HE PATHOPHYSIOLOGY OF NONcystic fibrosis (CF) bronchiectasis is generally considered to be characterized by an airway inflammatory response to bacterial pathogens, and recent data provide further evidence to support this "vicious cycle" hypothesis. 1 However, studies of maintenance therapies designed to interrupt this cycle at differing points have failed to demonstrate convincing evidence of clinical efficacy, including prolonged oral antibiotics, 2 inhaled tobramycin, 3 inhaled corticosteroids, 4 and mucolytics. 5 Until recently, 6 there have arguably been no therapies with proven clinical benefit in non-CF bronchiectasis.Maintenance azithromycin was shown to reduce exacerbations in non-CF bronchiectasis 6 ; however, limitations of that study 7 included a treatment period of only 6 months and a lack of systematic evaluation for macrolide See also pp 1251 and 1295.

Prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. We hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signaling and reducing synthesis/secretion of proteins that form the protective mucus barrier. In cultured intestinal cells non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. A prolonged HFD elevated the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity with a decrease in goblet cell differentiation and Muc2, a loss in the tight junction protein, claudin-1 and increased serum endotoxin levels. In Winnie mice, that develop spontaneous colitis, HFD-feeding increased ER stress, further compromised the mucosal barrier and increased the severity of colitis. In obese mice IL-22 reduced ER/oxidative stress and improved the integrity of the mucosal barrier, and reversed microbial changes associated with obesity with an increase in Akkermansia muciniphila. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free-fatty acids on intestinal cells, and this can be reversed by IL-22 therapy.

Endoplasmic reticulum (ER) stress may be both a trigger and consequence of chronic inflammation. Chronic inflammation is often associated with diseases that arise because of primary misfolding mutations and ER stress. Similarly, ER stress and activation of the unfolded protein response (UPR) is a feature of many chronic inflammatory and autoimmune diseases. In this review, we describe how protein misfolding and the UPR trigger inflammation, how environmental ER stressors affect antigen presenting cells and immune effector cells, and present evidence that inflammatory factors exacerbate protein misfolding and ER stress. Examples from both animal models of disease and human diseases are used to illustrate the complex interactions between ER stress and inflammation, and opportunities for therapeutic targeting are discussed. Finally, recommendations are made for future research with respect to the interaction of ER stress and inflammation.