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ACE-2 and Immune System Changes in Smokers May Underlie COVID-19 Vulnerability

Jessica Monterrosa Mena

Clinicians report that people with pre-existing conditions such as cardiac disease, hypertension, and diabetes are at higher risk of mortality from COVID-19. With tobacco smoking being the leading cause of preventable death worldwide, it is surprising that smokers are underrepresented in hospital records1. While hospital record data gives insight into the risk factors that influence COVID-19 outcomes, tobacco studies provide a further understanding of how smoking compromises the immune system. In fact, many human and rodent studies show that smoking increases the expression of angiotensin-converting enzyme 2, also known as the ACE-2 receptor and entry point for the SARS-CoV-2 virus2. Normally, ACE-2 has a protective role in the cardiovascular system by regulating vasoconstriction, inflammation, and tissue damage. These protective functions are inhibited once the SARS-CoV-2 virus binds to ACE-2, and receptors levels then decrease following infection3, thereby allowing disease-causing biochemical processes to develop. ACE-2 levels are also known to vary among individuals, and people with cardiopulmonary diseases and those who take medications that help lower blood pressure also have high expression of the receptor 4. Therefore, human and animal studies focusing on the role of ACE-2 in cardiopulmonary disease and immune defenses provide insight that may be helpful for establishing biomarkers of COVID-19 disease progression and developing medication strategies for susceptible populations

Recent studies provide evidence that both traditional cigarettes and electronic cigarette (eCig) devices alter ACE-2 activity. One study assessed the levels of ACE-2 and transmembrane serine protease-2, which also facilitates viral entry, in peripheral blood mononuclear cell samples of young smokers collected before the pandemic2. These young smokers had elevated levels of ACE-2 compared to non-smokers, and the effects were stronger in traditional cigarette smokers than in eCig users. Interestingly, the plasma cotinine levels (a measure of tobacco smoke exposure) were comparable between cigarette and eCig smokers, suggesting that non-nicotine components of traditional cigarettes may play a significant role in altering the immune system. While the study demonstrates that changes in ACE-2 could potentially increase susceptibility to viral entry and promote COVID-19 complications even among young healthy smokers, this study does not suggest that eCigs can be used as an effective harm-reduction strategy.

Animal models allow researchers to study biological effects in a controlled environment, in which animals are exposed to identical conditions. Studies using rodent models also confirm that the molecular players involved in SARS-CoV-2 infection are modulated by smoking. In one study, mice were exposed to eCigs with and without nicotine for 21 days and developed airway inflammation and immune cell infiltration in the lung5. Interestingly, ACE-2 protein levels were also increased in eCig exposed animals, but the effect was stronger in male mice as compared to female mice. There was also a greater effect as male mice exposed to eCig vapor and co-exposed to nicotine, which suggests that changes in ACE-2 protein are influenced by nicotine in a dose-dependent manner and sex-based differences may also be relevant to infection. While replicating such a study in humans to determine whether smoking directly influences viral entry may not be realistic, rodent studies provide valuable insights into sex-specific effects in animals exposed to controlled levels of toxicants.

While it is well established that smoking can promote immune dysregulation and COVID-19 complications, many questions remain as to  how nicotine dosage, non-nicotine components, and pollutants unique to eCig devices also influence health outcomes. Processes like genetic heterogeneity of human populations and human expression of proteins that promote viral entry may also underlie susceptibility to COVID-19 mortality, which remains an exciting area of research. Scientific efforts across many fields of discipline continue to uncover the relationship between smoking and ACE-2, and novel findings continue to inform developing clinical trials to study the efficacy of medication for COVID-19 among smokers and patients with cardiopulmonary diseases.

References.

  1. Monterrosa Mena, J. Insights About COVID-19 Health Outcomes in Smokers from Hospital Records, https://earlycareervoice.professional.heart.org/insights-about-covid-19-health-outcomes-in-smokers-from-hospital-records/
  2. Kelesidis, T., Zhang, Y., Tran, E., Sosa, G., & Middlekauff, H. R. (2021). Instigators of COVID-19 in Immune Cells Are Increased in Tobacco Cigarette Smokers and Electronic Cigarette Vapers Compared With Nonsmokers. Nicotine & Tobacco Research, ntab168. https://doi.org/10.1093/ntr/ntab168
  3. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267.
  4. Igase, M., Kohara, K., Nagai, T. et al. Increased Expression of Angiotensin Converting Enzyme 2 in Conjunction with Reduction of Neointima by Angiotensin II Type 1 Receptor Blockade. Hypertens Res 31, 553–559 (2008). https://doi.org/10.1291/hypres.31.553
  5. Naidu, V., Zeki, A. A., & Sharma, P. (2021). Sex differences in the induction of angiotensin converting enzyme 2 (ACE-2) in mouse lungs after e-cigarette vapor exposure and its relevance to COVID-19. Journal of Investigative Medicine, 69(5), 954–961. https://doi.org/10.1136/jim-2020-001768

“The views, opinions, and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness, and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions, or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your health matters. If you think you are having a heart attack, stroke, or another emergency, please call 911 immediately.”
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What Does Tobacco 21 Mean for Adolescent Tobacco Use?

William Aitken, MD

We’ve come a long way from the Joe Camel commercials I remember watching as a kid on TV. As a culture, we’ve become a lot less tobacco friendly. Indoor smoking bans, stricter advertising restrictions (meaning no more cartoon characters advertising cigarettes), and other policies have been enacted to curb tobacco use across the country. Despite these changes, teen smoking is still a big problem.

In 2015, the Institute of Medicine reported that raising the legal age for using tobacco products from 18 years to 21 years would significantly decrease, delay, or differ adolescent tobacco use [1]. Just last month Congress decided to test this prediction by passing House Resolution 1865 – Further Consolidated Appropriations Act, 2020 which was subsequently signed into law by President Trump. This spending package includes an amendment to the Federal Food, Drug, and Cosmetic Act, raising the minimum age for purchase of tobacco products to 21 years [2]. This certainly signals a bipartisan effort to curb adolescent tobacco use, but only time will tell the lasting impact of this and other new policies.

Despite laws existing to restrict tobacco sales to adults, there is limited evidence of interventions able to achieve high levels of adherence with these laws [3]. In fact, a majority of smokers endorse first using tobacco products before being of age. While the is ample evidence that exposure to tobacco advertising is related to youth picking up smoking, there are no randomized clinical trials (RCTs) that assess the effectiveness of different advertising restrictions or bans on adolescent tobacco use [4]. What percentage of potential under-age smokers are deterred by age restrictions? What effect would increasing the tobacco tax have on youth sales? What effect could flavor restrictions have on youth smoking? One approach to better understand the health effects of possible tobacco legislation could be to incorporate RCTs into this new law’s implementation.

Last year the Nobel Memorial Prize in Economics was awarded to three researcher who used RCTs to better understand the effects of economic policies on people’s lives [5]. This approach to policy interventions has allowed developmental economists inform legislation aimed at alleviating poverty and its negative externalities. Using these same standards to assess the efficacy of policies aimed at preventing youth tobacco use could have a lasting impact on the health of our nation.

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.

References:

  1. Committee on the Public Health Implications of Raising the Minimum Age for Purchasing Tobacco Products; Board on Population Health and Public Health Practice; Institute of Medicine; Bonnie RJ, Stratton K, Kwan LY, editors. Public Health Implications of Raising the Minimum Age of Legal Access to Tobacco Products. Washington (DC): National Academies Press (US); 2015 Jul. https://www.ncbi.nlm.nih.gov/pubmed/26269869
  2. R.1865 – Further Consolidated Appropriations Act, 2020 (Subtitle E, Section 603: Minimum age of sale of tobacco products) https://www.congress.gov/bill/116th-congress/house-bill/1865/text#toc-H1CB3CAE840AA412285E15A86531C8446
  3. Stead LF, Lancaster T. Interventions for preventing tobacco sales to minors. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD001497. DOI: 10.1002/14651858.CD001497.pub2. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001497.pub2/information
  4. Lovato C, Watts A, Stead LF. Impact of tobacco advertising and promotion on increasing adolescent smoking behaviours. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD003439. DOI: 10.1002/14651858.CD003439.pub2. (Page 1, 12) https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003439.pub2/abstract
  5. The Prize in Economic Sciences 2019. https://www.nobelprize.org/prizes/economic-sciences/2019/press-release/