Differential Effects of α7nAChR Activation in a Murine Model of Asthma

Nicotine, a primary component of tobacco, cigarette smoke and miscellaneous vaping products, can significantly impact respiratory health. Nicotine can exacerbate asthma through its actions on multiple cell types in airways. In this context, airway smooth muscle (ASM) is a key cell type for contractility and remodeling and could be a target of nicotine. We previously showed that ASM expresses functional nicotinic acetylcholine receptors (nAChRs) and that asthmatic ASM have higher α7nAChR expression and function, which could make them more susceptible to deleterious effects of nicotine. We explore this paradigm in the current study by evaluating the effect of short-term vs. chronic nicotine exposure in regulating airway hyperreactivity (AHR) and remodeling in a mixed allergen (MA) model of asthma applied to wildtype (WT) vs. global α7nAChR knockout (Glα7KO) vs. smooth muscle-specific α7nAChR KO (smα7KO) mice. We hypothesized that the detrimental effect of nicotine occurs via α7nAChR in ASM, and that global α7nAChR KO has worsened impact of airway remodeling. Interestingly, we found that smα7KO improved lung function and AHR in MA-challenged alone as well as in the presence of nicotine. In contrast, MA-challenged Glα7KO in the presence of nicotine showed worsened AHR. Lung histology of smα7KO mice showed reduced airway collagen deposition compared to WT and Glα7KO mice. Immunofluorescence analysis showed smα7KO reduced remodeling proteins. These data suggest that in vivo, α7nAChR has complex effects on AHR vs. remodeling with worsening of ASM-mediated AHR or remodeling, but protective effects in non-ASM mediated AHR potentially involving epithelial cells and the immune system.