md_a
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The Dilemma of COVID-19, Aging, and Cardiovascular Disease
.......
ACE inhibitors, ARB inhibitors, ARDS
Coronavirus is more severe and deadly in the aged, hypertensive, and diabetic.
It is also of note that ATR-1 Receptors increase with age and are increased in cancer, diabetes, hypertension, chronic obstructive pulmonary disease. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children.
As the SARS-COV2 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher Angiotensin II and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19.
Another factor playing a role is that hypoxia causes cells to produce more AT-1. So the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.
If young people have higher ACE2, and that was the factor allowing faster viral inoculation, then it would be worse in the young, but it is not.
Cancer, hypertension, diabetes, chronic obstructive pulmonary disease are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.
ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
ACE2 has been shown to be the entry point into human cells for some coronaviruses, including SARS-CoV, the virus that causes SARS. A number of studies have identified that the entry point is the same for SARS-CoV-2, the virus that causes COVID-19.
This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.
In fact, the interaction of the spike protein of the virus with the ACE2 induces a drop in the levels of ACE2 in cells.
Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disorder that is frequently associated with multiple organ dysfunction leading to high mortality. The mechanisms underlying ARDS are multi-factorial, and are thought to include the renin-angiotensin system (RAS).
The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensin-converting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Angiotensin I into the octapeptide Angiotensin II, while ACE2 cleaves a single residue from Angiotensin II to generate Ang 1-7, which in turn blocksiotensin Angiotensin II and inhibits ACE.
Conversion of Angiotensin I to Angiotensin II can readily occur in the lung by abundant ACE in pulmonary vessels. This may contribute to rapid responses of vasoconstriction in the pulmonary circulation and low blood flow, leading to ventilation/perfusion mismatch in conditions such as tissue hypoxia. On the other hand, ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells and epithelial injury is a critical event in the development of ARDS in humans; thus, the ability to produce ACE2 is severely impaired, resulting in dominant ACE activities during ARDS and/or ventilator-induced lung injury.
Since ACE2 protected the lung from developing ARDS and functioned as a coronavirus receptor for severe acute respiratory syndrome, the recombinant ACE2 (rACE2) protein may have an important place in protecting ARDS patients and as a potential therapeutic approach in the management of emerging lung diseases such as avian influenza A infections.
Bradykinin is an inflammatory mediator. Bradykinin could also contribute to the pathogenesis of ARDS
ACE converts Angiotensin I to Angiotensin II and also inactivates bradykinin.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.
ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Bradykinin contracts airway smooth muscle, is a potent bronchial vasodilator, increases microvascular leakage, stimulates epithelial cells to release bronchodilators and stimulates mucus secretion.
Inhaled bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation, and mucus secretion.
KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.
During inflammation, it is released locally from mast cells and basophils during tissue damage.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.
Inflammation results in the release of mediators that cause vasodilation, increase microvascular permeability, and induce leukocyte infiltration.
Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome.
In ARDS, fluid accumulation in lung interstitium, the alveolar spaces, and the small airways causes the lungs to stiffen, thus impairing ventilation and reducing oxygenation of the pulmonary capillary blood. The resulting injury reduces normal blood flow to the lungs. Damage can occur directly – by aspiration of gastric contents and inhalation of noxious gases – or indirectly – from chemical mediators released in response to systemic disease.
Platelets begin to aggregate and release substances, such as serotonin, bradykinin, and histamine, which attract and activate neutrophils.
These substances inflame and damage the alveolar membrane and later increase capillary permeability.
Increase in vascular permeability:
Due to the action of inflammatory mediators (histamine, serotonin, bradykinin, leukotrienes C4, D4, and T4); Occurs rapidly and does not last long; Results in opening of interendothelial spaces and paracellular leakage of plasma; Endothelial injury; Results in endothelial cell necrosis and detachment; Leakage lasts until the damaged area is thrombosed or repaired.
Effects:
Leads to leakage of plasma content into the interstitial tissue, causing local edema; Allows migration of immune cells and proteins to site of injury or infection.
Mediators released by neutrophils and macrophages also cause varying degrees of pulmonary vasoconstriction, resulting in pulmonary hypertension. The result of the changes is a ventilation-perfusion mismatch. Although the patient responds with an increased respiratory rate, sufficient oxygen can’t cross the alveolar capillary membrane. Carbon dioxide continues to cross easily and is lost with every exhalation. As oxygen and carbon dioxide levels in the blood decrease, the patient develops increasing tachypnea, hypoxemia, and hypocapnia (low partial pressure of arterial carbon dioxide [PaCO2]).
Pulmonary edema worsens, and hyaline membranes form. Inflammation leads to fibrosis, which further impedes gas exchange. Fibrosis progressively obliterates alveoli, respiratory bronchioles, and the interstitium. Functional residual capacity decreases, and shunting becomes more serious. Hypoxemia leads to metabolic acidosis. At this stage, the patient develops increasing PaCO2, decreasing Ph and partial pressure of arterial oxygen (PaO2), decreasing bicarbonate (HCO3-) levels, and mental confusion.
The end result is respiratory failure. Systematically, neutrophils and inflammatory mediators cause generalized endothelial damage and increased capillary permeability throughout the body. Multiple organ dysfunction syndrome (MODS) occurs as the cascade of mediators affects each system. Death may occur from the influence of ARDS and MODS.
…………
Ray Peat: The virus uses ACE2 (angiotensin converting enzyme 2) as receptor and enters cells by the angiotensin receptor. Losartan (recommended in China), an angiotensin blocker, is effective protection, and has many other antiinflammatory effects. The Chinese also have good results with cinanserin, a serotonin blocker. I think cyproheptadine might help, too. Progesterone lowers the angiotensin receptor, but doesn’t act immediately as losartan does.
Ray Peat said:
-Angiotensin excess causes the negative symptoms we associate with the virus - dry cough, fever, high blood pressure, etc.
-Angiotensin excess is caused by ACE2, the enzyme that deactivates Angiotensin, not being available to do its job.
-ACE2 is not available to do it's job because the virus binds to it.
I asked Dr. Ray Peat about protection against the CV, and he said, "I heard from a relative of a confirmed case in Italy, very sick, who took losartan yesterday, and is o.k. today, no fever. Progesterone is another inhibitor of the angiotensin receptor, the entry point of the virus."
Ray Peat: The virus inactivates the enzyme that protects against angiotensin, and one of the effects of angiotensin is to increase shedding of microparticles.
“The virus activates the angiotensin receptor, so the receptor blockers are protective—losartan, telmisartan, etc. Progesterone is a natural inhibitor of that receptor. Also the usual antiinflammatory things, aspirin, eggnog, orange juice would be helpful.” Ray Peat
I asked Peat about serotonin and endotoxin here is what he said:
"Endotoxin commonly increases serotonin and it increases sensitivity to angiotensin. The virus acts through both of those. The Chinese have found that cinanserin, an serotonin antagonist, and losartan, an angiotensin receptor blocker, are protective both before and after virus exposure.
……….
Losartan an angiotensin receptor blocker (ARB), also may lead to protection of lung fibrosis through other molecular mechanisms such as downregulation of TGF-β1.
Losartan and Cinanserin Offers Protection Against Lung Fibrosis
….
Several viral proteins have been reported to modulate TGF-ß1 signaling, which could induce the proliferation of fibroblasts [25]. Pang et al [27] found higher serum concentrations of TGF-ß1 in SARS patients compared to controls for all clinical courses, including initial, peak, remission, and recovery stages [26,27]. During shortterm follow-up, persistent ground glass opacities, reticular opacities, and pathologic fi ndings of fi brosis have been found in some SARS survivors [28,29]. ...
... Willis et al [30] pointed out that TGF-ß1 was necessary but not sufficient to induce the formation of pulmonary fibrosis [30]. In our study, TGF-ß1 levels increased significantly and remained high after treatment in the severe group, coinciding with reports of patients with SARS-CoV infection [23,26]. This phenomenon could well be explained by the existence of imminent pulmonary fibrosis. ...
https://www.researchgate.net/public...dulates_Transforming_Growth_Factor-_Signaling
Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung.
In conclusion, the present study has demonstrated the antifibrotic effect of specific serotonin 5-HT2A and 5-HT2B receptor antagonists in vivo using the animal model of bleomycin-induced lung fibrosis, and the involvement of the transforming growth factor-β1, connective growth factor and plasminogen activator inhibitor-1 pathways. The observations in human samples support the hypothesis that the serotonin pathway might be involved in the pathophysiology of human lung fibrosis.
Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice
Cinanserin is a serotonin antagonists, the benefits of this is from its 5-HT2 antagonism.
The molecule is an inhibitor of the 3C-like protease of SARS-coronavirus (SARS)
Cinanserin - Wikipedia
https://www.nejm.org/doi/full/10.10...9sdkO5Vlgz-AIA3Pm-Uq2xSQAk0Hdgegy7OfJ8wLB160Y
https://www.cambridge.org/core/serv...n_against_coronavirus_induced_lung_damage.pdf
Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. - PubMed - NCBI
Cancer, inflammation and the AT1 and AT2 receptors | Journal of Inflammation | Full Text
https://pubmed.ncbi.nlm.nih.gov/16007097/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229671/
https://en.wikipedia.org/wiki/Angiotensin#Angiotensin_I
https://en.wikipedia.org/wiki/Bradykinin
https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme
https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2
https://bgr.com/2020/03/19/coronavirus-drugs-losartan-blood-pressure-cure/
https://jvi.asm.org/content/79/11/7...QJgk5wO00kzAwCubbMI959jJPxoWpF66w7P1ayfQaZQEA
https://www.ncbi.nlm.nih.gov/pubmed/16730806
https://pubmed.ncbi.nlm.nih.gov/314...YNm7HlBt_gvDMrE-26JxcUEwv-oQQZrbYYy9oxkMN-tps
https://www.ncbi.nlm.nih.gov/pubmed/22155301?dopt=Abstract
ARDS Acute Respiratory Distress in Adults
Proteinases as Mediators of the Disturbance of Pulmonary Vascular Permeability in Sepsis, Polytrauma, and ARDS
Figure 4.4, [Inflammation results in the release...]. - Capillary Fluid Exchange - NCBI Bookshelf
An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. - PubMed - NCBI
Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718378/
.......
ACE inhibitors, ARB inhibitors, ARDS
Coronavirus is more severe and deadly in the aged, hypertensive, and diabetic.
It is also of note that ATR-1 Receptors increase with age and are increased in cancer, diabetes, hypertension, chronic obstructive pulmonary disease. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children.
As the SARS-COV2 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher Angiotensin II and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19.
Another factor playing a role is that hypoxia causes cells to produce more AT-1. So the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.
If young people have higher ACE2, and that was the factor allowing faster viral inoculation, then it would be worse in the young, but it is not.
Cancer, hypertension, diabetes, chronic obstructive pulmonary disease are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.
ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
ACE2 has been shown to be the entry point into human cells for some coronaviruses, including SARS-CoV, the virus that causes SARS. A number of studies have identified that the entry point is the same for SARS-CoV-2, the virus that causes COVID-19.
This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.
In fact, the interaction of the spike protein of the virus with the ACE2 induces a drop in the levels of ACE2 in cells.
Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disorder that is frequently associated with multiple organ dysfunction leading to high mortality. The mechanisms underlying ARDS are multi-factorial, and are thought to include the renin-angiotensin system (RAS).
The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensin-converting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Angiotensin I into the octapeptide Angiotensin II, while ACE2 cleaves a single residue from Angiotensin II to generate Ang 1-7, which in turn blocksiotensin Angiotensin II and inhibits ACE.
Conversion of Angiotensin I to Angiotensin II can readily occur in the lung by abundant ACE in pulmonary vessels. This may contribute to rapid responses of vasoconstriction in the pulmonary circulation and low blood flow, leading to ventilation/perfusion mismatch in conditions such as tissue hypoxia. On the other hand, ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells and epithelial injury is a critical event in the development of ARDS in humans; thus, the ability to produce ACE2 is severely impaired, resulting in dominant ACE activities during ARDS and/or ventilator-induced lung injury.
Since ACE2 protected the lung from developing ARDS and functioned as a coronavirus receptor for severe acute respiratory syndrome, the recombinant ACE2 (rACE2) protein may have an important place in protecting ARDS patients and as a potential therapeutic approach in the management of emerging lung diseases such as avian influenza A infections.
Bradykinin is an inflammatory mediator. Bradykinin could also contribute to the pathogenesis of ARDS
ACE converts Angiotensin I to Angiotensin II and also inactivates bradykinin.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.
ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Bradykinin contracts airway smooth muscle, is a potent bronchial vasodilator, increases microvascular leakage, stimulates epithelial cells to release bronchodilators and stimulates mucus secretion.
Inhaled bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation, and mucus secretion.
KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.
During inflammation, it is released locally from mast cells and basophils during tissue damage.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.
Inflammation results in the release of mediators that cause vasodilation, increase microvascular permeability, and induce leukocyte infiltration.
Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome.
In ARDS, fluid accumulation in lung interstitium, the alveolar spaces, and the small airways causes the lungs to stiffen, thus impairing ventilation and reducing oxygenation of the pulmonary capillary blood. The resulting injury reduces normal blood flow to the lungs. Damage can occur directly – by aspiration of gastric contents and inhalation of noxious gases – or indirectly – from chemical mediators released in response to systemic disease.
Platelets begin to aggregate and release substances, such as serotonin, bradykinin, and histamine, which attract and activate neutrophils.
These substances inflame and damage the alveolar membrane and later increase capillary permeability.
Increase in vascular permeability:
Due to the action of inflammatory mediators (histamine, serotonin, bradykinin, leukotrienes C4, D4, and T4); Occurs rapidly and does not last long; Results in opening of interendothelial spaces and paracellular leakage of plasma; Endothelial injury; Results in endothelial cell necrosis and detachment; Leakage lasts until the damaged area is thrombosed or repaired.
Effects:
Leads to leakage of plasma content into the interstitial tissue, causing local edema; Allows migration of immune cells and proteins to site of injury or infection.
Mediators released by neutrophils and macrophages also cause varying degrees of pulmonary vasoconstriction, resulting in pulmonary hypertension. The result of the changes is a ventilation-perfusion mismatch. Although the patient responds with an increased respiratory rate, sufficient oxygen can’t cross the alveolar capillary membrane. Carbon dioxide continues to cross easily and is lost with every exhalation. As oxygen and carbon dioxide levels in the blood decrease, the patient develops increasing tachypnea, hypoxemia, and hypocapnia (low partial pressure of arterial carbon dioxide [PaCO2]).
Pulmonary edema worsens, and hyaline membranes form. Inflammation leads to fibrosis, which further impedes gas exchange. Fibrosis progressively obliterates alveoli, respiratory bronchioles, and the interstitium. Functional residual capacity decreases, and shunting becomes more serious. Hypoxemia leads to metabolic acidosis. At this stage, the patient develops increasing PaCO2, decreasing Ph and partial pressure of arterial oxygen (PaO2), decreasing bicarbonate (HCO3-) levels, and mental confusion.
The end result is respiratory failure. Systematically, neutrophils and inflammatory mediators cause generalized endothelial damage and increased capillary permeability throughout the body. Multiple organ dysfunction syndrome (MODS) occurs as the cascade of mediators affects each system. Death may occur from the influence of ARDS and MODS.
…………
Ray Peat: The virus uses ACE2 (angiotensin converting enzyme 2) as receptor and enters cells by the angiotensin receptor. Losartan (recommended in China), an angiotensin blocker, is effective protection, and has many other antiinflammatory effects. The Chinese also have good results with cinanserin, a serotonin blocker. I think cyproheptadine might help, too. Progesterone lowers the angiotensin receptor, but doesn’t act immediately as losartan does.
Ray Peat said:
-Angiotensin excess causes the negative symptoms we associate with the virus - dry cough, fever, high blood pressure, etc.
-Angiotensin excess is caused by ACE2, the enzyme that deactivates Angiotensin, not being available to do its job.
-ACE2 is not available to do it's job because the virus binds to it.
I asked Dr. Ray Peat about protection against the CV, and he said, "I heard from a relative of a confirmed case in Italy, very sick, who took losartan yesterday, and is o.k. today, no fever. Progesterone is another inhibitor of the angiotensin receptor, the entry point of the virus."
Ray Peat: The virus inactivates the enzyme that protects against angiotensin, and one of the effects of angiotensin is to increase shedding of microparticles.
“The virus activates the angiotensin receptor, so the receptor blockers are protective—losartan, telmisartan, etc. Progesterone is a natural inhibitor of that receptor. Also the usual antiinflammatory things, aspirin, eggnog, orange juice would be helpful.” Ray Peat
I asked Peat about serotonin and endotoxin here is what he said:
"Endotoxin commonly increases serotonin and it increases sensitivity to angiotensin. The virus acts through both of those. The Chinese have found that cinanserin, an serotonin antagonist, and losartan, an angiotensin receptor blocker, are protective both before and after virus exposure.
……….
Losartan an angiotensin receptor blocker (ARB), also may lead to protection of lung fibrosis through other molecular mechanisms such as downregulation of TGF-β1.
Losartan and Cinanserin Offers Protection Against Lung Fibrosis
….
Several viral proteins have been reported to modulate TGF-ß1 signaling, which could induce the proliferation of fibroblasts [25]. Pang et al [27] found higher serum concentrations of TGF-ß1 in SARS patients compared to controls for all clinical courses, including initial, peak, remission, and recovery stages [26,27]. During shortterm follow-up, persistent ground glass opacities, reticular opacities, and pathologic fi ndings of fi brosis have been found in some SARS survivors [28,29]. ...
... Willis et al [30] pointed out that TGF-ß1 was necessary but not sufficient to induce the formation of pulmonary fibrosis [30]. In our study, TGF-ß1 levels increased significantly and remained high after treatment in the severe group, coinciding with reports of patients with SARS-CoV infection [23,26]. This phenomenon could well be explained by the existence of imminent pulmonary fibrosis. ...
https://www.researchgate.net/public...dulates_Transforming_Growth_Factor-_Signaling
Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung.
In conclusion, the present study has demonstrated the antifibrotic effect of specific serotonin 5-HT2A and 5-HT2B receptor antagonists in vivo using the animal model of bleomycin-induced lung fibrosis, and the involvement of the transforming growth factor-β1, connective growth factor and plasminogen activator inhibitor-1 pathways. The observations in human samples support the hypothesis that the serotonin pathway might be involved in the pathophysiology of human lung fibrosis.
Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice
Cinanserin is a serotonin antagonists, the benefits of this is from its 5-HT2 antagonism.
The molecule is an inhibitor of the 3C-like protease of SARS-coronavirus (SARS)
Cinanserin - Wikipedia
https://www.nejm.org/doi/full/10.10...9sdkO5Vlgz-AIA3Pm-Uq2xSQAk0Hdgegy7OfJ8wLB160Y
https://www.cambridge.org/core/serv...n_against_coronavirus_induced_lung_damage.pdf
Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. - PubMed - NCBI
Cancer, inflammation and the AT1 and AT2 receptors | Journal of Inflammation | Full Text
https://pubmed.ncbi.nlm.nih.gov/16007097/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229671/
https://en.wikipedia.org/wiki/Angiotensin#Angiotensin_I
https://en.wikipedia.org/wiki/Bradykinin
https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme
https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2
https://bgr.com/2020/03/19/coronavirus-drugs-losartan-blood-pressure-cure/
https://jvi.asm.org/content/79/11/7...QJgk5wO00kzAwCubbMI959jJPxoWpF66w7P1ayfQaZQEA
https://www.ncbi.nlm.nih.gov/pubmed/16730806
https://pubmed.ncbi.nlm.nih.gov/314...YNm7HlBt_gvDMrE-26JxcUEwv-oQQZrbYYy9oxkMN-tps
https://www.ncbi.nlm.nih.gov/pubmed/22155301?dopt=Abstract
ARDS Acute Respiratory Distress in Adults
Proteinases as Mediators of the Disturbance of Pulmonary Vascular Permeability in Sepsis, Polytrauma, and ARDS
Figure 4.4, [Inflammation results in the release...]. - Capillary Fluid Exchange - NCBI Bookshelf
An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. - PubMed - NCBI
Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718378/
