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

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 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 sexdependent manner. electronic cigarette aerosol and inhaled nicotine effects on periodontal and pulmonary tissues. Oral Dis 2017, 23:1052-1057. 3. Kaur G, Muthumalage T, Rahman I: Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and nontobacco products. Toxicol Lett 2018, 288:143-155.4.

COVID-19 and Smoking: What Evidence Needs Our Attention?

“…When people smoke, nicotine induces overexpression of the ACE2 receptor in pulmonary epithelial cells (e.g., bronchial epithelial cells, type II alveolar epithelial cells.) through nAChRα7 (Biron et al, 1969;Wang Q. et al, 2020), and studies have confirmed that smokers (including e-cigarettes) have higher serum levels of ACE-2 in Figure 2 (Brake et al, 2020). In healthy human volunteers, serum ACE activity increased significantly immediately after smoking and returned to control levels 20 min after smoking cessation (Kitamura, 1987).…”

“…Buscetta et al (2020) found that cigarette smoke extract could increase the activity of caspase-1 through an NLRP3-independent and TLR4-TRIFcaspase-8-dependent pathway, leading to a decrease in basic glycolytic flux and response to lipopolysaccharide, which may eventually lead to macrophage dysfunction and increase the risk of infection in smokers. Simultaneously, in the context of subchronic electronic cigarette exposure, the body increases the release of pro-inflammatory factors and ACE2 receptors by regulating nAChRα7, leading to an inflammatory response and dysregulated repair (Wang Q. et al, 2020). The De Cunto team (De Cunto et al, 2016) showed that, under chronic smoking conditions, the expression of some pro-inflammatory cytokines was upregulated (e.g., Il-6, TNF-α, KC).…”

The Role of Smoking and Nicotine in the Transmission and Pathogenesis of COVID-19

“…The ratio of AT 1 R to AT 2 R increased five to six fold in bronchiole areas with enhanced fibrosis, which were associated with diminished lung function in COPD patients (Bullock et al, 2001). A recent study also showed that sub-chronic e-Cig exposure enhances lung inflammation and ACE2 expression which were shown to be mediated by α7 nAChRs (Wang et al, 2020c disorders in association with COVID-19 infection (Maremanda et al, 2020). These results indicate that smokers and/or vapers may have an increased risk of COVID-19 related complications which can aggravate disease severity and treatment outcome.…”

“…nAChRs (Wang et al, 2020c). Further studies are definitely warranted to determine the effects of nicotine on inflammation.…”

Nicotine Changes Airway Epithelial Phenotype and May Increase the SARS-COV2 Infection Severity

“…Interestingly, a recent population-study, that surveyed 4351 adolescents and young adults aged 13-24 years, highlighted that the effects of vaping may collide with the risk of COVID-19, thus users are at a five--seven-times increased risk of a COVID-19 diagnosis, compared with non-users (data adjusted for major confounders, such as age, sex, and obesity [63]. It has been recently 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 (nAChR α7) [64]. On the other hand, Changeux et al [65] advanced the hypothesis that SARS-CoV-2 may enter the body through neurons of the olfactory system and/or through the lung, and no through ACE2.…”