Increased TSLP and oxidative stress reflect airway epithelium injury upon cigarette smoke exposure. Is there a role for carbocysteine?

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory degenerative disease. Disease exacerbations accelerate lung function deterioration. Airway epithelium has a central role in COPD pathophysiology. Airway epithelium releases alarmins including the thymic stromal lymphopoietin (TSLP) in response to exogenous stressors. Notch-1 in the nucleus acts as inhibitor of TSLP gene expression. Here, we investigated, in human bronchial epithelial cells, the effects of cigarette smoke extract (CSE) in TSLP production exploring the relationship with oxidative stress events and with Notch-1 signaling. In CSE exposed 16HBE, the effects of carbocysteine were assessed on: intracellular and extracellular oxidative stress; nuclear Notch-1 expression; TSLP gene expression. The TSLP levels in sera from non-smokers, smokers and exacerbated COPD patients (before and after therapy with carbocysteine) were also explored. CSE induced TSLP gene expression and oxidative stress and reduced nuclear expression of Notch-1 in 16HBE. The use of an electrochemical sensor allowed a reliable tool to assess oxidative stress. TSLP concentrations were higher in sera from smokers and exacerbated COPD than in sera from non-smokers. Carbocysteine was able to counteract the effects of CSE in oxidative stress and in TSLP gene expression in 16HBE and to reduce TSLP in exacerbated COPD. In conclusion, increased oxidative stress induced by smoke exposure in airway epithelium leads to increased TSLP production and carbocysteine in vitro and in vivo mitigates the induced TSLP production. Oxidative stress detection by electrochemical sensors can open new avenues for evaluating epithelial damage and for identifying patients eligible to alarmin targeted biologics.