OP
md_a
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- Aug 31, 2015
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I do not know if it is correct, but I try to understand, apparently the acute accelerating lung fibrosis induced by COVID-19 infection can be justified through ACE – ACE2 - AT1 overactivation caused by the virus. Losartan is an AT1 antagonist with a selective, competitive function which decreases the end
organ responses to Angiotensin II. It is a common anti-hypertensive agent which is currently prescribed for high blood pressure patients, particularly those who are prone to diabetic nephropathies. Losartan may lead to protection of lung fibrosis through other molecular mechanisms such as downregulation of TGF-β1.
After entrance to the body, COVID-19 fuse their envelopes with membranes of the host cells, then transport their genetic material into the affected cells. This essential fusion is mediated by glycosylated spike proteins on the surface of the virion interacting with proper surface receptors on the membrane of host cells. Angiotensin-converting enzyme 2 (ACE2) receptor is a known surface human cell proteins on which COVID-19 spike proteins are specifically bound.
The activation of RAS is triggered by secreting of renin from kidney, through juxtaglomerular cells. Renin is a protease that cleaves angiotensinogen, the precursor of angiotensin, which is made by liver. It produces an inactive peptide: Angiotensin I (AngI).
Then, ACE mediate the conversion of AngI to AngII, a major RAS effector. ACE is a protein with high expression on membranes of vascular endothelial cells, predominantly in lung tissue. The most of the RAS associated physiologic effects are run by interacting of AngII with a G-protein coupled AngII type 1 (AT1) receptor. This activates a physiologic pathway in different tracts, such as kidney, liver, central nervous system, respiratory, and cardiovascular system. Some crucial events are regulated via active AT1 receptors including arterial pressure, fluid and sodium balance, fibrosis, and cellular growth and migration.
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.
Some studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung. Altogether given the several studies, the ACE-AngII-AT1 axis in the RAS system shows a predominant role in the organ fibrosis, particularly in lung and liver.
According to some recent studies, 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.
The most common complication leading to the CoV-induced mortality is respiratory failure due to an extensive, accelerating lung fibrogenesis. Rather than PCRbased testing to detect CoV infection, a radiologic lung infiltration pattern in chest X ray could have a diagnostic value to screen the suspicious patients. It seems the cytopathic effects of virus resulted from its massive replication in infected cells need more time than what happens to cause acute manifestation of the disease. So, the acute accelerating lung fibrosis induced by COVID19 infection can be justified through ACE-AngII-AT1 overactivation caused by the virus.
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 diabetes, hypertension, COPD. 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 AngII 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.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
Angiotensin-converting enzyme or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II
ACE is also part of the kinin-kallikrein system where it degrades bradykinin, a potent vasodilator, and other vasoactive peptides.
Other less known functions of ACE are degradation of bradykinin and amyloid beta-protein.
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
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.
During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically, in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
ACE inhibitors - lower your blood pressure by reducing Angiotensin II in the body.
I understand that, the large number of deaths in Italy are old people with hypertension, heart disease and diabetes and probably have used ACE inhibitors drugs.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Angiotensin converting enzyme 2 (ACE2) - is a protein that sits on the lining cells within alveoli of the lung. It acts as an enzyme, being an exopeptidase that catalyses the conversion of Angiotensin II to angiotensin 1–7, which acts as a vasodilator. It also converts angiotensin I to nanopeptide angiotensin[1–9] It is a single-pass type I membrane protein expressed on the surface of epithelial cells of the pulmonary alveolus, and on small intestine enterocytes and other cell types.
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. (A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury - PubMed)
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 Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE. Thus, the ACE2 axis negatively regulates the ACE axis.
Conversion of Ang I to Ang 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.
The RAS—specifically Ang II via AT1 and AT2 receptors—has a number of effects: induction of pulmonary vasoconstriction and vascular permeability in response to hypoxia resulting in pulmonary edema; stimulation of the lung production of inflammatory cytokines directly and indirectly by targeting bradykinin; acceleration of the Fas-induced apoptosis in alveolar epithelial cells; and promotion of extracellular matrix synthesis and human lung fibroproliferation. These effects of the RAS highlight the crucial role of Ang II in ACE/ACE2-regulated ARDS. Indeed, enhanced ACE activity and decreased ACE2 activity contribute to lung injury during cyclic stretch of human lung epithelial cells and to VILI in animal models. In models of ARDS, the use of ACE2 gene knockout mice demonstrated that ACE2 and Ang 1-7 are protective.
The use of Ang II receptor blockers or ACE inhibitors has been effective in decreasing lung injury in animal models, but this approach could have potential side effects, including systemic hypotension in humans. 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. ([https://pubmed.ncbi.nlm.nih.gov/16007097/]. Acute respiratory distress syndrome, also known as ARDS, is a common killer among critically ill patients hospitalized with COVID-19.
organ responses to Angiotensin II. It is a common anti-hypertensive agent which is currently prescribed for high blood pressure patients, particularly those who are prone to diabetic nephropathies. Losartan may lead to protection of lung fibrosis through other molecular mechanisms such as downregulation of TGF-β1.
After entrance to the body, COVID-19 fuse their envelopes with membranes of the host cells, then transport their genetic material into the affected cells. This essential fusion is mediated by glycosylated spike proteins on the surface of the virion interacting with proper surface receptors on the membrane of host cells. Angiotensin-converting enzyme 2 (ACE2) receptor is a known surface human cell proteins on which COVID-19 spike proteins are specifically bound.
The activation of RAS is triggered by secreting of renin from kidney, through juxtaglomerular cells. Renin is a protease that cleaves angiotensinogen, the precursor of angiotensin, which is made by liver. It produces an inactive peptide: Angiotensin I (AngI).
Then, ACE mediate the conversion of AngI to AngII, a major RAS effector. ACE is a protein with high expression on membranes of vascular endothelial cells, predominantly in lung tissue. The most of the RAS associated physiologic effects are run by interacting of AngII with a G-protein coupled AngII type 1 (AT1) receptor. This activates a physiologic pathway in different tracts, such as kidney, liver, central nervous system, respiratory, and cardiovascular system. Some crucial events are regulated via active AT1 receptors including arterial pressure, fluid and sodium balance, fibrosis, and cellular growth and migration.
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.
Some studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung. Altogether given the several studies, the ACE-AngII-AT1 axis in the RAS system shows a predominant role in the organ fibrosis, particularly in lung and liver.
According to some recent studies, 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.
The most common complication leading to the CoV-induced mortality is respiratory failure due to an extensive, accelerating lung fibrogenesis. Rather than PCRbased testing to detect CoV infection, a radiologic lung infiltration pattern in chest X ray could have a diagnostic value to screen the suspicious patients. It seems the cytopathic effects of virus resulted from its massive replication in infected cells need more time than what happens to cause acute manifestation of the disease. So, the acute accelerating lung fibrosis induced by COVID19 infection can be justified through ACE-AngII-AT1 overactivation caused by the virus.
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 diabetes, hypertension, COPD. 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 AngII 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.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
Angiotensin-converting enzyme or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II
ACE is also part of the kinin-kallikrein system where it degrades bradykinin, a potent vasodilator, and other vasoactive peptides.
Other less known functions of ACE are degradation of bradykinin and amyloid beta-protein.
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
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.
During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically, in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
ACE inhibitors - lower your blood pressure by reducing Angiotensin II in the body.
I understand that, the large number of deaths in Italy are old people with hypertension, heart disease and diabetes and probably have used ACE inhibitors drugs.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Angiotensin converting enzyme 2 (ACE2) - is a protein that sits on the lining cells within alveoli of the lung. It acts as an enzyme, being an exopeptidase that catalyses the conversion of Angiotensin II to angiotensin 1–7, which acts as a vasodilator. It also converts angiotensin I to nanopeptide angiotensin[1–9] It is a single-pass type I membrane protein expressed on the surface of epithelial cells of the pulmonary alveolus, and on small intestine enterocytes and other cell types.
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. (A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury - PubMed)
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 Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE. Thus, the ACE2 axis negatively regulates the ACE axis.
Conversion of Ang I to Ang 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.
The RAS—specifically Ang II via AT1 and AT2 receptors—has a number of effects: induction of pulmonary vasoconstriction and vascular permeability in response to hypoxia resulting in pulmonary edema; stimulation of the lung production of inflammatory cytokines directly and indirectly by targeting bradykinin; acceleration of the Fas-induced apoptosis in alveolar epithelial cells; and promotion of extracellular matrix synthesis and human lung fibroproliferation. These effects of the RAS highlight the crucial role of Ang II in ACE/ACE2-regulated ARDS. Indeed, enhanced ACE activity and decreased ACE2 activity contribute to lung injury during cyclic stretch of human lung epithelial cells and to VILI in animal models. In models of ARDS, the use of ACE2 gene knockout mice demonstrated that ACE2 and Ang 1-7 are protective.
The use of Ang II receptor blockers or ACE inhibitors has been effective in decreasing lung injury in animal models, but this approach could have potential side effects, including systemic hypotension in humans. 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. ([https://pubmed.ncbi.nlm.nih.gov/16007097/]. Acute respiratory distress syndrome, also known as ARDS, is a common killer among critically ill patients hospitalized with COVID-19.
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