Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression

• Published in: Scientific reports 2023-05, Vol.13 (1), p.7894-7894, Article 7894
• Main Authors: Kuo, Chin-Wei, Su, Po-Lan, Huang, Tang-Hsiu, Lin, Chien-Chung, Chen, Chian-Wei, Tsai, Jeng-Shiuan, Liao, Xin-Min, Chan, Tzu-Yi, Shieh, Chi-Chang
• Format: Article
• Language: English
• Subjects: 631/250/2504; 631/250/255; 692/699/255; 692/699/255/2514; ACE2; Acetylcysteine; Alveoli; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Animals; Bronchus; Cigarette smoke; Cigarette Smoking; Cigarettes; Coronaviruses; COVID-19; Cytokine storm; Enzymes; Humanities and Social Sciences; Humans; Lavage; Macrophages; Macrophages, Alveolar - metabolism; Mice; multidisciplinary; Multivariate analysis; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - metabolism; Reactive Oxygen Species; SARS-CoV-2 - metabolism; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Smoking
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-34785-6

Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical–regulatory factors for the entrance protein of SARS-CoV-2, angiotensin–converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman’s r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019–1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb –/– mice; however, exogenous ROS increased the ACE2 in Cybb –/– AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS–induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.