretion, and why ENaC is hyperactive in CF [9,97]. More recently, it was found that neutrophil elastase (NE), a major neutrophil product, other proteases released from inflammatory cells, as well as bacteria in CF airways, can activate ENaC directly by proteolytic cleavage independent of mutant CFTR [98][99][100][101][102][103].…”

Automated acquisition and analysis of airway surface liquid height by confocal microscopy

“…ASL hydration is controlled by the transepithelial movement of ions and water (5,6,17,36). At the apical membrane of airway epithelia, anions are mostly secreted by CFTR and Na ϩ is absorbed by the epithelial sodium channel (ENaC) (5,17,23,33,36). In the case of cystic fibrosis (CF), where CFTR is mutated and has disrupted or diminished function, the balance between anion secretion and Na ϩ absorption is altered (5,6,17,23,36,38).…”