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HMGB1, microRNA, Inflammation, and Coagulation Charles Lewis, MD
MPH
NOTICE: This is a largely theoretical discussion of agents that
may be useful in the treatment of COVID-19,
sepsis and cytokine storm. It is being posted to suggest
potential lines of inquiry for researchers interested
in conducting laboratory research or use in well-controlled,
sanctioned clinical trials. It should not be
assumed to be correct. It should not be construed as medical
advice.
In COVID-19, there is both inhibition of immune processes and
hyperactivity of immune systems. In the
simplest terms, the adaptive immune system is down-regulated
making the production of protective
antibodies inefficient, while parts of the innate immune system
are quiescent and other parts go into hyper-
drive, causing tissue injury while not effectively stemming
viral replication.
One part of innate immunity that is upregulated is illustrated
below.
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ZBP1 is an intracellular protein that is part of the innate
immune system. It is activated by the presence of
viral RNA or DNA. Both ZBP1 and TRIF (not shown here) activate
RIPK3. RIPK3 activates the “necrosome”
which activates numerous functions that result in the death of
cells infected by a virus. As part of this
process, HMGB1 is released from the cell. HMGB1 act locally as a
Damage-Associated Molecular Pattern
(DAMP) signal, promoting a higher level of inflammation. ZBP1
also activates Interferon Related Factors,
IRF3 and IRF7, which are nuclear transcription factors for the
expression of interferon α and β (IFNα and
IFNβ). ZBP1 also activates JNK. SARS-CoV-2 is a single stranded
RNA virus. Thus, presence of SARS-CoV-2
RNA in the cells activates ZBP1.
The SARS-CoV viral protein Papain-Like Protease (PLPro) inhibits
the production of IFNα and IFNβ. IFNα
and IFNβ are essential to both innate and adaptive immunity. In
adaptive immunity, they stimulate T-
helper cells which help coordinate B-cell production of
antibodies, among other functions. These cytikines
also stimulate Natural Killer cell function.
Another SARS-CoV viral protein, ORF3a also activates the NRLP3
inflammasome via TRAF3,1 and ACS.
This stimulates the assembly of the NRLP3 inflammasome that
promotes the pyroptosis form of
programmed cell death. NLRP3 is a cellular stress sensor.
Activation of the NLRP3 inflammasome leads to
Casp1 activation and IL-1β and IL-18 release and active
secretion of HMGB1. In this process HMGB1 is
released along with inflammatory cytokines. HMGB1 binds with
TLR4 and TRL2, stimulating additional
inflammatory activity.
This virus may also causes inflammation by depleting ACE2, an
anti-inflammatory protein. ACE2 is the
protein the SARS-CoV-2 binds to on the surface of the alveolar
cells and certain other cells of the body.
Without an adequate anti-viral and innate immune signalling
response from the target cells of SARS-CoV-2,
i.e.; the alveolar endothelial cells, there is delayed
protective immune response and poorly control over virus
proliferation. There is likely little cytokine signaling to
myelogenous immune cells, (NK cells, Monocytes, T
helper cells) until the infected cells start necroptosis or form
inflammasomes that induce pyroptosis. Under
these cascades, there is the late release of IL-1, IL-33 and
DAMPSs including HMGB1, ATP and
mitochondrial DNA.
Once DAMPS are released, they activate macrophages and
monocytes. HMGB1 and IL-1 and other DAMPs
thus can act as delayed stimuli for immune response. HMGB1 is
ligand for the pattern recognition receptors
(PRRs) TLR4 and TLR2 receptors that promote the inflammatory
response in white blood cells. TLR4
activation by DAMPS activates NK-κB as well as other
transcription factors for the inflammatory response
that produce TNFα and other cytokines.
DAMPs are largely released as a part of pyroptosis and
necroptosis; it can be understood that these
cytokines signal the need for “a cleanup crew” to breakdown and
clear up dead and injured cells after injury.
This mechanism did not evolve to act as a primary immune
mechanism to get rid of a virus, but rather as
demolition after injury, prior to repair. When this process
becomes the primary immune response, it
functions through tissue destruction. Thus, DAMPs act as
cytokines for macrophages to move into the
alveoli, where they clear up dead cells, but also cause injury.
Additionally, filling the alveoli with white blood
cells, the leaking of serous fluid, and the injury they provoke
can cause acute respiratory distress syndrome
(ARDS). It is neutrophils and macrophages that have migrated to
the lungs which are the major source of
cytokines fueling the inflammatory reaction.2
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Over-production of TNFα or vigorous releases of HMGB1 fuel the
acceleration of the inflammatory
response. It can become like a fire that will burn until it runs
out of fuel. While TNFα and INF appear in
hours, and can remit as quickly, HMGB1 release from the cell
nucleus into the cytoplasm and subsequent
release from the cell can take one to two days. After that,
HMGB1 remains in the blood stream for several
days, and can affect most of the organs as well as white blood
cells. In the lungs it causes neutrophil
infiltration, edema and alveolar injury.
In SARS and severe influenza, the development of a sepsis-like
lung disease can develop. There is
recruitment of macrophages to the lung and destruction of the
alveolar endothelium. In severe COVID-19
there are cytokine storm-like processes, however we now
understand that the primary disease is vascular,
involving the endothelium, and the lung disease is at least
usually a secondary effect.
There is emerging evidence that there are two different
presentations of severe COVID-19; a wet and a dry
form.3 Recognizing these two presentations of severe COVID-19
not just important in the respiratory
management of the disease, but also because it suggests that the
two different presentations may involve
different immune pathways.
In the dry form, which is more common and less severe, the
amount of fluid in the lung is not greatly
elevated and the lungs have near normal compliance. The patient
is able to breathe, but does not get
sufficient oxygen. It is thought that there may be either
vasoconstriction of the pulmonary venules so that
the blood is not getting sufficiently oxygenated, and/or there
may be micro-thrombi, blocking blood flow to
the pulmonary capillaries. Another additional theory is that the
red blood cells are not carrying oxygen
normally. In the dry form of COVID-19, the lung maintains good
compliance (elasticity) and the patient can
move air in and out of the lungs without excessive difficulty,
but is not having good gas exchange in the
lungs. Intubation with the use of a ventilator with PEEP
(positive end expiratory pressure) may not be
helpful and may be dangerous to the patient; however oxygen
therapy is typically required. The dry form
appears to be the more common, or perhaps may just appear
earlier in the disease.
In the wet form, the lung has a high level of fluid in the
alveoli. This presentation is like the typical ARDS
(acute respiratory distress syndrome) with macrophage and
neutrophil infiltration, edema and alveolar
injury. Here therapy with a ventilator and PEEP to expand the
alveoli may be helpful.
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In COVID and influenza, OxPL (oxidized phospholipids) are
released from virally infected cells as a result of
oxidative stress.4 This response is protective, as it allows the
mounting of the TLR4 (Toll-like receptor-4)
triggered immune defense.5 TLR4 is a cell surface protein that
is activated by DAMPS and PAMPs
(pathogen-associated molecular patterns). Several Toll-like
Receptors activate MyD88. MyD88 mediates
several downstream events culminating in the release of NF-κB, a
transcription factor for TNFα, IL-1β, IL6,
and IL-12. MyD88 also promotes the transcription for INFα and
INFβ.
As a secondary trigger, intracellular TLR3 (Toll-like
receptor-3) response is activated by the presence of
single-stranded RNA (ssRNA) in the cell. TLR3 triggers TRIF,
which is a MyD88-independent pathway that
also promotes INF-α and INF-β.
Viral ssRNA is sensed in the cell by RIG-I-like receptors (RLR),
which causes ubiquitination of STING,
which promotes the phosphorylation and activation of TRAF3.6
TRAF3 promotes activation of TBK1/IKKε
which promotes NF-κB and activates IRF-3 dimerization, which
that allows IRF-3 to enter the nucleus,
where it is a transcription factor for interferon that is
essential to mounting an adequate antiviral defense.7 8
Both SARS-CoV and SARS-CoV-2 viruses code for a viral enzyme,
Papain-like Protease (PLPro - EC
3.4.22.B50). This protein inhibits the ubiquitination of STING,
and the phosphorylation of TRAF3. Thus,
the virus can defeat much of the TLR3 – TRIF – TRAF3 pathway for
expression of interferon, and thereby
inhibit the activation of NK cells and T cells and their
production of antibodies to the virus. PLPro also
interferes with the TLR7 signalling pathway.9 Viral protein
inactivation of IFNα and IFNβ depress innate
immunity and limit T-cell activation towards the formation of
antibodies by B cells.
Another SARS-CoV viral protein, ORF3a also known as Viroporin
3a, activates the NOD-like receptor P3
(NRLP3) inflammasome. Viporin acts as an ion channel allowing K+
efflux and release of ROS from the
mitochondria.10 The inflammasome activates Caspase 1, which
cleaves pro-IL-1β into the active
proinflammatory cytokine IL-1β.11 This action may be further
upregulated by HMGB1 TLR2 activation.12
ORF3a activates ACS and thus pyroptosis – thus can induce
programmed cell death. Why would it be to
virus’s evolutionary advantage to kill its host cell on which it
is dependent for reproduction?
It appears that SARS-CoV-2 can also infect lymphocytes. Although
lymphocytes bear very low levels of
ACE2, the virus appear to be able to enter these cells via CD147
(aka basigin).13 CD147 is essential for T-cell
and NK cell development and differentiation and mediates the
specific type of immune target these cells
recognize.14 Thus, the coronavirus may cause lymphopenia by
inducing pyroptosis in lymphocytes or
common lymphoid precursor cells. Viral ORF3a may thus help
eliminate Natural Killer cells and T cells
essential for anti-viral defense.
Red blood cells bear very high levels of CD147, however, these
cells lack the cellular machinery to reproduce
viruses.
-
(Adapted from KEGG Influenza pathway, modified to reflect COVID
and viral proteins PLPro and ORF3a)
In a study of mice infected with SARS virus, mice with MyD88
knockout had a mortality rate over 90%
within 6 days, while all the wild-type test mice survived the
infection.15 Clearly the MyD88 pathway is
critical to survival of this infection.
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In a subsequent study, mice with TLR4, TLR3, or TRAM knockout
mice, were infected with the SARS virus.
They were found to lose more weight as a result of the infection
than wild-type mice, but there were no
deaths. When TRIF (toll-like receptor adapter molecule 1)
knock-out mice were infected with the SARS virus
they had reduced lung function, more lung injury, higher viral
loads and higher mortality than wild-type
mice. Thus the TRIF pathway is an important for survival from
SARS COVID infections.16
If both TRIF and MyD88 pathways are impaired, there is little
way to fight these infections. SARS-CoV viral
papain-like protease (PLPro) is a protein that impairs the
adaptive immune system, by inhibiting the
formation of interferon alpha and beta. If the virus can defeat
the TRIF pathway at the level of TRAF3 via its
enzyme PLPro,17 that leaves the NFκB pathways. As a result of an
incompetent response to the virus and
inability to adequately mount T cell activation and antibody
response, there is then a cycling upregulation of
IL-1, IL-6, TNFα, and other cytokines. The recruitment of
monocytes and macrophages causes tissue injury
and activation of the NF-κB activates JAK/STAT1 and activation
of the inflammasome, which cause the
release of HMGB1. HMGB1 activates and reinforces TLR4, creating
a positive feedback loop of cytokine
release, inflammations, macrophage recruitment, and injury but
without activation of NK and T-cells.
It can thus be understood that inhibiting the immune response
early in the TLR3 and TLR4 pathways in
viral target cells, wherein activation of MyD88 or TRIF are
inhibited, it impedes the ability to signal for the
development of an appropriate immune response. Production of
interferon α and β, the activation of NK
cells, and development of T1 helper cells and of antiviral
antibodies are essential to mount a defense and
recovery from SARS, influenza and COVID.
TLR4 also mediates the MAPK signalling pathway and AP-1 which
promote the chemotaxis and survival of
white blood cells. AP-1 signally may worsen tissue damage in the
lungs and endothelial cells. While some
aspects of the pathway are essential to forming immunity, INF-β
production from non-infected cells
stimulated by DAMPs can stimulate the JAK/STAT1 signalling
pathway, which further promotes HMGB1
migration from the nucleus to the cytoplasm. Cell death also
releases HMGB1, which like OxPL, activates
TLR4. Thus HMGB1 can create a positive feedback that ramps up
tissue injury. Thus, incomplete TLR4
response in infected cells mutes the immune response and allows
viral proliferation; excessive immune
response promotes severe life-threatening damage by monocytes
and macrophages in response to PAMPS
such as HMGB1 later in the disease process.18 HMGB1 is a potent
chemokine and activator of immune
mediated cell destruction that plays an important role in the
lung damage occurring in SARS, influenza and
presumably COVID-19.
Medication:
The beta blocker labetalol has been identified as potentially
having SARS-CoV viral papain-like protease
(PLPro) enzyme inhibitory effects. 19 Thus, it may help prevent
SARS-CoV-2 immune evasion. Additionally,
labetalol lowers blood pressure and should protect the heart
from arrhythmias caused by long QTc,20 (both
common issues in patients with severe COVID-19) and thus may
reduce risk of sudden cardiac death
associated with this disease.
I suggest a trial of labetalol in appropriate COVID-19 patients.
I suggest a starting treatment dose at about
150 mg/ day in divided doses for a 70 kg adult.
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Cytokines in COVID-19
In a Chinese study comparing severe and critical ICU COVID-19
patients to those with less serious illness,
those with severed disease had higher blood levels of
interleukin-2 (IL-2), IL-7, granulocyte-colony
stimulating factor (GSCF), interferon-γ inducible protein 10
(IP10), monocyte chemoattractant protein 1
(MCP1) (aka; CCL2)), macrophage inflammatory protein 1-α
(MIP1α), and tumor necrosis factor-α
(TNFα).21
In a separate study of bronchoalveolar lavage fluid and
monocytes of COVID-19 patients, CCL2 (MCP-1),
CXCL10 (IP-10) CCL3 (MIP-1A) and CCL4 (MIP1B) were highly
expressed.22
In SARS-COV, the spike protein triggers ACE2 signalling, which
activates the Ras →ERK→AP-1 pathway.
TNFα transcription is induced by AP-1 as well as by other
inflammatory transcription factors.
TNFα strongly induces numerous inflammatory molecules. In breast
cancer cells, exposure to TNFα was
found to increase the transcription of CCL2 by over 60 times,
CXCL10 by 29 times, and complement C3 by
six times.23 TNFα strongly induces the expression of
fibrosis-associated CCL2. CCL2 is a chemokine for
monocytes and macrophages. Additionally, CCL2 limits the
survival of antibody forming cells in the lymph
nodes.24 CCL2 was associated with severe lung injury and
fibrosis in SARS.25
Treatment:
Apigenin, a phenolic compound present in certain edible plants,
inhibits the canonical and non-canonical
NLRP3 inflammasome pathways by decreasing caspase-1 and
caspase-11 enzyme expression and activity.
Apigenin strongly down-regulates CCL2.26 In tumor cells, a
non-toxic dose of apigenin was found to reduce
TNFα induced transcription of IKBKε by 108%, MLKL (a mediator of
the necrosome/inflammasome
pathway) by 106%, CCL2 by 97%, complement C3 by 91%, IL-6 by
88%, CXCL10 by 83%, TLR2 by 79%,
PAI-1 by 77%, the IL7 receptor by 76%, and Complement Factor B
(CFB) by 68%.27 Apigenin upregulates
miR-155.28 miR-155 inhibits TNFα and the NF-κB signaling pathway
in cytokine storm in animal models
and human cell macrophages.29 The down regulation of C3 and CFB
by apigenin are of significant interest in
this disease, as complement activation is associated with worse
outcome in mice with SARS, as discussed
below.
Cathespin S (CAT S) expression was found to be increased six
times by TNFα in cancer cells in the study
above, and was down regulated by apigenin by 66%.27 CAT S is a
lysosomal cysteine protease. This enzyme
has an important role in antigen presentation; it cleaves
proteins into little chucks so that they can be
presented on MHC II (major histocompatibility complex II)
molecules for display on the cell surface. This
allows immune cells to tell if the cell is adorned with “self”
proteins or foreign proteins – in which case the
T-cells will attack the cell and promote the development of
antibodies to the foreign antigen. If there is
insufficient CAT S, then large pieces of the proteins are
displayed on the MHC II; this decreases immune
recognition of foreign proteins and immune response to them. If
there is over-abundant CAT S, it can cause
the proteins to be cut into small fragments and be presented by
the MHC II; this can trigger autoimmunity.
Thus, while up-regulation of TNFα assists in mounting an immune
response, excessive levels can promote
autoimmune injury.30 Perhaps during cytokine storm, non-infected
cells, over stimulated by TNFα and over-
producing CAT S, may become targets of attack by the immune
system. Furthermore, CAT S from alveolar
macrophages, a cysteine protease, can also act as elastase. Thus
it may promote alveolar injury similar to
-
that caused by neutrophil elastase, which causes emphysema. This
may be especially damaging during
mechanical ventilation.31
I recommend the use of apigenin for the prevention and treatment
of COVID-19, cytokine storm, sepsis, and
viral pneumonia, and herein, specifically for the prevention and
treatment of severe COVID-19. The dose
estimate for apigenin for a severely ill COVID-19 patient is
about 250 to 400 mg per day, while 100 mg per
day in divided doses maybe helpful for persons at high risk of
severe COVID-19 associated with chronic
endothelial disease (HTN, type 2 diabetes, CAD, etc.).
Preferably apigenin should be used in combination
with other agents, such as pomegranate juice, as discussed
below.
Coagulation/Complement Cascade
In another mouse study of SARS-CoV, mice with complement C3
knock-out mice (C3-/-) were infected with
the SARS virus. Wild-type (C3+/+) mice when infected with the
virus generally have viral infection in the
lungs, lose weight and have an increase in inflammatory
cytokines, but do not die. With SARS infection C3-/-
mice has less weight loss, reduced lung pathology and lower
cytokine levels in both the lung and blood. The
viral load in the lungs of the C3-/- mice was no different than
in the C3+/+ mice. This suggests that the
complement cascade while exacerbating the pathology of SARS
provides little if any benefit in clearing the
disease. Thus therapy that inhibits the complement cascade may
be helpful in treating the disease.32
There are multiple pathways for activation of the complement
system; some of the pathways are closely
aligned with coagulation. Microbes can activate C3, but it is
also activated by plasmin and thrombin. When
C3 becomes activated, it activates C5. Thrombin may activate C5
directly.
Complement factor B mediates the alternative pathway activation
of both C3 and C5. The alternative
pathway is activated by infection. Apigenin down-regulates TNFα
induced upregulation of C3 and CFB.
In severe SARS-CoV infections there is diffuse alveolar damage,
vascular leakage into the alveolar spaces,
premature breakdown of fibrin clots and possible
micro-hemorrhage in the lungs. Similar pathology is seen
with severe strains of influenza, including the 1918 and 2009
H1N1 influenza viruses. In the 1918 H1N1
pandemic, many young patients died a hemorrhagic death. With the
outbreak of SARS in 2002, we were
fortunate that the outbreak was small, and there were a limited
number of cases. With COVID-19, were have
found, that while presenting as a pulmonary disease with
hypoxia, it likely primarily affects the endothelial
cells of the vasculature, and microvasculature, causing
vasoconstriction and micro emboli to the lungs.
COVID-19 patients with elevated levels of D-dimer, a fibrin
degradation product, have a higher mortality.33
D-dimer is an indicator that there has been clot formation and
breakdown. Heparin and warfarin inhibit
coagulation Factor Xa, an enzyme that promotes cleavage of
prothrombin to thrombin, which activates C3.
Heparin therapy in COVID-19 patients appears to lower
mortality.
A series of autopsy of four COVID-19 cases was performed at
Tulane University Medical Center. All the
decedents had had elevated ferritin, fibrinogen, PT (prothrombin
time), and very elevated D-dimer,
indicating disseminated intravascular coagulation. Nevertheless,
on autopsy, thrombotic microangiopathy
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was restricted to the lungs. The lungs were heavy (wet) lungs
and the decedents had dilated right heart
ventricle, suggestive of right heart failure following pulmonary
hypertension and pulmonary edema. There
was an abundance of megakaryocytes in the lungs, as had been
found with SARS infections. These cells
produce platelets, and likely play a role in micro-thrombosis
and blockage of the pulmonary capillary bed. 34
In early disease, such pulmonary capillary blockage would cause
the shunting of blood through un-aerated
parts of the lung, causing hypoxia. This would be exacerbated by
vasoconstriction. As the disease
progressed, the elevated capillary pressure would cause leakage
of fluid into the intestinal fluid and into the
alveoli causing pulmonary edema and worsening hypoxia.
Eventually, the right ventricle of the heart may
become unable to pump sufficient blood through the lungs and
suffer exhaustion and fail.
There is renal injury in severe COVID-19. More than half of
hospitalized COVID-19 patients with severe not
prior history of kidney disease were found to have proteinuria,
hematuria and leukocyturia.35 Many COVID-
19 survivors require dialysis.
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The coagulation/complement cascades is likely important in the
causation of the “dry” lung manifestation of COVID-19. Virally
induced endothelial injury in blood vessels causes oxidative
injury, los of nitric oxide production and thus vasoconstriction,
platelet activation, activation of prothrombin to thrombin as a
result of activation of Factor X to Factor Xa. This causes the
formation of microemboli that are filtered in the capillaries of
the lung. This would explain the hypoxia with normal lung
compliance seen in the dry manifestation of the disease. Heparin
inhibits the enzymatic activity of Factor Xa.
As illustrated above, the coagulation cascade promotes
activation of the complement system via both
thrombin (pro-fibrin production) and plasmin (pro-fibrinolysis).
The complement system is part of the
innate immune system. It promotes chemotaxis, drawing more white
blood cells to the area and promotes
degranulation and phagocytosis. C5 activation (by C3) promotes
assembly of the Membrane Attack
Complex, which targets and kills virally infected cells; in
COVID-19, the alveolar cells are the target.
Activation of the complement cascade occurs as early as the
first day following inoculation of animals with
the SARS-CoV virus. Complement activation is known to increased
vascular permeability, a feature of severe
SARS-CoV infection that is associated with poor outcome.
Baseline complement activity increases with age,
and is consistent with the increase mortality with age in SARS.
Furthermore, complement activation is
predictive of the development of ARDS. Complement activation
increases inflammation and promotes lysis
of cells, causing the release of damage associated molecular
patterns, (DAMPs) such as HMGB1. DAMPS
can then further activate the inflammatory cascade and the
complement system.36
IL-1β and TNFα → uPA → Plasmin → C3 → C3a, C3b and C5
activation
DAMPs → C1, C4 → C3 → C3a, C3b and C5 activation
Viral endothelial injury → X → Xa → Thombin → C3
Tissue plasminogen activator (tPA) (EC 3.4.21.68) also activates
plasminogen as does uPA. Kallikrein also
promotes plasminogen.37 Later in the disease course of severe
SARS, there is fibrin degradation and
bleeding into the alveoli. This may be followed by lung fibrosis
in survivors.
Medications:
Anti-coagulation therapy likely needs to be part of the
treatment of regimen of hospitalized patients with
COVID-19. Acetylsalicylic acid, P2Y12 inhibitors, and
glycoprotein IIb/IIIa antagonists, may reduce lung
injury and mortality in COVID without increased bleeding risk.38
Nevertheless, many studies have failed to
find a survival benefit using anticoagulant therapy in
sepsis.39
As shown in the figure above, heparin (LMWH) is a logical choice
in the treatment of severe COVID-19 for
the prevention of coagulopathy and complement activation.
Statin drugs also impact the PAI-1 and tPA. Statins induce tPA
and inhibits plasminogen activator inhibitor-
1. Thus, statins have an anti-fibrosis effect on wound healing
by promoting the degradation of fibrin
-
products.40 41 Atorvastatin has been found to increase the
expression of ACE2 in the heart of animals.42 43
This may or may not be a class effect. Statins also downregulate
ICAM-1, a protein whose expression is
required for Killer T-cells to adhere and eliminate
viral-infected cells.44 I suggest that simvastatin and other
statin medications be avoided during the course of COVID. If
they are used, I suggest they be used at very
low dose, i.e.; 5 mg of simvastatin per day.
Urokinase plasminogen activator (uPA) has been found to play a
central activating role in causing fibrosis
and lung injury in SARS.45 uPA activates the conversion of
plasminogen to plasmin which also activates C3
via activation of plasminogen to plasmin. uPA also activates
uPAR (plasminogen activator urokinase
receptor) which induces cell adhesion, migration, and
proliferation.46 The inflammatory cytokines IL-1β 47
and TNF-α 48 induce the activation/expression of uPA.
A literature search for readily available medications that
inhibit uPA revealed amiloride as a potential
candidate. 49 This is an anti-hypertensive drug, and this seems
to be a unique feature of this medication. This
medicine may also inhibit tissue kallikrein,50 an enzyme that
upregulates plasminogen.51 This is not the
drug’s mechanism of action as an anti-hypertensive medication,
but rather a side effect that may be useful in
treating ARDS in SARS and severe influenza. It may reduce injury
and help prevent late effects of the
disease.
In COVID-19, the development of hypertension is part of the
disease pathology in severe disease. Thus
treatment is often needed for hypertension and congestive heart
failure in severely and critically ill COVID
patients. Amiloride is a potassium-sparing diuretic. Hypokalemia
has been found in 93 percent of patients
with severe or critical COVID-19, as a result of urinary loss of
potassium resulting from degradation of
ACE2.52 Amiloride may decrease potassium loss; however,
potassium levels will still need to be monitored. I
suggest a trial using low-dose amiloride (2.5 mg/day) for its
anti-uPA effect. Higher doses may have adverse
effects, especially if the patient is not anticoagulated.
HMGB1
HMGB1 is a moderator of inflammation and survival of phagocytic
white blood cells, and causes prolonged,
vigorous tissue destruction in influenza and SARS, and likely
COVID-19. HMGB1 is a key pathway in sepsis
and septic shock and mediates organ damage. HMGB1 is a nuclear
protein that leaks into the cytoplasm in
inflammation and the out of the cell in cell injury of cell
death. In cancer, HMGB1 promotes cancer cell
proliferation, migration and tissue invasion. It is a DAMP
(damage-associated molecular pattern) that
activates TLR4 (and TLR2) and induces inflammatory cytokines in
cytokine storm. DAMPs create an
inflammatory cascade (HMGB1/TLR4/ MyD88/NF-κB) that can result
in tissue destruction.
Hypoxia/reperfusion, oxygen glucose deprivation, oxidative
stress, and other stressors can cause the
acetylation of the nuclear HMGB1 promoting its translocation
into the cytosol and then into the
extracellular space. Pathogen-associated molecular pattern
(PAMP) molecules, such as LPS and Ox-PL,
which is released in viral infections such as influenza A and
SARS, can activate the TLR4 pathway. The
TLR4 pathway can activate the JAK/STAT1 pathway that also
promotes the acetylation and translocation of
HMGB1 from the cell’s nucleus to the cytoplasm.
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Pyroptosis, a form of induced programmed cell death that is part
of the innate immune response to protect
against intracellular microbial infection. In pyroptosis there
is inhibition of internal pathogen reproduction
and promotion of phagocytosis. Pyroptosis involves TLRs, Casp1
activation the inflammasome and NOD-
like receptors. Extracellular ATP, oxidized mitochondrial DNA,
mitochondrial ROS, and leakage of
cardiolipin from the mitochondria together promote the
activation of the NRLP3 inflammasome, which
activates pro-caspase-1 to Casp-1. Casp-1 activates pro-IL1β and
pro-IL-18 to IL1β and IL-18. TLR4 can also
induce IL-1β processing via Casp-8. Activation of the TNF
receptor promotes pro-IL-1β and NLRP3
inflammasome transcription via nuclear factor-κB (NF-κB)
activation.
MicroRNAs (miR) are non-coding small hairpin-shaped sections of
RNA that bind to specific mRNAs, and
prevent the mRNA from moving through the ribosome. They thus
inhibit the production of the protein for
that the mRNA translates. This is an important way the cell
stops the production of various proteins when
there is a sufficient supply or when there is no further need
for that protein. Many medications act by
inhibiting enzymes or inhibiting or activation cell receptors.
Other proteins are considered non-drugable.
Promoting or inhibiting the production of miR may allow
pharmacologic control of some traditionally “non-
drugable” proteins and pathways. Thus, I explored miRNA
induction as a potential treatment of virally
induced cytokine storm.
Several miR have been identified that, some experimentally in
cell culture and others by chemical modeling,
that down-regulate HMGB1 protein translation. Additionally,
several compounds have been identified that
either up or down-regulate the production of miR that reduce
HMGB1 activity. HMGB1 promotes an
increase in the expression of miR-21 and miR-129-2, and some of
its effects are mediated by these
microRNA. It may be possible to intervene by inhibiting these.
Certain miR have also been identified to be
in higher concentration in patients with cytokine storm or
sepsis, and these may provide clues to treatment,
however, with this type of data, it is essential to understand
whether the rise is part of the cause of injury,
part of the response to injury.
Human pulmonary/cardiac microvascular endothelial cells (HMVECs)
are available that can be grown in
cell culture. Cultured HMVECs grown in the presence of thrombin
have increased permeability. Over-
expression of miR-126 decreased endothelial space, thus
preventing he increase in permeability.53 In mice,
over-expression of miR-126 decreased serum levels of IL-6 and
TNF-α in a model of sepsis, and lowered the
mortality rate. In humans, miR-126 has been found to be
down-regulated in patients with hospitalized with
sepsis, and the degree of down-regulation correlated to the
severity of sepsis early in the disease
progression.54 In a separate study, miR-126 was found to protect
HCMECs against hypoxia/reoxygenation
injury and to decrease inflammatory Reactive oxygen species ROS,
and reduce the expression of IL6, IL10
and TNFα, while increasing the vasodilator NO, and the
antioxidant SOD.55
The table below summarizes the effect of several microRNA on
HMGB1 and cytokine storm relevant to
COVID-19, and list some agents that impact the expression of
these miR. Those estimated to be most
important in COVID-19 and are highlighted in bold. Note that
that the medications metformin and the PPI,
esomeprazole as well as carnosic acid inhibit the expression of
miR that reduce HMGB1 translation and thus may worsen COVID-19
disease. All PPIs may have this effect. Olive oil and vitamin D
deficiency may
increase HMGB1 activity, and thus perhaps should also be
avoided.
Pomegranate Juice: In a gene assay, pomegranate juice
up-regulated genes involved in cell adhesion
such as E-cadherin, intercellular adhesion molecule 1 (ICAM-1)
and down-regulates genes involved in cell
-
migration such as hyaluranan-mediated motility receptor (HMMR)
and type I collagen. It up-regulated
microRNAs including miR-335, miR-205, miR-200, and miR-126, and
down-regulates miR-21 and miR-
373. Pomegranate juice reduces the level of pro-inflammatory
cytokines/chemokines such as IL-6, IL-
12p40, IL-1β and RANTES. 56 In an in vivo study, rats receiving
pomegranate juice had significantly down-
regulated proinflammatory enzymes nitric oxide synthase and
cyclooxygenase-2 messenger RNA (mRNA)
and protein expression. NF-κB and VCAM-1 mRNA and proteins
expression were suppressed. There was
also inhibition of phosphorylation of PI3K/AKT and mTOR
expression and increased the expression of miR-
126.57 Pomegranate juice also is expected to down-regulates
HMGB1 via miR-200a and likely by miR-20558
and also reduces HMGB1 downstream activity as a result of
reduced expression of miR-21 and let-7c. 59
I recommend the use of pomegranate juice (but not other
pomegranate extracts) for the prevention and
treatment of cytokine storm, sepsis, and viral pneumonia, and
herein, specifically for the prevention and
treatment of severe COVID19. I suggest trials beginning with 4
to 8 ounces of pomegranate juice or about 4
to 10 grams of freeze dried pomegranate juice powder per day;
higher end doses may be required for more
severe disease and larger patients.
-
miRNA and HMGB1 60 61 62 63 64 65 66 67 68 69
miRNA MicroRNA Effect Upregulates (Desirable)
Downregulates (Undesirable)
miR-126 Decreases serum IL-6 and TNF-α in sepsis, decreased
intracellular permeability in cell culture. Protects from
hypoxia/re-oxygenation/ reperfusion injury
Pomegranate juice70 Mango polyphenols71 72
miR-129-5p Suppresses HMGB1, RAGE Metformin Downregulated by
40%73
miR-193a-3p74 Targets HMGB1, TGF-β, and HYOU1 Resveratrol
Metformin lowers by 55%75
mir-200a Lowers HMGB1 expression Pomegranate Juice
miR-34a Suppresses HMGB1 (Downregulated in septic shock)
Honokiol, resveratrol and n3-PUFA Pomegranate rind76 EGCG
Carnosic acid77 (Present in rosemary and sage) Quercetin
Curcumin
miR-376a Lowers HMGB1 expression Esomeprazole, (proton pump
inhibitors)78
miR-15579 Inhibits the NF-κB signaling pathway and TNFα.
Apigenin80 Resveratrol81
Quercitin82 Pomegranate
extract
miR-320a, miR-325 and miR-505
Lower HMGB1 expression
miRNA MicroRNA Effect Upregulates (Undesirable)
Downregulates (Desirable)
miR-21 83 HMGB1 promotes miR-21 and NF-κB pathway activity
Oleic acid (olive oil) DIM, Choline, and Folic acid up-regulate.
Curcumin Vit. D3 deficiency n-3 fatty acid deficiency
Resveratrol Avoid vitamin D3 and n-3 fatty acid deficiencies
miR-129-2 HMGB1 increases
let-7c HMGB1 increases EGCG Quercetin curcumin
Pomegranate Juice, Resveratrol
Note: Not intended to be a comprehensive listing of miRNA
related activity, but rather list those
encountered that are pertinent to HMGB1 and cytokine storm in
viral pneumonia and COVID-19.
-
Summary
Medications that may be helpful for COVID-19 and similar
cytokine storm, DIC, sepsis conditions, dose
estimate per day for a 70 kg adult:
1. Low molecular weight heparin (LMWH) All treatment patients
should be heparinized and monitored
with aPTT as per usual hospital protocol. This may already be
part of the hospital’s usual care for
COVID patients. I recommend that all patients (test and control
patients) without contraindication
be placed on LMWH.
2. Labetalol 150 mg (75 mg/BID)
3. Amiloride 2.5 mg QD
4. Vitamin D3 500 IU QD
Natural Agents that may be helpful in the prevention or
treatment of severe COVID with daily dose. In
addition to those agents already discussed, I also recommend
ginger juice as an antiviral agent for use in
COVID infection.
Divided into 4 or five doses per day:
1. Pomegranate Juice: 3 ml/kg day of juice or 100 mg of powder
per Kg Juice Source Powder Source
2. Apigenin 250 mg Source
Notes:
Freeze dried pomegranate juice may be used as a substituted for
pomegranate juice, using about 1.5 grams
per ounce of juice.
A small dose of vitamin D3 is recommended daily as 25
hydroxyvitamin D3 is required for new WBC
function as new cells are created daily, but the body stores
vitamin D as 1-25 hydroxyvitamin D3. Studies of
vitamin D3 use in influenza support the use of low doses, but
not higher doses.
I am unaware of any other contraindication to using these
medications together or together with the natural
agents listed above.
I also recommend avoidance of statin medications, proton pump
inhibitors, and metformin during the
course of this disease, as well as avoidance of olive oil, sage,
rosemary and curcumin/turmeric as a result of
their miRNA activity on HMGB1. Since oleic acid may remain in
the body for an extended time, it may be
prudent to avoid it if there is high risk of COVID infection
morbidity.
These agents are not intended to displace of other
anti-SARS-CoV-2 medications. Antiviral agents such as
Camostat mesilate84 or remdesivir may be helpful, especially
early in the disease. The focus here in is to
improve the immune response to the disease.
https://www.amazon.com/POM-Wonderful-Pomegranate-Juice-Count/dp/B004O4BB4Whttps://www.amazon.com/Navitas-Organics-Pomegranate-Powder-oz/dp/B001TNW23Uhttps://www.amazon.com/Swanson-Apigenin-Prostate-Supplements-Capsules/dp/B001TEIJIQ/
-
Additional notes:
TMPRSS2, the host cell protein on cells that that mediates
uptake of the SARS-CoV-2 virus after binding to
ACD2, is inhibited by plasminogen activator inhibitor-1
(PAI-1).85 PAI-1 in inhibited by statin drugs.
TMPRSS2 is even more strongly inhibited by antithrombin, which
is activated by heparin86 in physiologic
levels of calcium. PAI-1 expression greatly augmented by TNF-α,
and this greatly down-regulated by
apigenin.
Apigenin is a Src-tyrosine kinase inhibitor that inhibits
activation of SHP1 and SHP2, thus inhibiting the
IDO mediated downregulation of Th1 and NK cell immune activity.
87
Apigenin reduces NLRP3 inflammasome activation.88
Please let me know if tested in patients. Thanks
dr.charles.lewisgmail.com
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