Kinins And Cytokines In COVID-19: A Comprehensive Pathophysiological Approach

[Jam]

Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach

Abstract
Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

 

[Jam]

It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues.[15] Other substances that act as bradykinin inhibitors include aloe[16][17] and polyphenols, substances found in red wine and green tea.

 

[md_a]

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.

 

[md_a]

There is an extremely important connection between ACE-inhibitor medication for hypertension and the virus.
SUMMARY:
Pre-SARS-CoV-2, if someone went to an emergency dept. with a dry cough and trouble breathing, and was taking the blood pressure medication ACE-inhibitors, they would likely diagnose it as a side effect of the medication and take the person off of their ACE-I, and switch it to Losartan. This would be especially true if the person was African-American or a smoker, who are most susceptible to this side effect, and also have more hypertension than other ethnicities. In prescribing instructions, people who are taking ACE-I’s should be immediately taken off when these side effects present. Now, they don’t take them off their ACE-I and, instead, test for the virus, which has the same symptoms. The patient then remains on their ACE-I, and is treated with epinephrine and corticosteroids, as well as with a respirator, but many die. According to the American Heart Association, they keep patients on their ACE-I to protect their heart from “cardiac injury”, which is the cause of death in many cases of SARS-CoV-2. The test for cardiac injury is an increased level of troponin. However, ACE-I’s themselves not only cause the same symptoms as the virus-they also might “potentiate” (increase) an increase in troponin from the virus (as a study showed it did with alcohol). So, cardiac injury might be avoided if patients were taken off their ACE-I, like they would have been pre-virus, in which case they probably wouldn’t have cardiac injury and die. Furthermore, the Wuhan study of 89 fatalities, published on April 3, found that respiratory failure was the cause of death for 94%, so cardiac injury may play a small part in increased fatalities. Also noted in this study was that, unusually, hypertension alone was a common comorbidity with fatalities, with a total of 68% having co-morbidities that would have included blood pressure medication such as ACE-inhibitors. The researchers commented on this occurrence, noting that “the increased prevalence of hypertension in China may play a role in COVID-19 related deaths.” So, if the patient remains on ACE-I, then bradykinin, creatinine and troponin would likely increase, raising the risk of death, either from respiratory failure (bradykinin-induced angioedema) or cardiac injury (troponin) or other organ failure, which can be the result of prolonged ventilation. So, a conservative approach would be to treat a patient, who is taking an ACE-I, as they would if they were having the serious side effect of their medication, and immediately take them off of it so as not to increase the side effect, whether or not they test positive for the virus. Also, we could go back to the pre-2018 definition of hypertension, which would, from the many indications and studies included here, take many millions of Americans out of danger from the virus. Finally, as many people as possible could be switched to Losartan.
WHAT DOCTORS ARE SAYING:
Comments on an April 1 article by the American College of Cardiologists and the American Heart Association stating to not stop giving COVID-19 patients ACE-inhibitors.

Dr. William DeMedio-This article says don’t stop ACEI Or ARB meds in people with CoV19, but the science is not settled. I want to see if SARS outcomes are improved or impaired by these meds; or no net change. There is more than one way to lower BP for the short term in these people. How about a study switching some to a different class of antihypertensive, eg CCB or even a PDE 5 inhibitor? We could compare rate of SARS and death. ACE inhibitors increase pulmonary inflammation. That is why some people cough on them. Some studies suggest they may be associated with lung cancer. I do not think they are fully exonerated yet. This needs more work for an answer.

Dr. Wayne Greaves
@Dr. William DeMedio I am concerned that recommendations are being made on so little data and such limited concern. As a HCW myself I am unsure what to do. The data from Italy is very troubling with pre-hospital use of 36%ACEIs and 16% ARBs among Covid-19 persons that died. I sure hope someone is looking carefully at the emerging US data as the cases increase so we can have an answer based on more robust data. On another note, some have suggested at least for those on ACEIs which tend to increase bradykinin and thereby pro-inflammatory response that Vitamin D levels should be checked proactively and those with low levels be given Vit D to decrease inflammation in those who are at risk of pneumonia/ARDS.
Dr. STEPHEN ALGEO-Now with reports that in the US African American patients are recording worse outcomes with Covid-19 you have to wonder whether racial differences in ACE metabolism/physiology are a factor. As a cardiologist I am aware that African-Americans do not respond as well to ACE-inhibitors when used for both hypertension and CHF as other groups.

Dr. Francine Moring-ACE inhibitors block zinc. Zinc is needed in T cells. It helps decrease viral replication. Hydroxychloroquine acts like an ionophore, allowing zinc to get into cells.
https://www.medscape.com/viewarticle/927952
Furthermore, Dr. Fauci, from a March 18 interview, focuses just on ACE-inhibitors:
HB: Another clinical issue that really come up the last few days is this issue about ACE and ARBs in individuals who are either on them or develop disease. Now the Heart Failure Society of America, ACC, and AHA just came out with a statement yesterday. I don't know how familiar you are with the question, Tony, but I'll let you comment.
AF: Well, I am quite familiar with the question. So, here's the issue -- and this is something that I take a little bit more seriously about we really need to get data and we need to get data fast, Howard, and here's the reason why. If you look at the mechanistic rationale for concern, it's there and it's -- and it's firm, and that is, that when you give an ACE inhibitor or an ACE inhibitor can result -- I say can -- can result in an increased expression of the receptor for ACE. So, what is possible is that people who are on ACE inhibitors, a very commonly used drug for hypertension, that they may be, without knowing it, increasing the expression of receptors for the virus, itself.
That's an extrapolation, that's not based on known data, but it is a possibility that we need to address. I was struck by something that I read just early this morning, Howard, there was an article -- I think Bloomberg published it from a medical summary that in -- I believe it was Italy or in Europe, but I think it was in Italy, that 99% of the people who died had an underlying condition, that's not surprising. However, when they broke down the underlying conditions, 75% of it was hypertension, which was, to me, a bit of a red flag, because Italy is a very developed country. And I would imagine, if you knew the patient had hypertension, then the patient, almost certainly, had a physician.
And that physician almost certainly treated the person for their hypertension. So, if you could imagine -- and again, this is just my putting some dots together, Howard. This is no data, I'm just -- you know, giving you right off the top of my head. If 75% of those so-called underlying conditions was hypertension, and the hypertension was well-controlled, why should someone who has hypertension that's well controlled have a much greater chance of dying than somebody else with any other kind of underlying condition? I mean I look upon someone who has well-controlled hypertension and nothing else wrong with them as a reasonably healthy person, yet it was skewed towards people with hypertension, which tells me I don't know what the answer is, but somebody better look really carefully and that's what we're hopefully going to get that data from the Italian scientists. https://edhub.ama-assn.org/jn-learning/audio-player/18324686

The following is a series of studies and articles describing:
1. The action of ACE-inhibitors and its side effects: dry cough and angioedema (swollen airways) mainly due to increased bradykinin
2. Symptoms of SARS-CoV-2 are the same as side effects of ACE-inhibitors, again from bradykinin, so people taking ACE-inhibitors would have a magnified effect of symptoms if they become infected. Also, the unusually high number of people with only hypertension that have died connects the virus with ACE-I’s.
3. Unlike with other viruses, people often become “re-infected”, which doesn’t make sense normally, but this does make sense if they are still on their ACE-inhibitor, which has so much to do with the excessive symptoms.
4. How prescription guidelines recently changed, and how countries differ re: ACE-inhibitor prescriptions.
5. Official position of Medical Community: no one should stop taking ACE-inhibitors, even if infected with SARS-CoV-2.
6. What to do about the problem.

REFERENCES
1.The action of ACE-inhibitors and its side effects: dry cough and angioedema (swollen airways) mainly due to increased bradykinin
https://edhub.ama-assn.org/jn-learning/audio-player/18324686
http://www.scielo.br/scielo.php…
https://www.ncbi.nlm.nih.gov/pubmed/11827930
https://cvpharmacology.com/vasodilator/ACE
https://www.ncbi.nlm.nih.gov/pubmed/10893650 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638407/… https://www.nationaljewish.org/conditions/angioedema
https://www.merckmanuals.com/…/allergic,-autoimm…/angioedema
2.Symptoms of SARS-CoV-2 are the same as side effects of ACE-inhibitors, again from bradykinin, so people taking ACE-inhibitors would have a magnified effect of symptoms if they become infected. Also, the unusually high number of people with only hypertension that have died connects the virus with ACE-I’s.
https://www.usatoday.com/…/what-coronavirus-doe…/5009057002/ https://www.preprints.org/manuscript/202004.0023/v1 https://aliveandwellaustin.com/…/what-we-want-you-to-know-…/
www.jacionline.org › article › pdf
" Ibuprofen augments bradykinin-induced ... - JACI
www.jacionline.org › article › pdf
https://www.ncbi.nlm.nih.gov/pubmed/28935640 https://www.scientificamerican.com/…/snakes-could-be-the-o…/ https://www.pharmaceutical-journal.com/…/…/10884359.article…
3.Unlike with other viruses, people often become “re-infected”, which doesn’t make sense normally, but this does make sense if they are still on their ACE-inhibitor, which has so much to do with the excessive symptoms.

https://www.france24.com/…/20200328-can-the-coronavirus-inf…
4.How prescription guidelines recently changed, and how countries differ re: ACE-inhibitor prescriptions. US used new guidelines for prescribing ACE-inhibitors in late 2017, greatly increasing people on these meds, especially younger people and newly prescribed. Side effects of cough and angioedema can occur up to a year after new prescription. That flu season was especially bad with far more illnesses, hospitalizations and deaths. The exact same problem of greater deaths from angioedema occurred in 2003, with the SARS virus, because there was another increase in ACE-inhibitor prescriptions due to the 2003 change in the threshold defining “hypertension”. So, both in 2003 and in 2018, when there was a large spike in “pneumonia and flu deaths”, there were suddenly far more people being prescribed ACE-inhibitors, the first-line med for hypertension.
https://newsroom.heart.org/…/high-blood-pressure-redefined-…

https://www.tctmd.com/…/new-european-hypertension-guideline…

5.Official position of Medical Community: no one should stop taking ACE-inhibitors, even if infected with SARS-CoV-2, even though Dr. Fauci wants this connection to be looked at “very carefully”.
https://www.ahajournals.org/doi/10.1161/JAHA.120.016219
https://newsroom.heart.org/…/patients-taking-ace-i-and-arbs…
https://jamanetwork.com/journals/jama/fullarticle/2763803
http://www.scielo.br/scielo.php…
https://edhub.ama-assn.org/jn-learning/audio-player/18324686
6.How to lower hospitalizations and deaths: 1.by lowering the number of people on ACEI’s by changing definition of hypertension back to 2017 guidelines, 2.by mandatory self-quarantine for those staying on ACEI’s, and 3.by treating hospital cases, for those on ACEI’s, first for the ACEI side effect, and immediately take them off ACI’s, which is only following the prescription instructions! Then, possibly use Icatibant, which breaks down bradykinin, may be effective. Possibly in the future, block bradykinin B1 receptor, which ACEI actually induces instead, with SSR240612. This also lowers blood pressure!Those who have blood pressure that is not considered to be high according to the original definition of hypertension should stop taking ACE-inhibitors, as is the case in Germany, Netherlands, and South Korea. ACE normally breaks down bradykinin, but it is low with zinc-deficiency (ACE is a zinc enzyme). ACE-inhibitors lower zinc, as does smoking and oral contraceptives, and all of these increase risk for angioedema. Plaquinil, on the other hand, increases zinc in the cells, so it can be used to treat angioedema. Also, bradykinin is high in lupus, which is effectively treated with plaquinil. So, plaquinil has been shown to work on virus-induced angioedema, which is apparently ACE-inhibitor and bradykinin-induced as well.
https://www.google.com/search… https://www.preprints.org/manuscript/202004.0023/v1 https://www.ncbi.nlm.nih.gov/pubmed/11827930
R. Sehgal 1, R. Khan 2, https://doi.org/…/ajrccm-conference.2019.199.1_MeetingAbstr…
https://link.springer.com/article/10.1186/s13075-018-1774-x
https://www.ncbi.nlm.nih.gov/pubmed/3003288
Compiled by Joan Tendler, M.Arch., West Allis, [email protected] 414-828-3637

 

[md_a]

ACE inhibitors reduce zinc, and ACE2 depends on zinc which is also reduced by 'virus'. Probably the lack of taste and smell is related to the lack of zinc, and zinc is also important in the restoration of the thymus gland.


Modern Medicine Knew Of Zinc Cure For Coronavirus Infections A Decade Ago But Failed To Put Into Practice

Emergency Room Doctor Doesn't Realize Major Signs & Symptoms of COVID-19 Coronavirus Cases Match Evidences Of Zinc Deficiency

Restoration of the thymus in aging mice by in vivo zinc supplementation. - PubMed - NCBI

 

[ecstatichamster]

ACE inhibitors reduce zinc, and ACE2 depends on zinc which is also reduced by 'virus'. Probably the lack of taste and smell is related to the lack of zinc, and zinc is also important in the restoration of the thymus gland.


Modern Medicine Knew Of Zinc Cure For Coronavirus Infections A Decade Ago But Failed To Put Into Practice

Emergency Room Doctor Doesn't Realize Major Signs & Symptoms of COVID-19 Coronavirus Cases Match Evidences Of Zinc Deficiency

Restoration of the thymus in aging mice by in vivo zinc supplementation. - PubMed - NCBI

I think Bill Sardi is a crank. He does some good research but his conclusions are ridiculous and he sells resveratrol. he had a heart attack at a relatively young age, got stent put in, and had his friends smuggle some resveratrol to him in the hospital. There is no miracle cure with zinc. It is useful, yes, but it is no cure and no remedy and no real preventive.

 

[Terma]

It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues.[15] Other substances that act as bradykinin inhibitors include aloe[16][17] and polyphenols, substances found in red wine and green tea.

I had an urge to eat tons of pineapple for a month out of nowhere (before)

This kinin-dependent pulmonary edema is resistant to corticosteroids

They should get a raise for including that in the abstract.

If you have a bradykinin receptor antagonist you might get extra stress resistance benefits: Dynorphin - Wikipedia

A study by Lai et al. found that dynorphin might actually stimulate pain.[8] The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.[8] Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.[8]

According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.[8] Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.[8] A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.

 

[md_a]

I think Bill Sardi is a crank. He does some good research but his conclusions are ridiculous and he sells resveratrol. he had a heart attack at a relatively young age, got stent put in, and had his friends smuggle some resveratrol to him in the hospital. There is no miracle cure with zinc. It is useful, yes, but it is no cure and no remedy and no real preventive.

Thanks. I don't know who Bill Sardi is, I was just looking for something related to zinc and coronavirus. A higher concentration of zinc I take almost weekly from oysters along with beef liver.

 

[ecstatichamster]

Thanks. I don't know who Bill Sardi is, I was just looking for something related to zinc and coronavirus. A higher concentration of zinc I take almost weekly from oysters along with beef liver.

he write your first two articles.

 

[md_a]

he write your first two articles.

I understood this, but I read only part with zinc, otherwise I'm not interested. And I'm not just focusing on zinc.