key: cord-0851335-8241pjpe
authors: Mahmudpour, Mehdi; Roozbeh, Jamshid; Keshavarz, Mohsen; Farrokhi, Shokrollah; Nabipour, Iraj
title: COVID-19 cytokine storm: The anger of inflammation
date: 2020-05-30
journal: Cytokine
DOI: 10.1016/j.cyto.2020.155151
sha: 9d990a819a91575a7590bac9cb0e2f32a092e6b9
doc_id: 851335
cord_uid: 8241pjpe

Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.

The coronavirus infectious disease 2019 that is spreading at the global scale is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped singlestranded RNA virus belonging to the Coronaviridae family, genus beta-coronavirus [1] . Nonstructural proteins of this virus play a crucial role in virus replication while structural and auxiliary proteins are involved in morphogenesis and interfere with the host immunity response, respectively [2] .

Accumulating evidence suggests that the host immunity response is contributing in severe forms of MERS-CoV, SARS-CoV and SARS-CoV-2 infections [3] [4] [5] . This immune response has been associated with a higher intensive care unit (ICU) admissions and mortality in COVID-19. In fact, higher concentrations of granulocyte-colony stimulating factor (G-CSF), interferon gammainduced protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1alpha (MIP1A), and tumor necrosis factor alpha (TNFα) in comparison to non-ICU patients were reported in patients with COVID-19 [5] . In another study, higher levels of interleukin-2 (IL-2) receptor, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and TNFα were found in deceased patients with COVID-19 compared to patients who had recovered from the disease [6] .

These immunologic reactions in severe COVID-19 may characterize the cytokine storm that is associated with untoward clinicopathological consequences. The cytokine storm is an out-ofcontrol cytokine release that has been observed in some infectious and noninfectious diseases, leading to a hyperinflammation condition in the host ( Fig.1) [7] . This uncontrolled cytokine response might be accompanied with more immune cells activation including T helper 17 cell (Th17) differentiation from CD4+ lymphocytes. In fact, increased Th17 responses were reported in MERS-CoV, SARS-CoV and SARS-CoV-2 [8] [9] [10] [11] .

At least 10% of the patients with severe COVID-19 will eventually present lung injury, acute respiratory distress syndrome (ARDS) and involvement of multiple organs within 8-14 days of the onset of their illness [12] . These severe cases that develop respiratory failure show a series of pathological findings such as hyaline membrane formation, inflammatory infiltration with multinucleated syncytial cells in their lung pathology and a burst of cytokine release leading to morbidity and mortality [6, 12] .

The initial cellular entry phase of the SARA-CoV-2 requires binding of its envelope homotrimeric spike glycoprotein to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) on the target cell [12, 13] . The attachment of the virus with ACE2, as its cellular receptor, triggers internalization of the complex into the target cell, leading to the down-regulation of the ACE2 [14] .

ACE2 internalization and its subsequent down-regulation would potentially result in unopposed function of angiotensin II (AngII) and decreased levels of angiotensin-(1-7) [14] . Since angiotensin-(1-7) has a key counter-regulatory role in many of the angiotensin type 1 receptor (AT1R)-related physiopathological functions, the SARA-CoV-2-mediated downregulation of ACE2 and the resulting increased overall ratio of Ang II to angiotensin-(1-7) leads to the deterioration of the pulmonary function and lung injury [13, 15] .

Therefore, the imbalance of ACE2/ACE levels in COVID-19 and the dysregulated angiotensin-II /AT1R axis of the renin-angiotensin-aldosterone system (RAAS) may partially be responsible for the cytokine storm and the resulting pulmonary damage [16, 17] . The loss of the modulatory effect of angiotensin-(1-7) via its binding to the Mas receptor (MasR) that attenuates inflammatory response may be a further contributing factor to the hyper-inflammation status of severe cases of COVID-19.

Beyond ACE2 catalytic activity in RAAS and MasR-mediated actions, it has interesting effects on multiple molecular pathways which are involved in inflammatory response and cytokine release.

However, potential cellular and molecular mechanisms of the cytokine storm in COVID- 19 have not yet been explored extensively.

In this review, we specifically discuss the complex inflammatory molecular consequents of downregulation of ACE2 in the context of SARS-CoV-2, with a particular emphasis on the complement system and [des-Arg9]-BK or (DABK) in addition to ACE/ angiotensin-II/AT1R and ACE2/MasR axes. We propose a unifying molecular model to better understand the complex molecular events behind out-of-control cytokine response in severe COVID-19 patients.

Undoubtedly, this insight will be pivotal to obtain a harmonized therapeutic strategy to confront this deadly viral infection and to protect the lungs during the cytokine storm.

The renin-angiotensin-aldosterone system (RAAS), through its vasoactive peptides, regulates blood pressure, fluid volume, sodium and potassium balance. This elegant system also plays a significant role in the promotion and maintenance of inflammation [18] .

It appears that activation of the RAAS system can induce inflammation in an independent mechanism of blood pressure through the AT1 receptor (AT1R) in the kidney and vasculature [19] .

The secretion of profibrotic cytokines such as transforming growth factor beta (TFG-β) is stimulated during RAAS activation [20] [21] [22] . Furthermore, increased production of Ang II and activation of AT1R are accompanied with a pro-inflammatory response via activation of the complement cascade including C5a, C5b-9 [23] . This implies a cross-talk between RAAS and the complement system.

Ang II can activate the nuclear factor kappa B (NF-κB) pathway [24, 25] via stimulation of the phosphorylation of the p65 subunit of NF-κB [26] . This will lead to increased production of IL-6 [27] , TNFα, IL-1B and IL-10 [26] . After AT1R activation, Ang II regulates Mitogen-Activated Protein Kinases (MAPK) (ERK1/2, JNK, p38MAPK), which have important functions on cellular processes including the release of cytokines such as IL-1, IL-10, IL-12 and TNFα (Fig.2 ) [28] [29] [30] .

ACE2 enzyme is expressed in the heart, kidneys, testes, gastrointestinal tract and lungs [15, 31] .

It cleaves the Angiotensin I (Ang I) to generate the inactive Ang-(1-9) peptide, which can be changed to the vasodilatory peptide Ang-(1-7) by ACE or other peptidases. ACE2 can also directly metabolize Ang II to generate Ang-(1-7) [32] .

SARS-CoV-2 uses ACE2 in type II pneumocytes of lung alveoli and club cells in bronchioles as the cellular entry receptor. Very recently, TMPRSS2 (as a major host protease), and ACE2 coexpression was reported among a subset of type II pneumocytes in the lung [31] .

After the attachment of SARS-CoV-2 spike (S)-protein to ACE2, its intracellular binding site down-regulates ACE2. Consequently, following this down-regulation of ACE2, Ang II level increases in the serum leading to augmentation of the Ang II/AT1R axis activation, which is followed by trans-signaling of IL-6-sIL-6Ra complex, in which the gp 130-mediated activation of STAT3 occurs in the lungs' epithelial cells. Although SARS-CoV-2 itself activates NF-κB through pattern recognition receptors, it is the simultaneous activation of NF-κB and STAT3 that enhances NF-κB activation machinery (the IL-6 amplifier). This hyper-activation of NF-κB via the IL-6

Amp in the lungs induces a cytokine storm with subsequent ARDS that had been observed in severe COVID-19 patients [33, 34] .

Indeed, down-regulation of ACE2 which was accompanied with enhancement of Ang II levels in different types of lung injury triggered those pulmonary pathological changes that are commonly observed in ARDS [35] .

Given the above premises, it seems reasonable to speculate that depletion of ACE2 and activation of ACE/Angiotensin II/AT1R axis might have a pivotal role in the clinical presentations of COVID-19. In fact, higher circulatory levels of Ang II were reported in COVID-19 patients than the control subjects and these plasma levels of Ang II were linearly associated with lung injury [36] . Therefore, in contrast to earlier clinical experts' opinions, RAAS inhibitors should not be discontinued in stable cases of COVID-19 because the discontinuation of ACE inhibitors and ARBs may potentially have detrimental effects on these patients [14, 37, 38] . In a recent study, the first clinical evidence has shown that ACE inhibitors or ARB therapy in COVID-19 patients with hypertension were associated with a lower rate of disease severity, a trend toward lower IL-6 levels, and higher circulatory CD3+ and CD4+ T cells counts [39] .

The protective effect of ACE2 in severe acute lung failure has been shown in animal models [40] .

The accumulating clinical-epidemiological evidence about COVID-19 implies that SARS-CoV-2 associated ACE2 depletion is accompanied with a severe clinical course of disease in those clinical and epidemiological conditions that jeopardize the levels of ACE2 expression including older age, male sex, and medical conditions (diabetes mellitus, hypertension and cardiovascular diseases, and obesity) [41, 42] . Under these medical conditions, the COVID-19 infection-induced ACE2 depletion could not overcome already exaggerated ACE/Angiotensin II/AT1R axis activity.

Hence, administration of recombinant soluble ACE2 to patients with severe COVID-19 infection may be a therapeutic modality. However, it is worthwhile to consider targeting downstream of ACE/Angiotensin II/AT1R axis, such as IL-6-STAT3 axis [34] to combat the observed cytokine storm in COVID-19 in order to prevent lung inflammation and end organ damage.

ACE2, Ang-(1-7) and Ang-(1-7) receptor Mas are the constituents of the other arm of the RAS system which counteracts and attenuates the effects of ACE-Ang II-AT1R axis [43, 44] . ACE2 derives vasodilatory peptide Ang-(1-7) from Ang II following a cleavage activity. This vasodilatory peptide has anti-proliferative, anti-thrombotic and anti-inflammatory activities [45] [46] [47] .

Ang-(1-7) reduces the expression of p38 MAPK and NF-κB and inflammatory factors such as IL-6, TNFα and IL-8 [48] [49] [50] [51] . Thus, Ang-(1-7) per se has an anti-inflammatory effect and ameliorates inflammatory damages, as revealed in several animal studies [52, 53] . It has been shown that Ang-(1-7) reduces inflammatory cardiac injury in diabetic hypertensive rats [52] and glomerular involvement in mesangial proliferative glomerulonephritis (MPGN) rat models [53] .

The protection of vascular endothelium and renal tubular cells, diuresis and vasodilationdependent Ang-(1-7) effects occur via MasR [54, 55] . Mas receptors express in the epithelium and bronchial smooth muscle; therefore, Ang (1-7) could modulate acute and chronic inflammatory processes in the lung via activation of MasR [56] . A range of physiological effects of Ang- (1-7) is present in different tissues such as heart, brain and kidney by its action on MasR [57] .

Ang-(1-7) also attenuates Ang II induced intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and MCP1 expression by MasR activation leading to inhibition of the p38MAPK and NF-κB pathways [58] . ERK 1/2 pathway modulates production of IL-10 [59] that induces differentiation of T-helper toward Th2-type. Th-2 regulates immune responses by producing anti-inflammatory cytokines like IL-4, IL-5, IL-9 and IL-13 [60] . Additionally, IL-10 is an anti-inflammatory cytokine that may be involved in the prevention of tissue damage [61, 62] . Ang-(1-7) modulates the activity of ERK 1/2

Therefore, Ang-(1-7) has an anti-inflammatory function via modulation of NF-κB, MAPK and ERK 1/2 pathways. Hence, it may be proposed that SARS-CoV-2 associated suppression of ACE2, which would be accompanied with reduction of all Mas receptor-mediated functions, leads to accentuation of the cytokines release and frank inflammatory responses. Because Ang-(1-7) exerts a critical role in counteracting the pro-inflammatory effect of RAAS, protecting from endothelial cell activation and resulting lung damage from inflammatory mediators in the cytokine storm, the administration of Ang-(1-7) or one of its similar agents to patients with COVID-19 pneumonitis has been suggested [35, 66] .

The kinin-kallikrein system includes kininogen, kallikrein enzyme, bradykinin (BK-1-9 or BK), and [des-Arg9]-BK or DABK [67, 68] . The active products of this system interact with two distinct G-protein coupled receptors, the bradykinin B1 receptor (BKB1R) and bradykinin B2 receptor (BKB2R); the main ligand of BKB1R is DABK and the ligand of BKB2R is BK [69, 70] . BKB1R could hardly be detected in peripheral tissues in normal states; however, it is expressed on the cell types involved in inflammation. Therefore, it is an inducible pro-inflammatory receptor [71] . The expression of BKB1R, as a specific receptor of bradykinin pathway, is highly sensitive to inflammatory mediators such as lipopolysaccharide (LPS) and interleukins [70, [72] [73] [74] . It is also up-regulated by cytokines such as IL-1B and TNFα [75] [76] [77] . IL-2, IFNɣ, epidermal growth factor (EGF), and oncostatin increase the rate of BKB1R receptor mediated response [77] [78] [79] [80] . It should be mentioned that IL-1B and TNFα-induced BKB1R expression is related to NF-κB activity [81] .

Sodhi et al. [82] showed that activation of BKB1R enhances the neutrophil attraction to tissue by release of chemokine C-X-C motif chemokine 5 (CXCL5). Activity of this receptor leads to expression of FGF-2 [83] , and to increased levels of IL-1B [84] and MCP1 (Fig.3) [85] .

DABK is a known pulmonary inflammatory factor [86] [87] [88] [89] . It is interesting that ACE2 also cleaves terminal residue of DABK [90, 91] . This reaction results in deactivation of DABK. Therefore, it could be postulated that COVID-19-induced reduction of ACE2 activity would be accompanied with increased activity of DABK and the resulting accentuation of the aforementioned inflammatory cascade, leading to increased cytokine release. Hence, targeting the ACE2 /DABK/ Bradykinin B1 Receptor axis has been suggested by some authors [92, 93] . to prevent or control ARDS in patients with severe COVID-19. Although several BKB1 antagonists have passed phase II clinical trials, none have been approved yet for clinical use [71] .

The complement system is an ancient system that contributes to innate immune response. This system includes many proteins and cleavage products that plays a key functional role in defense against microorganisms including viruses. The viral inactivation by the complement cascade involves virus uptake and clearance by phagocytic cells, coating virions resulting in prevention of attachment with their receptors, virus lysis by pore formation, and destruction of its membrane by membrane attack complex formation (C5b-9) [94] .

Following viral-induced complement cascade activation, inflammatory processes are promoted.

Complement factor 5a (C5a) is the strongest inflammatory peptide in the complement cascade that induces release of pro-inflammatory cytokines [95] [96] [97] [98] . ]. C5a can also induce secretion of TNF-α [99, 100] . Terminal products of the complement cascade can induce the production of cytokines such as TNF-α and IL-1 [98, [101] [102] [103] [104] . Terminal complement component C5b-9 induces release of IL-6 via activation of redox-sensitive transcription factor NF-κB and Activator Protein-1 (AP-1) [105] and Monocyte Chemoattractant protein-1 (MCP1) from vascular smooth muscle cells [106] . Also, the increased production of C3a leads to production of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α [107] .

The involvement of the complement system in the pathogenesis of syncytial virus infection, [108] [109] [110] . The hyper activation of complement components including C5a in sera and C5b-9 in lungs was observed in MERS-CoV-infected hDPP4-transgenic mice. The lung and spleen-induced pathological damages and inflammatory responses were alleviated through blockade of the C5a-C5aR axis in those transgenic mice [110] .

Gralinski et al. [109] showed that mice models deficient in C3(C3-/-) loads in the lung had milder SARS-CoV induced pathologic features such as better respiratory function, lower weight loss, reduced pathologic findings in respiratory system, and lower circulatory and tissue cytokines and chemokines, despite equal lung viral loads compared to the controls. These results showed that although the complement system had no role in virus replication, activation of complement system in the lungs of SARS-CoV infected mice might lead to immune mediated damages in the lungs [109] .

The complement cascade can be activated by the lectin pathway (Fig.4) . By priming the immune system and enhancing clearances of viruses and virus-infected cells [111] ], the lectin pathway may also be involved in COVID-19 pathogenesis. Recently, Gao et al. [108] reported in a very stimulated macrophages [113, 114] . However, the C5a-C5R axis inhibition by the available pharmaceutical agents would be partial, and the activity of residual terminal complement components might remain. Therefore, targeting the upstream activators of the complement cascade such as C3a-C3aR axis may be more effective in restraining the uncontrolled complement pathway activation in severe COVID-19 [115] . Very recently, the compstatin-based complement C3 inhibitor AMY-101 was administered to a patient with ARDS due to COVID-19, in which very good clinical responses with a high level of safety were reported [116] .

The overall clinical benefits of targeting the C3a-C3aR/C5a-C5aR axis in order to control maladaptive immune-inflammatory consequences of the complement pathways in severe COVID-

The Covid-19 cytokine storm, like the other cytokine storms in infectious and non-infectious conditions, may be considered as a complex network. The complex network of the cytokine response was described by Tisoncik et al. [7] as "a series of overlapping networks, each with a degree of redundancy and with alternative pathways".

Our aforementioned pathogenesis of the so-called COVID-19 cytokine storm through the four described distinct axes clarified that this cytokine storm complex network has many components which might cross-talk with each other in multiple known and unknown interfaces. These interactions in a network state imply the complex nature of the COVID-19 cytokine storm. The dynamic equilibrium of the network components could be disturbed at multiple sites to emerge an untoward behavior. In COVID-19 cytokine storm, this perturbation is initiated via attachment of the SARS-CoV-2 spike protein to its receptor, ACE2, followed by the ACE/Ang II/AT1R axis activation leading to hyper-activation of NF-κB by IL-6 STATs axis [34] . In the normal dynamic equilibrium state, the ACE/Ang II/AT1R axis activation is counterbalanced by ACE2/MasR axis and production of Ang-(1-7) that reduces the expression of p38 MAPK and NF-κB and inflammatory factors such as IL-6, TNFα and IL-8 [49] [50] [51] . However, SARS-CoV-2 associated down-regulation of ACE2 suppresses these immunomodulatory effects, leading to accentuation of the cytokine release response.

We currently know that DABK is a pulmonary inflammatory factor whose deactivation by ACE2 is deranged by COVID-19-induced reduction of ACE2 activity. This derangement is followed by ACE2 /DABK/ Bradykinin B1 Receptor axis activation that creates a pro-inflammatory synergistic effect for SARS-CoV-2 associated ACE/Ang II/AT1R axis activation. The resulting effect would be a more inflammatory state, neutrophil recruitment and enhancement of pathological pulmonary changes that are observed in ARDS of severe COVID-19.

We have already discussed the involvement of the complement system in the pathogenesis of SARS-CoV-2 via its nucleocapsid (N) protein-mediated MASP-2 auto-activation and binding to MLB in the lectin arm of C3a-C3aR/C5a-C5aR axis [108] . However, the increased production of Ang II and activation of AT1R may be accompanied with pro-inflammatory response via activation of the complement cascade including C5a, C5b-9 [23] . This implies a cross-talk between ACE/Angiotensin II/AT1R axis and the complement system. Similar to other complex networks, elements from the complex network of the COVID-19 cytokine storm may experience much cross-talk with elements from known and unknown pathways and networks. For example, Ang II as an element from ACE/Ang II/AT1R induces TGFβ expression [22, 117] . TGF-β has a role in the differentiation of T helper 17 cells from naive CD4+ T-cells. Th-17 cells generate IL-17, GM-CSF, IL-21 and IL-22. IL-17 itself promotes the production of a vast amount of pro-inflammatory cytokines and chemokines [8, 118] . IL-17 was among the cytokines that were significantly correlated with the lung injury Murray score and disease severity in COVID-19 [119] . An increment of the highly pro-inflammatory CCR6+ Th17 in CD4 T cells was reported in COVID-19 associated with ARDS [9] . Therefore, targeting IL-17 and T helper 17 responses in the cytokine storm of COVID-19 have been suggested [8, 118] . 

Therapeutic plasma exchange is a well-known therapeutic option that can be considered in the treatment of autoimmune diseases. The beneficial effect of this modality works through elimination of autoantibodies, complement components, immune complexes and cytokines.

Therefore, this option may be valuable in the treatment of severe COVID-19 [120] . However, application of this therapeutic modality is a general approach to confront the cytokine storm.

Hence, other approaches may be considered in the treatment of the COVID-19 driven cytokine storm in order to protect lungs from injury (Table-1 ).

According to the aforementioned axes which may be involved in the cytokine storm of severe cases of COVID-19, some potential targets could be considered as therapeutic options.

The first one is recombinant human ACE2. There are some trials regarding the efficacy and safety of this agent in clinicopathological settings related to ACE2 decrement such as congestive heart failure (CHF) [121] , ARDS [122, 123] , and lung injury due to viral illness such as respiratory syncytial virus (RSV) [124] . The reported findings about safety and efficacy were promising. Very recently, Monteil et al. [125] reported that human recombinant soluble ACE2 (hrsACE2) can prevent entry of SARS-C0V-2 to the human blood vessel organoid and human kidney organoid;

this finding may suggest a highly compelling therapeutic intervention to protect lung injury in COVID-19.

We suggested ACE2/Bradykinin/DABK may be involved in the inflammatory response of SARS CoV-2; therefore, blockade of this axis by inhibiting BKB1R may ameliorate a part of the cytokine storm which occurs in COVID-19 infection. LF22-0542 (Safotibant) is a BKB1R antagonist with promising anti-inflammatory results [126, 127] . Several clinical trials have been conducted to evaluate the effect of this drug in multiple medical settings; they have had promising results (Fig.3) [71].

Regarding the pivotal role of the complement system in the cytokine storm and activation of Th-17, every effort should be made to suppress the activation of this elegant cascade. C5a, as a potent component of this system, is a good target for alleviation of pro-inflammatory responses to severe COVID-19. Eculizumab is a monoclonal antibody with high affinity to C5 near its cleavage site [128] . This agent prevents the formation of C5a and C5b-9. It has been reported that this monoclonal antibody has beneficial effects in the treatment of diseases where their pathogenesis are based on complement activation [129] . In a preliminary study conducted by Gao (Fig.4) [130] .

In conclusion, accumulating evidence suggests that SARS-CoV-2 driven ACE2 down-regulation leads to an array of complex and intertwined molecular interactions via at least four axes consisting of dysregulation of the ACE/angiotensin II/AT1R axis, attenuation of ACE2/MasR axis, increased activation of ACE2/bradykinin B1R/DABK axis, and activation of the complement cascades, resulting in the observed cytokine storm in severe COVID-19.

The elucidation of molecular events of the aforementioned axes which might be involved in the pathogenesis of ARDS and lung injury in fulminant infections with SARS-Co-V-2 will promise novel therapeutic options for prevention or attenuation of the inflammatory cytokine release response that are observed nowadays in patients with severe COVID-19.

MM, IN, JR, SF and MK interpreted and wrote the manuscript. IN and MM supervised the study.

All authors read and approved the final manuscript.

An award was given to Iraj Nabipour by "Novo Nordisk Pars" (The Best Innovator of Diabetes in Iran 2013). For the remaining authors none were declared.

The technical assistance of Mr. Dara Joukar in drawing of figures is gratefully acknowledged. The authors also thank Ms. Melissa T. Yang, PhD for her kind language editing of the manuscript.

Captions for figures: 

A doubt of multiple introduction of SARS-CoV-2 in Italy: a preliminary overview

Emerging coronaviruses: genome structure, replication, and pathogenesis

Clinical features of patients infected with 2019 novel coronavirus in

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Into the eye of the cytokine storm, Microbiol

Th17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor fedratinib

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?

Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

COVID-19, ACE2 and the Cardiovascular Consequences

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Trilogy of ACE2: A peptidase in the reninangiotensin system, a SARS receptor, and a partner for amino acid transporters

COVID-19 induced Renin-Angiotensin System (RAS) imbalance may drive acute lung injury: the evidence and therapeutic options

Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

The renin-angiotensin-aldosterone system in vascular inflammation and remodeling

Immunologic effects of the renin-angiotensin system

Interactions of transforming growth factor-β and angiotensin II in renal fibrosis

Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta

Angiotensin II sustains brain inflammation in mice via TGF-β

Severe hypertension with renal thrombotic microangiopathy: what happened to the usual suspect?

Angiotensin II induces nuclear factor (NF)-κB1 isoforms to bind the angiotensinogen gene acute-phase response element: a stimulus-specific pathway for NF-κB activation

Proinflammatory actions of angiotensins

Angiotensin II stimulates the release of interleukin-6 and interleukin-8 from cultured human adipocytes by activation of NF-κB

Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes

Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system

MAP kinases in the immune response

Mitogen-activated protein kinases in innate immunity

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues

ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good

Pleiotropy and specificity: insights from the interleukin 6 family of cytokines

COVID-19: A new virus, but a familiar receptor and cytokine release syndrome

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients

COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Angiotensin-converting enzyme 2 protects from severe acute lung failure

COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Women and Children

Organ-protective Effect of Angiotensin-converting Enzyme 2 and its Effect on the Prognosis of COVID-19

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

ACE2 overexpression inhibits angiotensin II-induced monocyte chemoattractant protein-1 expression in macrophages

Beyond blood pressure: evidence for cardiovascular, cerebrovascular, and renal protective effects of renin-angiotensin system blockers

The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases

angiotensin-(1-7) and Mas: new players of the renin-angiotensin system

Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis

Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse

Angiotensin-(1-7) activates growth-stimulatory pathways in human mesangial cells

Endogenous angiotensin-(1-7) reduces cardiac ischemiainduced dysfunction in diabetic hypertensive rats

Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis

Angiotensin-(1-7) inhibits hypoxia-induced renal tubular epithelial-to-mesenchymal transition in rats, Xi bao yu fen zi mian yi xue za zhi=

Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells

-7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7)

Angiotensin-(1-7) attenuates angiotensin II-induced ICAM-1, VCAM-1, and MCP-1 expression via the MAS receptor through suppression of P38 and NF-κB pathways in HUVECs

Polar opposites: Erk direction of CD4 T cell subsets

T helper cytokine patterns: defined subsets, random expression, and external modulation

IL-10 dampens TNF/inducible nitric oxide synthaseproducing dendritic cell-mediated pathogenicity during parasitic infection

Interleukin-10 and the regulation of mitogenactivated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine?

Molecular mechanisms of inhibition of vascular growth by angiotensin

Inhibition of human lung cancer cell growth by angiotensin

Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor

Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARSCoV2 Infection?

Haemodynamic and cardiac effects of kinin B1 and B2 receptor stimulation in conscious instrumented dogs

Kinin receptors in experimental inflammation

Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder

A bradykinin (BK) 1 receptor antagonist blocks capsaicin-induced ear inflammation in mice

Kinin B1 receptors as a therapeutic target for inflammation

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Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts

Effect of glucocorticoids, monokines and growth factors on the spontaneously developing responses of the rabbit isolated aorta to des-Arg9-bradykinin

Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des-Arg9bradykinin-induced coronary vasodilation

Studies on the induction of pharmacological responses to des-Arg9-bradykinin in vitro and in vivo

Pulse exposure to protein synthesis inhibitors enhances vascular responses to des-Arg9-bradykinin: possible role of interleukin-1

Regulation of kinininduced contraction and DNA synthesis by inflammatory cytokines in the smooth muscle of the rabbit aorta

Reversal of bradykinin-induced relaxation to contraction after interferon-γ in bovine isolated mesenteric arteries

The B1 receptors for kinins

Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway

Brabykinin B1 receptor antagonism is beneficial in renal ischemia-reperfusion injury

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia-reperfusion injury

The kinin B1 receptor mediates alloknesis in a murine model of inflammation

Bradykinin promotes Toll like receptor-4 expression in human gingival fibroblasts

Kallikrein-kinin system mediated inflammation in Alzheimer's disease in vivo

Bradykinin-induced leukocyte-and plateletendothelium interactions in the cerebral microcirculation

Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins

Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase

COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a potential treatment

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome

The role of the complement system in virus infections

The role of the anaphylatoxins in health and disease

The harmful role of c5a on innate immunity in sepsis

Role of C5a in inflammatory responses

Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release

C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha

Recombinant C5a stimulates transcription rather than translation of interleukin-1 (IL-1) and tumor necrosis factor: translational signal provided by lipopolysaccharide or IL-1 itself

Beyond lysis: how complement influences cell fate

Complement membrane attack on nucleated cells: resistance, recovery and nonlethal effects

Terminal complement complex C5b-9-treated human monocyte-derived dendritic cells undergo maturation and induce Th1 polarization

Alternative pathway complement activation induces proinflammatory activity in human proximal tubular epithelial cells, Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association

The terminal complement complex C5b-9 stimulates interleukin-6 production in human smooth muscle cells through activation of transcription factors NF-κB and AP-1

Complementinduced release of monocyte chemotactic protein-1 from human smooth muscle cells: a possible initiating event in atherosclerotic lesion formation

Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation, medRxiv

Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis

Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV, Emerging microbes & infections

Human lectins and their roles in viral infections

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

C5a negatively regulates tolllike receptor 4-induced immune responses

Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo

Complement as a target in COVID-19?

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

COVID-19: a case for inhibiting IL-17?

Principles of separation: indications and therapeutic targets for plasma exchange

Roles of angiotensin peptides and recombinant human ACE2 in heart failure

Recombinant human ACE2: acing out angiotensin II in ARDS therapy

Angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Angiotensinconverting enzyme 2 inhibits lung injury induced by respiratory syncytial virus

Prosper, Inhibition of SARS-CoV-2 infections in engineered human tissues using clinicalgrade soluble human

N-methylacetamide, fumarate (LF22-0542), a novel nonpeptidic bradykinin B1 receptor antagonist

From bradykinin B2 receptor antagonists to orally active and selective bradykinin B1 receptor antagonists

Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria

Many drugs for many targets: novel treatments for complement-mediated glomerular disease

Soluble CR1 therapy improves complement regulation in C3 glomerulopathy

Increased activity of the RAAS system occurs in the COVID-19 induced cytokine storm.The COVID-19 induced cytokine storm is accompanied with attenuation of MasR activity.The SARS-CoV-2 associated ACE2 induces DABK and BKB1R hyper-activation.The COVID-19 induced cytokine storm leads to hyperactivity of the complement system.

An award was given to Iraj Nabipour by "Novo Nordisk Pars" (The Best Innovator of Diabetes in Iran 2013). For the remaining authors none were declared.