E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has conducted to understand the mechanism of toxicological and pulmonary effects of e-cigs. We hypothesized that sub-chronic exposure of e-cigs induced inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial-cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs were collected for determination of inflammatory responses and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the lung influx of macrophages and T-lymphocytes, and the levels of pro-inflammatory cytokines, while nAChR α7 knockdown blocked the inflammatory responses. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9, in both sex mice were altered at both protein and gene levels when WT mice were exposed to PG alone in a sex-dependent manner. Moreover, MMP12 increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7 dependent manner. Additionally, the abundance of ECM proteins, such as collagen and fibronectin, was significantly altered after sub-chronic e-cig exposure with or without nicotine in a sex-dependent manner, but nAChR α7 independent manner. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sex-dependent manner.