E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR α7 receptor: role of nAChR α7 in SARS-CoV-2 Covid-19 ACE2 receptor regulation

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 proinflammatory 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.

Tobacco, but not nicotine and flavor-less electronic cigarettes, induces ACE2 and immune dysregulation

“…However, e-cig use in any case did not increase ACE2 expression, which has not been reported in the literature. One recent study exposing mice to nicotine-containing e-cig for 1 month has found induction of ACE2 after exposure to nicotine-containing e-cig [51]. In our dataset, humans were also exposed to nicotine-containing e-cig for at least 1 month, suggesting that the in vivo results may not replicate physiological exposure.…”

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

“…NAC may also block COVID-19 binding by disrupting disulfide bind within its receptor-binding domain [ 29 ]. In addition to epithelial, endothelial, and myocardial cells [ 30 , 31 ], ACE2 is expressed on T lymphocytes [ 32 ], macrophages [ 33 ], and hepatocytes [ [34] , [35] , [36] , [37] ]. ACE2 controls the expression of pro-inflammatory transcription factor Stat3 [ [38] , [39] , [40] , [41] , [42] , [43] ], which also modulates the production of reactive oxygen intermediates by complex I of the mitochondrial electron transport chain (ETC) [ 44 ].…”

Tobacco, but Not Nicotine and Flavor-Less Electronic Cigarettes, Induces ACE2 and Immune Dysregulation

“…However, e-cig use in any case did not increase ACE2 or TMPRSS2 expression, which has not been reported in the literature. One recent study exposing mice to nicotine-containing e-cigs for 1 month has found induction of ACE2 after exposure to nicotine-containing e-cigs [ 53 ]. In our dataset, humans were also exposed to nicotine-containing e-cigs for at least 1 month, suggesting that the in vivo results may not replicate physiological exposure.…”