MicroRNA‐98 negatively regulates nicotine‐induced nerve growth factor expression in primary mouse lung fibroblasts (870.4)

Abstract

We previously demonstrated that chronic nicotine exposure 1) increases branching morphogenesis resulting in altered airway geometry associated with increased airway hyper‐responsiveness (AHR) in adulthood, and 2) increases Nerve Growth Factor (NGF) expression levels. To explore post‐transcriptional mechanisms of nicotine‐induced NGF expression, we hypothesized that microRNA (miR‐98) negatively regulates nicotine‐induced NGF expression to promote increased airway remodeling and AHR. Using bioinformatics prediction algorithms, we identified the miR‐98/let‐7 family as potential post‐transcriptional regulators of NGF. Of all of the miRNAs examined, only let‐7c, let‐7g, and miR‐98 were significantly decreased in mouse lung fibroblasts treated with nicotine for 72h compared to control conditions. Nicotine increased NGF, fibronectin, and ET‐1 (a known target of miR‐98) levels and reduced HUWE‐1 (host gene of miR‐98) levels, whereas these effects were reversed by miR‐98 overexpression. Overexpression of miR‐98 decreased branching morphogenesis in lung explants harvested from C57BL/6J mice at embryonic day 11.5 compared to control conditions. These findings suggest that miR‐98 may provide a novel therapeutic target for asthmatics exposed to nicotine in cigarette smoke.Grant Funding Source: Supported by AHA‐SDG 13SDG14150004, Atlanta VA1I01BX001910,CDA IK2BX001306,NIH HL074518,DK102167