Chris Masterjohn Opposes RP's View On ACE2/COVID-19

yoshiesque

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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A new study (as with virtually all circulating information on COVID-19, not yet peer-reviewed), shows that ACE2 can easily explain why smoking is correlated with worse outcomes in COVID-19.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:

  • 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.
The amount of ACE2 on the cell surface will determine the number of viruses that can get into cells, and thus the rate at which the infection progresses, especially before the immune system starts to get it under control. Since viral load is a major determinant of the illness, more ACE2 will generally mean a more severe disease. In mice that have been genetically engineered to express the human form of ACE2 and are then infected with SARS-CoV, closely related to SARS-CoV-2 and the cause of SARS, the more ACE2 they make, the worse the progression of their disease, and the faster they die.

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
 
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Dr Peat says take losartan. I am and it is s miracle. It works in a few hours and my chest doesn’t hurt.

I think Chris is wrong. Increasing ACE2 protects the lungs and small intestine against fibrosis and the effects can be felt in a few hours after taking it.
 

RealNeat

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I also get Chris's emails. They seem ok, but I get a whiff of panic in his behavior and writing. I think this may be blurring his judgment and giving him tunnel vision. I agree with Rays view of the organism more than Chris, however similar they may be plus Ray has always talked about the RAAS, Chris not so much.
 
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Angiotensin-converting enzyme 2 in lung diseases - ScienceDirect

Our group has investigated the role of ACE2 in ARDS by using ace2 knockout mice. In acid-aspiration-induced ARDS, endotoxin-induced ARDS and peritoneal sepsis-induced ARDS, ace2knockout mice exhibited severe disease compared with control mice that express ACE2 [26••]. Loss of ACE2 expression in mutant mice resulted in enhanced vascular permeability, increased lung edema, neutrophil accumulation and worsened lung function. Importantly, treatment with catalytically active, but not enzymatically inactive, recombinant ACE2 protein improved the symptoms of acute lung injury in wild-type mice, as well as in ace2knockout mice [26••]. Thus, ACE2 plays a protective role in acute lung injury.
 

Beastmode

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Dr Peat says take losartan. I am and it is s miracle. It works in a few hours and my chest doesn’t hurt.

I think Chris is wrong. Increasing ACE2 protects the lungs and small intestine against fibrosis and the effects can be felt in a few hours after taking it.

That's great that it's helped you. Nice to get a confirmation from someone in this forum.

Peat definitely has it on hand, but he didn't mention whether he was actually taking it.
 
J

jb116

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Dr Peat says take losartan. I am and it is s miracle. It works in a few hours and my chest doesn’t hurt.

I think Chris is wrong. Increasing ACE2 protects the lungs and small intestine against fibrosis and the effects can be felt in a few hours after taking it.
Happy to hear it :happy:
 

Elie

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Angiotensin-converting enzyme 2 in lung diseases - ScienceDirect

Our group has investigated the role of ACE2 in ARDS by using ace2 knockout mice. In acid-aspiration-induced ARDS, endotoxin-induced ARDS and peritoneal sepsis-induced ARDS, ace2knockout mice exhibited severe disease compared with control mice that express ACE2 [26••]. Loss of ACE2 expression in mutant mice resulted in enhanced vascular permeability, increased lung edema, neutrophil accumulation and worsened lung function. Importantly, treatment with catalytically active, but not enzymatically inactive, recombinant ACE2 protein improved the symptoms of acute lung injury in wild-type mice, as well as in ace2knockout mice [26••]. Thus, ACE2 plays a protective role in acute lung injury.

ACE2 protects against inflammation, but I think Chris's argument is that the SARS cov-2 virus (covid 19) uses ACE2 to infect cells and that's why ge suggests to keep ACE2 low.
Yet Ray recommends losaratan (to lower inflammation). So what am i missing?
 

yerrag

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ACE2 protects against inflammation, but I think Chris's argument is that the SARS cov-2 virus (covid 19) uses ACE2 to infect cells and that's why ge suggests to keep ACE2 low.
Yet Ray recommends losaratan (to lower inflammation). So what am i missing?

I've understood that losartan is an ARB - an ACE2 Receptor Blocker. If it blocks the receptor, doesn't it keep the virus from entering the cell because it's piggy-backed on ACE2, and since its (ACE2) receptor is blocked, then ACE2 (and the virus) can't get into the cell?

With this reasoning, does it matter much if ACE2 is increased or not, as far as infecting the cell is concerned, as long as an ARB is used?
 
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When I was really laid low, I felt much better after taking losartan. It really eased my breathing.
 

Zpol

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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:

  • 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.
The amount of ACE2 on the cell surface will determine the number of viruses that can get into cells, and thus the rate at which the infection progresses, especially before the immune system starts to get it under control. Since viral load is a major determinant of the illness, more ACE2 will generally mean a more severe disease. In mice that have been genetically engineered to express the human form of ACE2 and are then infected with SARS-CoV, closely related to SARS-CoV-2 and the cause of SARS, the more ACE2 they make, the worse the progression of their disease, and the faster they die.

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

Thanks, I just signed up. I do appreciate alternate perspectives.
I wonder what Chris has to say about kids having naturally higher ACE2 but seemingly less likely to become infected and typically have mild cases if they do.
 

Elie

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I've understood that losartan is an ARB - an ACE2 Receptor Blocker. If it blocks the receptor, doesn't it keep the virus from entering the cell because it's piggy-backed on ACE2, and since its (ACE2) receptor is blocked, then ACE2 (and the virus) can't get into the cell?

With this reasoning, does it matter much if ACE2 is increased or not, as far as infecting the cell is concerned, as long as an ARB is used?

Yes, this sounds right for losartan. However, having listened to his recent interview on Jodelle's podcast I am under the impression that he suggested that restoring and increasing the ACE2 system with other measures (B1, vitamin D, aspirin) is also helpful. So this is still at odds with Msterjhon's explanations.
 

Elie

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I've understood that losartan is an ARB - an ACE2 Receptor Blocker. If it blocks the receptor, doesn't it keep the virus from entering the cell because it's piggy-backed on ACE2, and since its (ACE2) receptor is blocked, then ACE2 (and the virus) can't get into the cell?

With this reasoning, does it matter much if ACE2 is increased or not, as far as infecting the cell is concerned, as long as an ARB is used?

Oh, and for clarity Losartan is a an angiotensin 2 receptor blocker, not an angiotensin converting enzyme 2 blocker. so it seems it doesn't do anything for the enzyme ACE2. it blocks the hypertensive / inflammatory activity of angiotensin 2, so it might actually result in decreased production of ACE2, since the prganism doesn't need more ACE2 anymore as the problem has been dealt with upstream.
 
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Dr Peat says Losartan increases ACE2. Works within a few hours. Other things eg progesterone work too but not fast enough.
 

Elie

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Dr Peat says Losartan increases ACE2. Works within a few hours. Other things eg progesterone work too but not fast enough.
So that would mean that Masterjon's concern is just theoretical but in practice it is the opposite, increasing ACE2 is desired...
 

Hugh Johnson

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Smoking causes systematic damage to health, and especially to the lungs. Would we respect the view that smoking would be harmless if you just take an ACE2 inhibitor? No, it's a ridiculous statement. Smokers are more vulnerable to pathogens attacking lungs because they abuse their lungs daily, and how ACE2 or whatever factors into this is irrelevant. It's just one of countless factors, and we can not definitely show it is relevant here. The general principle of lungs being damaged by smoke explains this way better.
 
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So that would mean that Masterjon's concern is just theoretical but in practice it is the opposite, increasing ACE2 is desired...

Yes that’s what Dr. Peat says. It is apparently the exact opposite of Masterjohn. Some investigation on my part has shown that Dr. Peat has good reason for his opinion and it has a lot to do with complex metabolic chains that are really beyond me.
 
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Smoking causes systematic damage to health, and especially to the lungs. Would we respect the view that smoking would be harmless if you just take an ACE2 inhibitor? No, it's a ridiculous statement. Smokers are more vulnerable to pathogens attacking lungs because they abuse their lungs daily, and how ACE2 or whatever factors into this is irrelevant. It's just one of countless factors, and we can not definitely show it is relevant here. The general principle of lungs being damaged by smoke explains this way better.

I think ACE inhibitors are very inflammatory, probably via bradykinin increase. Not sure what your comment has to do with the subject, though. We’re talking a about ACE receptor blockers, ARBs, which Dr. Peat claims are helpful in event of infection, not ACE inhibitors for which no claim has been made.
 

SB4

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Dr Peat says Losartan increases ACE2. Works within a few hours. Other things eg progesterone work too but not fast enough.
Does peat mean that ACE2 is more effective thanks to the angiotensin receptor blockage or that ACE2 levels actually do increase? Does anyone have the quote?
 

Hugh Johnson

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I think ACE inhibitors are very inflammatory, probably via bradykinin increase. Not sure what your comment has to do with the subject, though. We’re talking a about ACE receptor blockers, ARBs, which Dr. Peat claims are helpful in event of infection, not ACE inhibitors for which no claim has been made.
Masterjohn makes the assumption that one factor explains the increased trouble from infection. That is not a reasonable assumption.
 

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