Chronic Airway Infection/Inflammation Induces a Ca2+-dependent Hyperinflammatory Response in Human Cystic Fibrosis Airway Epithelia

The lactoperoxidase system links anion transport to host defense in cystic fibrosis

“…If the measured difference in apical SCN À between CF and non-CF airway epithelial cells is reflected in vivo, it is likely to be functionally significant since OSCN À production by LPO at the relevant SCN À concentrations are significantly different [33] and bacterial growth in vitro is inversely proportional to the [OSCN À ] [34]. Although certain changes in CF epithelial phenotype in culture have been noted by others, these changes were seen in primary cultures and disappeared after 6-11 days in culture [35]. Our re-differentiated cultures (passaged once) have been in culture for much longer and are not expected to exhibit these changes noted in primary cultures.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Somewhat surprisingly, these studies indicate that the defects do not intrinsically drive increased ER stress or UPR activation. Whilst ER expansion and increased ER Ca 2+ storage and signalling can be demonstrated in CF epithelial cells in short‐term cultures, these revert to normal in long‐term, nonstimulated cultures 9, 47. However, in another study, overexpression of F508del‐CFTR was reported to increase XBP1 splicing, suggesting that the mutant protein can increase ER stress 7.…”

“…Prolonged ER stress can eventually lead to inflammatory signalling and premature apoptosis through several different mechanisms 6. The UPR has been linked to the pathogenesis of diabetes, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and many respiratory conditions including cystic fibrosis (CF),7, 8, 9, 10 chronic obstructive pulmonary disease (COPD),11 asthma,12 idiopathic pulmonary fibrosis (IPF)13, 14 and infection 15, 16, 17…”

Small Airways in Asthma: Distal is Different

“…It has previously been demonstrated that excessive production of mucins leads to stress responses in the ER, the so called unfolded protein response (UPR) [28,51], and that this is necessary to maintain proper folding of mucins and therefore the secretory capacity of goblet cells (Figure 1) [52][53][54]. Excess ER stress can further increase inflammation by activation of nuclear factor kappa B (NFκB) and CAAT-enhancer-binding protein homologous protein (CHOP) and can even induce apoptosis.…”

“…Expression of Foxp1 in the murine lung acts as suppressor of GCM by repression of Agr2 [64,65]. Overwhelming ER stress caused by inappropriate regulation of mucus processing eventually leads to the induction of the stress proteins BiP and CAATenhancer-binding protein homologous protein (CHOP) [54]. Here we aimed to further extend our work on the role of distal airways in asthma and hypothesized that diminished mucus production in distal airways is not only caused by attenuated IL-13Rα1 expression and signaling but also by an inappropriate capability to process excessive amounts if mucins.…”