Heme Oxygenase-1 Prevents Airway Mucus Hypersecretion Induced by Cigarette Smoke in Rodents and Humans

Abstract

We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n ‫؍‬ 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT) n in the HO-1 promoter gene (>33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6% , P ‫؍‬ 0.047). No such results were observed in those who had never smoked (n ‫؍‬ 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS.

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

“…Heme oxygenase 1 has been shown to inhibit IL‐13‐induced‐MUC5AC expression and more recently, this process was shown to be associated with reduced CLCA1 expression in human bronchial epithelial cells (Almolki et al. 2008; Mishina et al. 2015).…”

Global metabolomic profiles reveal differences in oxidative stress and inflammation pathways in smokers and moist snuff consumers

“…In one antioxidant system, an increase in heme degradation by hemeoxygenase (HO-1) to biliverdin and bilirubin is a protective anti-inflammatory response to increased oxidative stress. Exposure to cigarette smoke (or its constituents) is known to increase the expression of HO-1 [34][35][36][37]. Plasma metabolomic profiles showed increased levels of heme, and decreased levels of bilirubin and biliverdin in SMK, relative to NTC, indicating a possible impairment of the heme degradation pathway.…”

Heme Oxygenase-1 Ameliorates Dextran Sulfate Sodium-induced Acute Murine Colitis by Regulating Th17/Treg Cell Balance

“…Studies have demonstrated that hemin, a substrate of HO-1, significantly increases the expression of HO-1 protein as well as its activity and ameliorates inflammation in a variety of animal models (29 -31). The competitive inhibitor Sn-protoporphyrin IX (SnPP) also induces the expression of HO-1 but blocks the enzymatic activity in both animal models and cultured cells, creating an opposite effect (32)(33)(34)(35). Because HO-1 has pleiotropic immunomodulatory effects, there are already numerous illustrations of therapeutic applications of HO-1 in multiple experimental models of IBD mediated by various immune mechanisms (36 -38).…”