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COVID-19

Hypoxia in COVID-19 and the possible activation of the immune-neuroendocrinology axis

Hypothesis and data

By Pari Rapti, Endocrinologist

To better understand what happens when the body is infected with the new coronavirus, we should go back to the basics, i.e., to the cell functions involved, and set out our observations and data obtained from international literature in order to better understand these mechanisms.

It is known that the new SARS-CoV-2 coronavirus is “tactical” in the sense that it binds with a specific type of ACE2 receptors that facilitates the infiltration and infection of certain cell types. Therefore, we are going to examine to how these alveolar type II epithelial cells operate. It is exactly in these cells that the receptor of the angiotensin-converting enzyme 2 (ACE2) of the renin-angiotensin system is found.

This receptor has been discovered only in recent years, while its ACE counterpart has been studied more. These two receptors are critical components of the renin-angiotensin-aldosterone system and their involvement in COVID-19 may be crucial in disease progression.

The crucial role of alveolar type II cells infection.

Hypoxia, HIF, MIF, the renin-angiotensin aldosterone system (RAAS), the hypothalamus-pituitary-adrenal (HPA) axis and gene polymorphism in COVID-19.

To date, the affinity of SARS-CoV-2 to alveolar type II epithelial cells (transmembrane ACE2) appears to play a key role in the onset, progression, and course of the disease.

This occurs due to the functions of these cells, which, among other things, are also performed through the transmembrane ACE2 receptor and its activation, and due to the production of surfactant by these cells.

Following infection and replication of the virus by cytoplasmic building blocks, alveolar type II cells are destroyed, thus affecting both ACE2 and surfactant levels.

In our opinion, the ACE2 and the SURFACTANT are two important factors which are crucial, along with genetic adaptability, for the onset and progression of COVID-19.

We need to deepen our understanding of the existence and function of these two determining factors and the possible mechanisms that may affect the expression and progression of the COVID-19.

The presence of the transmembrane ACE2 receptor in alveolar type II cells and its gene expression, the functions of this receptor in the RΑAS system and its regulation by various factors, as well as the results occurring when it binds to the Spike (S) protein of SARS-CoV-2 appear to be critical in COVID-19.

It is also important to look into the mechanism by which this protective ACE2 receptor is down regulated in COVID-19, since this may be crucial.

We are already aware of two mechanisms that lead to the down regulation of this receptor, a) following destruction of alveolar type II cells, b) due to the accumulation of HIF following hypoxia.

A second important function affected by the destruction of alveolar type II cells is the reduced production of surfactant, which is a critical factor.


BACK TO BASICS

ALVEOLAR TYPE II CELLS, ACE2, RAAS

The respiratory system is one of the most important defense systems of the body.

Cells and humoral factors are involved in respiratory immunobiology, which perform complex processes.

The epithelial cells in the airways have extremely important functions. These cells are in the body’s first line of defense and they produce a range of chemicals, chemotactic factors, antimicrobial factors and inflammatory transmitters, which induce the attraction of specific and non-specific immunity cells and the further secretion of pro-inflammatory factors.

A number of receptors are also expressed in these cells. The destruction of these cells following infiltration by SARS-CoV-2 is clearly disrupting immunological functions both locally and throughout the body.

ACE2 has been identified as a receptor for the Spike (S) protein of the new coronavirus.

Due to the reduction of ACE2 from the cell membrane of alveolar type II cells, that results when ACE2 binds to the Spike (S) protein of SARS-CoV-2, the virus is able to penetrate more easily into the alveolar cells and accelerate its “proliferation” inside the cells.

When ACE2 is reduced, as a result of binding to the Spike (S) protein and forming a complex, its protective effect on alveolar cells is also reduced. This way, the alveolar cells become even more vulnerable to the harmful effects of angiotensin II, because of the reduced production of angiotensin 1-7 which is catalyzed by ACE2.

This can affect the whole body.

 

ACE2  in COVID-19

The receptor of the ACE2 converting enzyme plays an important role in the renin-angiotensin-aldosterone system (RAAS), which is key to how the body functions.

The presence of ACE2 is protective, preventing the occurrence of lesions due to inflammatory processes involving various organs, such as the lungs, as well as certain conditions of the gastrointestinal tract and other organs.

The role of this receptor is likely to be critical in COVID-19, not only because it is an infiltration gateway for SARS-CoV-2, the new coronavirus, but also for the reasons described next.

The ACE2 receptor is encoded by the ACE2 gene on chromosome Xp22. There are two forms of ACE2 on the cells of different human organs, one that binds through a transmembrane mechanism to cells, and one in circulating soluble form.

The ACE2 receptor is cleaved and released into the circulation through the actions of two proteases, Adam17 and TMPRSS2.

The cellular form is abundantly expressed in alveolar type II cells, small intestinal epithelial cells, vascular endothelial cells, myocardial cells, brain cells, and cells of the genital system organs, the kidneys and other organs.

In a coronavirus infection, these organs may be involved and the function of each of the above-mentioned organs may be disrupted, either separately, or in a multiple organ syndrome.

The ACE2 cell receptor is cleaved from its transmembrane location mainly by the Αdam17 metalloprotease and then released into the extracellular environment and into the circulation, while the serine protease TMPRSS2 may antagonize the effects of Adam 17 to cleave the ACE2 receptor to release it extracellularly, but cleaves it otherwise.

Circulating ACE2 can also bind to the virus but requires an intracellular environment to replicate.

The coexistence of the ACE2 receptor and the serine protease TMPRSS2 in various organs of the human body (epithelial cells) is highly expressed and this may facilitate the involvement of these organs in the infection and progression of the disease.

These organs, such as the prostate, the large intestine, the small intestine, the pancreas, the kidneys, the liver, the lungs, have both ACE2 and TMPRSS2 present; it is of significance that serine activation requires the presence of androgens, since it is an androgen-dependent protease.

 Androgens, not only activate TMPRSS2, but also contribute decisively to host infectivity. The effect of Adam 17 metalloprotease, which cleaves the ACE2 receptor, appears to be inhibited by the activated protease serine, which antagonizes it.

It also seems likely that the circulating ACE2 receptor, which has been cleaved by the said metalloprotease, exercises a protective effect through the production of angiotensin 1-7. That is, the soluble receptor released compensates the effects of angiotensin II signaling.

 As is well known, ACE breaks down angiotensin I (Ang I) into Ang II. Ang II binds to the Ang II 1 receptor (AT1) and then mediates in many systems. This translates into known local actions (such as promoting vasoconstriction, fibrosis, activation of thrombotic mechanisms and sodium retention) in various systems, such as the cardiovascular system and others.

In RAAS, ACE2 plays an opposite role to ACE. ACE2 catalyzes the conversion of Ang I to Ang-(1-9) and the conversion of Ang II to Ang-(1-7). Ang-(1-7) binds to the G protein-conjugated MAS receptor to mediate various effects, such as vasodilation, cardioprotection, anti-fibrotic, anticoagulant, antioxidant anti-inflammatory activity and inhibition of Ang II-induced signaling.

The ACE2-Ang-(1-7) axis is considered to be a protective mechanism that balances the effects of angiotensin II. Since Ang II-AT1 receptor signaling also promotes an autoimmune response, ACE2 can control immune functions through angiotensin 1-7.

 

ACE 2/ACE and their effects

In humans there are two types of ACE known to date, physical and testicular, which differ from each other.  These two ACE isozymes, i.e., ACE and ACE2, are determined by genes found on 17q23 and Xx22 chromosomes in humans, respectively.

Testicular ACE is transcribed by the same gene with an alternative transcription initiation site in intron 13 of the ACE gene.

Physical ACE is expressed in a variety of tissues including blood vessels, intestine, adrenal glands, liver, uterus, kidneys, lungs, the retina or other tissues. Testicular ACE is mainly expressed in spermatids.

ACE 2 is expressed in the heart, kidneys, brain, lungs, liver, intestine, endocrine glands, and mainly in the testes.

The lung has the highest amount of ACE.  Its location in this site plays a key role, due to the existence of a huge pulmonary vascular network and release of nearly intact angiotensin II into circulation, which is catalyzed by ACE.

ACE expression is affected by steroids, thyroid and other hormones, but the exact mechanism has not yet been identified.

The best-known action of the ACE receptor is the conversion of angiotensin I to angiotensin II and the inactivation of bradykinin, which plays a very important role in regulating blood pressure.

The ACE receptor also acts on other substrates, such as substance P, neurotensin and enkephalin. In addition to regulating blood pressure, it is involved in other processes, such as male fertility, hematopoiesis, erythropoiesis, myelosis, kidney development, but also plays a dominant role in the body’s immune responses.

ACE2 can also convert angiotensin II to angiotensin 1-7. Therefore, it compensates the effects of angiotensin II by producing angiotensin 1-7.

 The effects of these different types of angiotensin are opposing. Furthermore, ACE2 can also convert angiotensin I to angiotensin 1-9 which is then converted to angiotensin 1-7 by ACE.

The high expression of ACE2 serves as a balance in the body, so that the levels of angiotensin 1-7 compensate the levels of angiotensin II, and therefore the harmful effects of angiotensin II.  For example, there appears to be a cardioprotective role of ACE2 through the angiotensin 1-7/Mas signaling pathway.

 

SURFACTANT, WHAT IT IS, HOW IT WORKS:

With the destruction of alveolar type II cells, in addition to the reduction of ACE2, the synthesis of surfactant is affected, subsequently resulting in alveolar collapse, respiratory distress, production of pro-inflammatory factors, recruitment of immune cells, activation of endothelial RAS, as well as hypoxia via multiple mechanisms and biological processes.

SURFACTANT

It was mentioned above that the surfactant is synthesized and secreted by alveolar type II cells, which cover less than 10% of the alveoli surface and make up about 15% of the alveolar cells, which also contain ACE2.

This surfactant is vital not only because it protects the lung from alveolar collapse, but also because it is involved in the body’s defense mechanism.

The proteins that make up the surfactant are four SPs and there is a genetic polymorphism of these proteins which is expressed in various conditions.

The surfactant is mainly produced by alveolar type II epithelial cells where lipids and proteins are synthesized.

Surfactant proteins also function as modifiers of the immune response, have antimicrobial effects and play an important role in the body’s defense against infections.

They also facilitate phagocytosis by non-specific immune cells, monocytes and macrophages due to opsonization of pathogens.

There are genes that decode lipoproteins SPA1 and SPA2, which act as immunomodulators.

 Many respiratory conditions are associated with its dysfunction or deficiency. In addition, conditions of the endocrine system, such as hyperthyroidism and hypothyroidism, have a direct impact on the surfactant.

 

The surfactant is found in the lungs.

This factor consists of a complex mixture of lipids and specific apoproteins and covers the alveolar surface of the lung.

Its function is crucial for survival already from embryonic life, mainly to maintain a low surface tension in the alveolar-arterial barrier and preventing alveolar collapse on exhalation.

It is produced by alveolar type II cells, in the same cells where the transmembrane ACE2 receptor is present, but also in the Clara cells and the submucosal cells.

The synthesis of surfactant glycerophospholipids and surfactant proteins is multifactorially controlled and regulated by a number of hormones and factors, such as glucocorticoids, prolactin, insulin, growth factors, estrogens, androgens, thyroid hormones and catecholamines acting via β-adrenergic receptors and cAMP.

It contributes to the lung’s natural immunity thanks to its immunoregulatory properties.

Its immunological properties are to collect and bind pathogens, but also to recruit the activation of polymorphonuclear and macrophages. Macrophages are thought to play a huge role in COVID-19.

It also induces phagocytosis and removes necrotic and apoptotic cells as well as other actions which are important to immune response.

Disorders of this factor have been reported in other diseases, such as ARDS, pulmonary edema, sarcoidosis, pulmonary fibrosis.

Four specific surfactant proteins have been identified to date and many of the surfactant’s immune effects are performed through these proteins.

The gene type of special surfactant protein-A (SP-A) is localized on 10q22-23 chromosome, while that of SP-B is localized on another chromosome.

Various polymorphisms have been identified in research for both SP-A and SP-B, and some of them have been linked to diseases.

Surfactant proteins have also been found in other organs of the body.

 

Two factors of alveolar type II cells affected by COVID-19.

With the assumption that “as evidenced in international literature” the SARS-CοV-2 infiltration and infection of alveolar type II cells is facilitated through the presence of the transmembrane ACE2 receptor.

It is possible, though, that ACE2 may not be the only infiltration gateway for SARS-CoV-2. Some further entry points are mentioned next.

In any case, infection of these cells is facilitated by the presence of these receptors to which SARS-CoV-2 binds.

In summary, SARS-CoV-2 infiltration in COVID-19 patients causes the destruction of alveolar type II cells when the Spike (S) protein binds to ACE2, the complex enters the cells and these cells are subsequently infected and destroyed, which results in the loss of at least two of their extremely important functions in immunoregulation, and not only.

  1. A) The destruction of alveolar type II cells by SARS-CoV-2 infection affects the body and results in loss of the immunoregulatory effects of ACE2 and reduction of the protective production of angiotensin 1-7 through this receptor and through Mas, consequently reducing its protective effects as well, which are vasodilatory, anti-inflammatory, anti-fibrotic, anti-thrombotic etc.
  2. B) The destruction of type II cells also causes loss of the protective effects of the surfactant produced by these type II cells and consequently alveolar collapse occurs.

These and other mechanisms, such as synthesis, secretion, action of pro-inflammatory factors, accumulation of inflammatory and immune cells, and tissue damage resulting from local inflammation, clearly cause hypoxia.

Hypoxia, among other mechanisms, caused the activation of hypoxia factor (HIF) with further consequences.

HYPOXIA:

Hypoxia is a complex phenomenon activating many transcriptional regulators.

It is known that in cases of hypoxia, when the production of oxygen in tissues is reduced, the body mobilizes important defense mechanisms.

In hypoxic conditions, activation of a hypoxia-inducible factor (HIF) is extremely important, because it appears to switch hypoxia genes, forcing the cells to adapt their metabolic processes to the new conditions. This causes cellular response and involvement of several substances, which drive cellular adaptation via metabolic changes in order to ensure that cells manage to maintain their functions in the new low oxygen conditions.

Cellular metabolism and its adaptability seem to be a key regulator for the further functioning of the cells involved in the case of infection as well, which concerns both the maintenance and adaptation of the immune system’s functions and cells.

Hypoxia can be either acute or chronic.  It has been documented in international literature that chronic oxygen reduction triggers changes in cellular function through genetic modification.

To date, we are aware that the most important regulator of oxygen homeostasis is hypoxia-inducible factor HIF-1. Under lack of oxygen, the activity of HIF-1 increases in all nucleated cells. It is a heterodimeric protein. Two subgroups are known, with different actions, HIF1-α and HIF1-β.

Various studies show that both HIF1-α and HIF2-α are regulated by pro-inflammatory factors, such as TNf-α, interleukin 6, interleukin 1b via different mechanisms.

HIF1-α modifies, regulates the transcription of a wide range of genes (over 100), including genes of important functions which relate to erythropoiesis, metabolism, apoptosis, control of oxygen free radical production, angiogenesis, vascular remodeling, vascular tone, vasomotor contractility and inflammation.

HIF is the most important regulator of oxygen homeostasis and affects cellular adaptability, in hypoxia conditions, in a complex way. It also increases enzyme production.

The role of glucose and Ph is likely to be crucial for cell metabolism.

What happens to Ph in hypoxia?

The expression and stabilization of HIF is affected by hypoxia and inflammatory conditions also in terms of immune cells.

HIF induces a number of actions at the level of the host’s immune function and may dictate changes in the function of both myeloid cells and lymphocytes.

That is, it is possible that HIF controls or modifies the responses of lymphocytes and myeloid cells and in general the actions of the immune system both in the infection microenvironment and in the body.

Under hypoxia, HIF regulates the function of many genes, e.g., the vascular endothelial growth factor, the glucose transporter 1 etc, and this is also the case in macrophages.

This process as well is achieved by the activation of genes as a result of hypoxia and this probably concerns the macrophages.

The expression and stabilization of HIF in the cells of the immune system, the enhancement of phagocytosis and the promotion of T cell differentiation, as well as the cytotoxic activity due to hypoxia, may be crucial in immune response via further secretion of pro-inflammatory and other factors that determine progression of the disease and, in some severe cases, lead to overreaction of the immune system in the form of a cytokine storm or a macrophage-activation syndrome (MAS).

 “Lung”

Hypoxia, among other things, also induces the release of nitric oxide and adenosine, which play an important role in the mobilization of the membrane protein kinase PKC.

In hypoxic conditions, the production of free radicals, the ATP decrease and calcium overload activate the PKC isozyme which phosphorylates SERINE AND THREONINE groups, the proteins of the mitochondrial channels, ultimately activating the ATP-sensitive potassium channels (K+ATP). These mechanisms are critical to the functioning of many organs.

Here lies the question: does hypoxia play a role in the activation of serine TMPRSS2, which is known to be a prerequisite for the binding of the Spike (S) protein to ACE2? That is, is hypoxia involved in the activation of serine TMPRSS2 or not?

This question arises since TMPRSS2 is an androgen-dependent serine, the activation of which is a prerequisite for the infiltration of SARS-CoV-2 into the lung’s epithelial cells.

It is possible that this protease is not the only one responsible for the infiltration of SARS-CoV-2, but there may also others. This eventuality is worth investigated further.

MIF

HIF1-a seems to be functionally interdependent with MIF. This apparently is critical, since MIF is a hypoxia-induced gene through a HIF1-dependent mechanism.

Macrophage migration inhibitory factor (MIF).

This is a protein which is produced by different cell types. It was initially thought that T cells are this protein’s main secretion source.

Recent studies, however, have shown that MIF is produced by the anterior pituitary gland, and was identified as a pituitary mediator which acts as a hormone that opposes the action of glucocorticoids in relation to the defense system.

Recent research has shown that it is a protein hormone which is released by the anterior pituitary gland and in particular by the same cells that secrete ACTH (Nisino et al.1995) and the adrenal glands in combination with the activation of the HPA axis. These pituitary cells, as well as the macrophages, contain a significant amount of preformed MIF in intracellular reservoirs and can be released immediately. MIF is an important modulator of immune and inflammatory responses.

There are many mechanisms via which MIF can regulate inflammatory responses and compensate the effects of glucocorticoids, one of which is through Nf-kB, an important regulator of inflammatory cytokine gene expression.

MIF also functions as a cytokine with multiple and specialized roles in regulating the immune response, which are different to those of other cytokines.

An important observation is the further investigation of the eventuality that MIF may maintain macrophage survival and pro-inflammatory function by suppressing the activation-induced p53-dependent cell apoptosis (Ayala et al. 1996 and William et al. 1997).

One possible scenario that needs to be further investigated is the role of MIF in the immune-inflammatory response as infiltration regulator, activation-inducer, and promoter of macrophage-type and eosinophil-type survival of inflammatory cells.

MIF genetic polymorphisms could be the cause of autoimmune-inflammatory conditions and other human diseases.

Finally, it is clear that MIF plays a decisive role in regulating both the innate and adaptive immune response, since it is a powerful key pro-inflammatory mediator in the immunoendocrine axis.*

It therefore appears that MIF occurs at all levels of the HPA axis (Baher 1998) and that MIF expression in the pituitary gland is induced by CRF in a cAMP-dependent fashion (Waedr et al. 1998), which then triggers production of ACTH and corticoids.*

Due to its effects and interaction with other hormones, as well as its action on endocrine axes involved in immunoregulation, further investigation of these effects from an endocrine point of view is of great interest.

However, MIF is not only a cytokine that plays a critical role in various inflammatory conditions, possibly even involved in COVID-19, but also has other endocrine and enzymatic functions.

It is an important neuroendocrine buffering factor that affects the functions of this axis and has immunosuppressive effects, mainly in relation to glucocorticoids.

MIF’s pro-inflammatory properties are strongly expressed by innate immunity cells, considering that this is a factor being released by stimulated lymphocytes, also involved in adaptive immunity playing an extremely important role.

One of MIF’s main production sources are the T cells of the immune system, but is also expressed in monocytes, dendritic cells, macrophages, polymorphonuclear cells, eosinophils and beta cells. It is also expressed in many other tissues, which are mainly in direct contact with the environment, such as the gastrointestinal, urinary and genital systems, skin, eyes, and lungs.

The high levels of MIF expression also found in tissues of the endocrine system and MIF’s role in the hypothalamus, the pituitary gland and the adrenal glands, possibly via close interdependence with glucocorticoids, are also of great interest.*

MIF appears to be a multifunctional buffering factor with pituitary hormone, pro-inflammatory cytokine and enzymatic activities.

It also appears to be involved in the complex network of immunoendocrine adaptation.

Just like prolactin, substance P, MIF antagonizes some of the peripheral actions of glucocorticoids, possibly also boosting the immune response, and promotes the expression of cytokines by macrophages and T cells

Further study of this factor is required, considering that MIF seems to play a key role in the immune system and further investigation into its effects could further help understand the mechanism of controlling inflammatory and immune responses.

An unusual feature of MIF is that glucocorticoids enhance its expression and are known to suppress the expression and activity of many cytokines.

Paradoxically enough, MIF has the ability to antagonize the anti-inflammatory effects of corticosteroids.

It is well known that glucocorticoids interfere with the immune response in the event of an infiltration. Among other things, MIF seems to act and compensate the inhibitory effects of steroids on immune response, the activation of immune cells and the production of cytokines.

In other words, it acts as an anti-regulatory hormone for the action of glucocorticoids.

Macrophages and T cells produce MIF in response to glucocorticoid secretion and upon activation by various pro-inflammatory stimuli.

Recent studies have shown the unique properties of this macrophage migration inhibitor, which acts as a cytokine, in a completely different fashion compared to other cytokines but also different compensatory hormone properties compared to other hormones, especially in connection with glucocorticoids.

At normal glucocorticoid concentrations, MIF is released by T cells and macrophages.

MIF’s secretion is strictly regulated and reduced at the presence of steroids in high concentrations when the anti-inflammatory effects of steroids are required, e.g., in situations of stress and infections.

Once released, this factor compensates the immunosuppressive effects of steroids on immune cell activation and cytokine production. This means that it acts as a regulator of glucocorticoid effects, however when it comes to MIF, activation is not enough; stabilization is also required

MIF is rapidly released by immune cells exposed to either pro-inflammatory cytokines or microbial products, or during activation of specific antigens. It has significant autocrine and paracrine secretion and promotes cell proliferation and survival, but also has further effects, e.g., it promotes directly or indirectly the production or expression of a large number of pro-inflammatory factors, such as IL-1, IL-2, IL-6, IL-8, and inflammatory macrophage protein 2, TNf, interferon gamma, nitrate oxide, prostaglandins, metalloproteases, etc.

MIF inhibits the immunoprotective effects of glucocorticoids. It antagonizes the effects of hydrocortisone on NFk-B.

The pro-inflammatory effects and immunoregulatory properties of MIF may be involved in the pathogenesis of various conditions and the high levels of MIF expression are related to the severity of such conditions (ARDS, sepsis, etc.).

Some conditions in which MIF appears to play a leading role at an experimental level are various diseases, such as type 2 diabetes and pancreatitis, dermatitis, psoriasis and collagen diseases, iridocyclitis, rheumatoid arthritis, ARDS, nephritis, sepsis and septic shock, as well as allergic and autoimmune conditions.

Patient blood counts in various studies have shown excessive MIF production at the acute phase of sepsis and septic shock. There is also a correlation between MIF levels and interleukin 6 levels, acute lung damage levels, cortisol levels, and the severity of sepsis.

MIF is recognized as an intracellular signaling molecule in various conditions. Its action is associated with HIF-1a.

It has been reported that neutralizing MIF activity, or inactivating the MIF gene, reduces inflammatory response and improves survival.

Macrophage-activation syndrome

Macrophage-activation syndrome is characterized by systemic stimulation and activation of macrophages in the bone marrow. It is a rare condition, classified as primary, genetically predetermined, but also as secondary, reactive to infections caused by viruses, bacteria, fungi and parasites.

It is characterized by an intense reactive process and multisystemic inflammation, resulting from the prolonged and intense activation of antigen-presenting cells, such as macrophages and mast cells, and TCD8 cytotoxic lymphocytes.

It is characterized by functional abnormalities of NK cells, intense hyperplasia and ectopic migration of T cells.

It is a recorded syndrome with fever, lymphopenia, cytopenia, low platelets, increased ferritin, increased soluble interleukin 2 receptor, splenomegaly etc among its diagnostic criteria.

 

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