Abstract
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 been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). 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 lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.
Highlights
E-cigarettes (e-cigs) are often considered as a safer alternative to combustible cigarettes, as well as a method for quitting traditional cigarette smoking [1, 2]
Gene expression levels of CCL9 (Chemokine ligand 9), KLF4 (Kruppel-like factor 4), DUSP1 (Dual Specificity Phosphatase 1), BTLA (B and T Lymphocyte Associated), and SMAD7 (SMAD Family Member 7) were significantly increased only in nAChRα7 KO mice exposed to propylene glycol (PG) with nicotine compared to WT mice (Fig. 4a)
In conclusion, nAChRα7 ablation attenuates the inflammation induced by sub-chronic e-cig exposure, which may be partly due to e-cig induced extracellular matrix (ECM) remodeling/dysregulated repair response in the lung
Summary
E-cigarettes (e-cigs) are often considered as a safer alternative to combustible cigarettes, as well as a method for quitting traditional cigarette smoking [1, 2]. E-liquids are composed of propylene glycol (PG) and/or vegetable glycerin (VG), with varying concentrations of nicotine (up to 100 mg/mL). Previous studies have shown that the amount of nicotine delivered by e-cigs is much higher than the amount delivered via cigarette smoke [6, 7]. We have shown that inflammation and extracellular matrix (ECM) remodeling/dysregulated repair are altered by acute exposure to e-cigs, with or without nicotine [8]. Considering that e-cig vaping is often a long-term habit, research on the chronic effects of e-cig aerosol exposure is essential to understand the mechanism resulting in augmented inflammatory responses and ECM remodeling, which are fundamental changes that occur during early stages of most chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) [9, 10]
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