yoshiesque
Member
- Joined
- Mar 9, 2014
- Messages
- 367
Firstly, I encourage you to sign up to his email list. Ray has in the past commented that he is a good researcher, but as time goes by I am not 100% certain. Anyway here is his latest email:
ACE2 Explains Why Smoking Leads to Worse COVID-19 Outcomes [COVID-19 Updates]
A new study (as with virtually all circulating information on COVID-19, not yet peer-reviewed), shows that ACE2 can easily explain why smoking is correlated with worse outcomes in COVID-19.
Background
ACE2 is an enzyme whose normal role in our physiology is to lower our blood pressure, and to prevent damage to tissues from fibrosis (laying down of scar tissue) and excess proliferation (cells reproducing at too high a rate, as occurs in tumors, for example).
SARS-CoV-2, the coronavirus that causes COVID-19, hijacks ACE2 on the cell surface in order to gain entry into the cell. All viruses must enter the cells of their host in order to hijack their protein-producing machinery, which they must do in order to replicate. No cell entry, no infection.
Since ACE2 is the entryway for SARS-CoV-2, it is the overwhelming determinant of infection, after exposure. As discussed in the new paper, this is supported by several lines of evidence:
This is true despite the fact that ACE2 is protective of lung tissue, and that SARS causes damage by binding up the ACE2 and preventing it from doing its job. Even though the loss of ACE2 plays a role in disease, it is the expression of ACE2 that allows the viral progression to become severe in the first place.
Smoking is a Risk Factor for Severe COVID-19 Outcomes
In COVID-19, one of the risk factors for disease severity is cigarette smoking. In a a cohort of 1099 cases of COVID-19, only 4.7% of non-smokers had progression to severe disease, such as ICU, ventilation, or death. In smokers, this rate was 12.3%.
In the current paper, the researchers found cigarette smoking to be a major determinant of ACE2 expression in the lung.
Smokings Have More ACE2 in Their Lungs
In three different cohorts, ACE2 expression was 50-60% higher in current smokers than non-smokers. Former smokers had similar levels of ACE2 as non-smokers, suggesting that quitting smoking is a good way to decrease ACE2 expression in the lung.
How much people had smoked for how long was also a major determinant of ACE2. This can be measured in pack-years, where the number of packs are multiplied by the number of years smoking. For example, smoking 1 packs a day for 20 years is 20 pack years. A smoking history of >80 pack years led to double the ACE2 compared to a history of <20 pack years.
Smoking Increases ACE2 by Increasing the Proportion of Mucus Cells
Then they looked at specific cell types.
ACE2 is mainly expressed in goblet cells, which secrete mucus, and club cells, which engulf toxins and break them down. Within individual cells of those two subtypes, they looked at the expression of other enzymes. The cells that made the most ACE2 were the cells that also made the most enzymes involved in antioxidant defense and detoxification.
Then they looked at how those subtypes differed in smokers and non-smokers. In epithelial cells of the bronchus (epithelial cells form the surface lining of tissues), 47% of cells in smokers were goblets, while only 17% of cells in non-smokers were goblets. In other words, smoking increases the proportion of mucus-producing, ACE2-expressing goblet cells by 2.8-fold.
Isolated lung epithelial cells can be put at the interface between air and a liquid, and this will make them turn into mucus-producing and cilia-producing cells. (Cilia are little hairlike projections that help brush along mucus and debris.) This is called mucociliary differentiation. Mucociliary differentiation increased ACE2 3-fold.
Exposing the cells to smoke increased ACE2 by 42%.
Conclusions
Altogether this shows that smoking increases mucus-producing cells as a means of protecting the airway from the smoke. ACE2, which is a protective enzyme under ordinary circumstances, increases as a result. Since it is the entryway of SARS-CoV-2 into cells, the higher ACE2 allows a greater rate of viral entry and thus a higher viral load, and thus a worse disease course.
Granted, chronic smoking is also associated with emphysema, atherosclerosis, and decreased immune function, and these may also play roles in COVID-19 severity. However, the ACE2 story offers a very clean explanation for why smoking predisposes to poor outcomes with this specific virus.
This suggests that quitting smoking will be protective, and it adds to the evidence that controlling ACE2 levels should be a primary strategy in prevention and early treatment.
Stay safe,
Chris
ACE2 Explains Why Smoking Leads to Worse COVID-19 Outcomes [COVID-19 Updates]
A new study (as with virtually all circulating information on COVID-19, not yet peer-reviewed), shows that ACE2 can easily explain why smoking is correlated with worse outcomes in COVID-19.
Background
ACE2 is an enzyme whose normal role in our physiology is to lower our blood pressure, and to prevent damage to tissues from fibrosis (laying down of scar tissue) and excess proliferation (cells reproducing at too high a rate, as occurs in tumors, for example).
SARS-CoV-2, the coronavirus that causes COVID-19, hijacks ACE2 on the cell surface in order to gain entry into the cell. All viruses must enter the cells of their host in order to hijack their protein-producing machinery, which they must do in order to replicate. No cell entry, no infection.
Since ACE2 is the entryway for SARS-CoV-2, it is the overwhelming determinant of infection, after exposure. As discussed in the new paper, this is supported by several lines of evidence:
- Blocking ACE2 with specific antibodies prevents SARS-CoV from infecting a cell.
- Cells that do not express ACE2 cannot be infected. However, experimentally inserting ACE2 into these cells allows them to be infected.
This is true despite the fact that ACE2 is protective of lung tissue, and that SARS causes damage by binding up the ACE2 and preventing it from doing its job. Even though the loss of ACE2 plays a role in disease, it is the expression of ACE2 that allows the viral progression to become severe in the first place.
Smoking is a Risk Factor for Severe COVID-19 Outcomes
In COVID-19, one of the risk factors for disease severity is cigarette smoking. In a a cohort of 1099 cases of COVID-19, only 4.7% of non-smokers had progression to severe disease, such as ICU, ventilation, or death. In smokers, this rate was 12.3%.
In the current paper, the researchers found cigarette smoking to be a major determinant of ACE2 expression in the lung.
Smokings Have More ACE2 in Their Lungs
In three different cohorts, ACE2 expression was 50-60% higher in current smokers than non-smokers. Former smokers had similar levels of ACE2 as non-smokers, suggesting that quitting smoking is a good way to decrease ACE2 expression in the lung.
How much people had smoked for how long was also a major determinant of ACE2. This can be measured in pack-years, where the number of packs are multiplied by the number of years smoking. For example, smoking 1 packs a day for 20 years is 20 pack years. A smoking history of >80 pack years led to double the ACE2 compared to a history of <20 pack years.
Smoking Increases ACE2 by Increasing the Proportion of Mucus Cells
Then they looked at specific cell types.
ACE2 is mainly expressed in goblet cells, which secrete mucus, and club cells, which engulf toxins and break them down. Within individual cells of those two subtypes, they looked at the expression of other enzymes. The cells that made the most ACE2 were the cells that also made the most enzymes involved in antioxidant defense and detoxification.
Then they looked at how those subtypes differed in smokers and non-smokers. In epithelial cells of the bronchus (epithelial cells form the surface lining of tissues), 47% of cells in smokers were goblets, while only 17% of cells in non-smokers were goblets. In other words, smoking increases the proportion of mucus-producing, ACE2-expressing goblet cells by 2.8-fold.
Isolated lung epithelial cells can be put at the interface between air and a liquid, and this will make them turn into mucus-producing and cilia-producing cells. (Cilia are little hairlike projections that help brush along mucus and debris.) This is called mucociliary differentiation. Mucociliary differentiation increased ACE2 3-fold.
Exposing the cells to smoke increased ACE2 by 42%.
Conclusions
Altogether this shows that smoking increases mucus-producing cells as a means of protecting the airway from the smoke. ACE2, which is a protective enzyme under ordinary circumstances, increases as a result. Since it is the entryway of SARS-CoV-2 into cells, the higher ACE2 allows a greater rate of viral entry and thus a higher viral load, and thus a worse disease course.
Granted, chronic smoking is also associated with emphysema, atherosclerosis, and decreased immune function, and these may also play roles in COVID-19 severity. However, the ACE2 story offers a very clean explanation for why smoking predisposes to poor outcomes with this specific virus.
This suggests that quitting smoking will be protective, and it adds to the evidence that controlling ACE2 levels should be a primary strategy in prevention and early treatment.
Stay safe,
Chris