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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 5  |  Page : 33-40

Renin–Angiotensin system and fibrinolytic pathway in COVID-19: One-way skepticism

1 Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
2 Department EA 3072 “Mitochondria, Oxidative Stress and Muscular Protection”, Institute of Physiology, Faculty of Medicine, Strasbourg Cedex, France

Date of Submission28-Jun-2020
Date of Acceptance07-Jul-2020
Date of Web Publication13-Aug-2020

Correspondence Address:
Prof. Hayder Mutter Al-Kuraishy
Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty College of Medicine, Al-Mustansiriya University, P.O. Box 14132, Baghdad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_105_20

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Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is a recent pandemic infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). The entry point of SARS-CoV-2 is via angiotensin-converting enzyme 2 (ACE2), which is highly expressed in the alveolar pulmonary cells. Besides, different peptides and co-mediators such as bradykinin (BK), plasmin, and trans-membrane serine protease may modulate the affinity and binding of SARS-CoV-2 to ACE2. Therefore, this study was planned to review the potential link between the pathogenesis, incidence, and severity of SARS-CoV-2 infection regarding the modulation of ACE2 by these mediators. Electronic database searches of Scopus, Web of Science, Medline, Cochrane Central Register of Controlled Trials, and PubMed was made using MeSH terms, keywords, and title words. Renin–angiotensin system inhibitors might be of value in the reduction of acute respiratory distress syndrome (ARDS), respiratory failure, and acute pneumonia that are induced by SARS-CoV-2. SARS-CoV-2 infection leads to noteworthy lung injury via downregulation of ACE2, which is attenuated by the administration of angiotensin receptor blockers (ARBs). In SARS-CoV-2 infection, BK and its metabolites are augmented due to the downregulation of ACE2 by SARS-CoV-2. SARS-CoV-2 pneumonia is also associated with hyperfibrinolysis as evident with high circulating fibrin degradation products, high plasmin, and presence of hemorrhagic spots in multiple organs. ACEIs improve fibrinolysis via inhibition of PAI-1, while ARBs have a neutral effect on both fibrinolysis and PAI-1. Therefore, these findings show ACEIs but not ARBs as a potential risk for the development of SARS-CoV-2 infection as both plasmin and BK facilitate the pathogenesis of SARS-CoV-2 and augment the development of ARDS in SARS-CoV-2 infection.

Keywords: Bradykinin, COVID-19, plasmin, renin–angiotensin system, SARS-CoV-2

How to cite this article:
Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Renin–Angiotensin system and fibrinolytic pathway in COVID-19: One-way skepticism. Biomed Biotechnol Res J 2020;4, Suppl S1:33-40

How to cite this URL:
Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Renin–Angiotensin system and fibrinolytic pathway in COVID-19: One-way skepticism. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 Oct 7];4, Suppl S1:33-40. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/33/292071

  Introduction Top

The renin–angiotensin system (RAS) is a signaling pathway involved in the regulation of blood volume, natriuresis, blood pressure, blood flow, and trophic response to different stimuli.[1] RAS consist of different regulatory components including angiotensin I (Ang I), which is formed from angiotensinogen by renal renin. Ang I is converted by angiotensin-converting enzyme (ACE) to Ang II, which acts on angiotensin receptors AT1 and AT2. Both Ang I and AngII are metabolized to Ang (1–9) and Ang (1–7) by ACE2, respectively. Ang (1–7) acts on Mas receptors leading to vasodilation and inhibition the release of pro-inflammatory cytokines.[2]

Moreover, ACE is involved in the metabolism of bradykinin (BK) to inactive peptides, therefore, ACE inhibitors (ACEIs), but not angiotensin receptor blockers (ARBs), increase BK, which increases the release of tissue plasminogen activator (t-PA), whereas ARBs improve the release of plasminogen activator inhibitor-1 (PAI-1) via AngII-mediated angiotensin type 1 receptor (AT1R) [Figure 1].[3]
Figure 1: Interactions of renin–angiotensin system, bradykinin system, and plasminogen pathway (Ang I: Angiotensin I, AngII: Angiotensin II, ACE: Angiotensin-converting enzyme, AT1R: Angiotensin type 1 receptor, AT2R: Angiotensin type 2 receptor, t-PA: Tissue plasminogen activator, PAI-1: Plasminogen activator inhibitor-1)

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On the other hand, coronavirus (CoV) is an enveloped, single-strand, positive-sense RNA genome known to cause mild respiratory tract infection in immunocompetent individuals. However, CoV may cause an epidemic outbreak such as severe acute respiratory syndrome (SARS), which was caused by SARS-Co-V in 2003 in China, and Middle East respiratory syndrome (MERS), which was caused by MERS-Co-V in 2012.[4] COVID-19 is a recent pandemic infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which started in Wuhan, China. SARS-CoV-2 infection was declared by the World Health Organization as a pandemic disease on March 11, 2020. As of April 14, 2020, there have been total of 2,000,043 confirmed cases with 126,753 deaths globally.[5]

Regarding the pathogenesis of SARS-CoV-2, there are three key important proteins in the structure of CoV, which are membrane protein, spike protein (SP), and nucleocapsid protein. These structural proteins are involved in the viral pathogenesis and regarded as targets for different experimental antiviral agents.[6]

Amide different recent researches, the entry point of SARS-CoV-2 is via ACE2, which is highly expressed in the alveolar pulmonary cells, renal proximal tubules, and vascular endothelium. Besides, different peptides and co-mediators such as BK, plasmin, and transmembrane serine protease (TMPRSS) may modulate the affinity and binding of SARS-CoV-2 to ACE2.[7]

Therefore, the aim of the present study was to review the potential link between the pathogenesis, incidence, and severity of SARS-CoV-2 infection regarding the modulation of ACE2 by BK, plasminogen, fibrinolytic pathway (FP), and RAS.

  Literature Search Strategy Top

The scheme of this study was to present a mini-review pertaining to RAS, FP, BK, and their inhibitors in relation to the pathogenesis, incidence, and severity of SARS-CoV-2 infection. Substantiations and evidences from different experimental, preclinical, and clinical studies were assessed. An array of search policy was done by electronic database searches of Scopus, Web of Science, Medline, Cochrane Central Register of Controlled Trials, and PubMed using MeSH terms, keywords, and title words during the search. The terms used for these searches were as follows: (COVID-19 OR CoV OR SARS-CoV-2] AND [plasmin OR renin angiotensin system) (COVID-19 OR SARS-CoV-2) AND [bradykinin OR tPA, PAI-1). (Incidence of COVID-19 OR CoV OR SARS-CoV-2) AND (hypertension OR orphan drugs OR ARBs OR ACEIs). Reference lists of previous and recent articles were reviewed. In addition, no languages, time, and article type's limitations were concerned in this review. The key features of predictable and suitable search studies were summarized in a mini-review.

  Sars-Cov-2 Infection and Renin–angiotensin System Top

SARS-CoV-2 binds ACE2, which is highly expressed by the epithelial cells of blood vessel, intestine, and lung. The expression of ACE2 is augmented by ACEIs and ARBs.[8] In addition, ibuprofen, pioglitazone, statins, and cigarette smoking also increase the expression of ACE2 at epithelial cells of the lung. Therefore, hypertensive patients on ACEIs or ARBs are at higher risk for SARS-CoV-2 infection.[9]

It has been reported that SARS-CoV-2 genome matches 96% to that of bat CoV, so SP and receptor binding domain (RBD) of both SARS-CoV-2 and bat CoV bind ACE2, which might explain the cross-species transmission.[10] In addition, the affinity of SARS-CoV-2-RBD to ACE2 is approximately twenty times more than that of SARS-CoV.[11]

The activity of RAS is high in the lung, which is the main source of circulating AngII due to higher expression of ACE. Lung ACE2 controls the balance of RAS activation via regulating AngII/Ang 1-7 ratio. Local pulmonary AngII induces vascular permeability, pulmonary edema, and the development of acute respiratory distress syndrome (ARDS).[12] However, in ARDS, the activation of RAS is necessary to maintain oxygenation because ACE2 knockout mice illustrated more severe pulmonary damage as compared with the controls. Therefore, pulmonary ACE2 appears to be a protective defense pathway during ARDS.[13] Besides, ACE2 has an important anti-inflammatory action and so ACE2 therapy is an effective molecule in the treatment of hypertension and diabetic nephropathy through reduction of AngII-induced inflammation and oxidative stress.[14] Therefore, recombinant ACE2 is an effectual agent in the management of animal model ARDS. As a result, the inhibition of ACE2 may lead to the fatal outcomes due to the reduction of vasodilator Ang1-7. Otherwise, chronic intravenous administration of Ang1-7 or MAS agonists leads to vasodilatation independent of circulating AngII levels. Therefore, ACE2/Ang1-7 has the opposite effect to that of ACE/AngII.[15]

Moreover, high circulating AngII level reduces the activity of ACE2 via AT1 receptor-dependent internalization mechanism and increases lysosomal degradation of ACE2.[15] Therefore, losartan attenuates AngII's detrimental effect via stabilization of ACE2–AT1 complexes, thereby the interaction of SARS-CoV-2 viral protein with ACE2 is prevented by this stabilization. In addition, reduction of ACE2 by SARS-CoV-2 leads to high AngII levels, which, in turn, activate the release of aldosterone which inhibits the action of Ang1-7 on the Mas receptors, hence aldosterone inhibitors may attenuate SARS-CoV-2 infection-induced ARDS.[16]

Depending on these clarifications, different studies show that RAS inhibitors might be of value in the reduction of ARDS, respiratory failure, and acute pneumonia that are induced by SARS-CoV-2. Although Wang, 2020, shows that RAS inhibitors may increase the risk of SARS-CoV-2 infection due to overexpression of pulmonary ACE2, this study recommend stopping RAS inhibitors during the SARS-CoV-2 infection outbreak. Nonetheless, all recruited patients with SARS-CoV-2 infection developed ARDS without any evidence of acute kidney injury (AKI) even with a higher expression of ACE2 in renal proximal renal tubules.[17] Hence, RAS system, mainly ACE2/Ang1-7, grows up to be the focal point and juncture of different researches to implicate this pathway in the pathogenesis of SARS-CoV-2 infection. Guo et al. found that the expression of ACE2 is higher in renal tubules than in the lung tissues, even so SARS-CoV-2 infection leads to ARDS in much higher than that of AKI, suggesting another mechanism other than ACE2 in the pathogenesis of COVID-19.[18]

It has been reported that AT2 receptor is activated by ACE2 and Ang1-7 that oppose the activity of AT1 receptor. Similarly, AT2 receptors are highly expressed in the lung epithelial cells compared with kidney tissues. Pulmonary AT2 receptors mediate lung injury through augmentation of pulmonary inflammation and vascular permeability as well as development of pulmonary fibrosis.[19] Therefore, pulmonary AT2 receptors are regarded as a novel pathway in SARS-CoV-2 infection-induced pneumonia and ARDS.

Amide myriad literature survey, polymorphism of ACE2 has been associated with different cardiometabolic disorders, thus implication of ACE2 and AT2 receptors in COVID-19-induced pneumonia should be considerably look upon with ACE2 polymorphisms.[20] Furthermore, the expression of ACE2 might not be necessary for COVID-19 infection and viral entry due to the absence of SARS-CoV-2 in some ACE2 expressing cell types, as well as this infection was observed in some cell lines lacking ACE2, suggesting an indistinct pathway and that other co-factors might be indispensable for human infection.[21],[22] Gurwitz shows that pulmonary COVID-19 infection leads to noteworthy lung injury via downregulation of ACE2, which is attenuated by the administration of ARBs.[23] As a result, the high frequency of COVID-19 in patients receiving ACEIs or ARBs might be, not because of these drugs, but because those patients were often older, hypertensive or diabetic which in fact increase the risk of COVID-19 infection. As well, a recent clinical trial on the effectiveness of recombinant ACE2 (rACE) in the management of COVID-19 infection has been started. Thus, according to the guideline for the management of hypertension, RAS inhibitors should be used irrespective of COVID-19 infection, as sudden withdrawal of these therapeutic regimens may increase the risk of deleterious outcomes in critically ill patients. Furthermore, recombinant ACE2 binds SARS-CoV-2 viral particles and acts as a competitive inhibitor with membrane-bound ACE2 for viral particles.[24]

Regarding gender differences in the expression of ACE2, Corley and Ndhlovu established that ACE2 gene is located on the X chromosome, which gives the possibility of gender differences in the susceptibility for COVID-19 infection. Females have lower levels of ACE2 compared with males, which gives a clue of male vulnerability to COVID-19 infection as compared with females.[25] Into the bargain, Shenoy et al. reports that estrogen attenuates AngII-induced pulmonary fibroblast proliferation due to the upregulation of ACE2.[26] Expression of ACE2 is regulated by different endogenous hormones and peptides, both endothelin-1 and aldosterone downregulated ACE2 expression in a rat model. Hence, RAS inhibitors may improve ACE2 expression via the suppression of endogenous endothelin-1 and aldosterone.[27],[28]

  Bradykinin and Covid-19 Top

BK is a peptide generated from endogenous kininogen(kallikrein) by specific proteolytic process. It is an important member of the vasodilator system that controls local blood flow. Two types of kallikrein, tissue kallikrein (TK) and plasma kallikrein (PK), release kinins. PK converts hepatic high-molecular-weight kininogen to BK, whereas TK converts hepatic low-molecular-weight kininogen to Lys-BK. Both BK and Lys-BK activate BK receptor type 2 (B2). Besides, ACE metabolizes BK to des-Arg9-BK and Lys-BK to Lys-des-Arg9-BK. Both of these metabolites activate BK receptor type 1 (B1). B2 receptors are normally found and responsible for vasodilatation, whereas B1 receptors are induced under pro-inflammatory conditions.[29]

BK is stimulated by different inflammatory mediators such as interleukins (IL) (IL-4, IL-6, IL-8, and IL-13) and tumor necrosis factor-alpha (TNF-α). ACE metabolizes BK and blocks its effect on B2 receptors, whereas ACE2 metabolizes des-Arg9-BK and Lys-des-Arg9-BK and blocks their effect on B1 receptors [Figure 2].[30] In addition, ACEIs lead to pulmonary angioedema due to excessive accumulation of BK causing vasodilation and induction of capillary permeability via activation of B2 receptors at vascular endothelium. However, ACE2 does not affect BK or Lys-BK, thereby activation or upregulation of ACE2 is linked with the reduction of lung inflammation, injury, edema, and development of ARDS.[31] Therefore, upregulation of ACE2 by different drugs such as ARBs and ACEIs is regarded as a protective effect rather than facilitating effect during SARS-CoV-2, which used ACE2 as an entry point. The higher expression of ACE2 by ACEIs is regarded as a compensatory mechanism to inactivate the metabolites of BK that are augmented by the action of ACEIs. However, the underlying mechanisms of upregulation of ACE2 by other drugs are not fully elucidated.[32] To date, anin vitro study by Sinha et al. shows that ACEIs is a potent upregulator of ACE2 expression, whereas ARBs are regarded as potent downregulator of ACE2 expression.[33] These conflicting findings may increase the debate about the role of RAS in SARS-CoV-2 infection.[34]
Figure 2: Bradykinin pathway in pulmonary inflammation and injury. PK: Plasma kallikrein, TK: Tissue kallikrein, HMWK: High-molecular-weight kininogen, LMWK: Low-molecular-weight kininogen, BK: Bradykinin, Lys-BK: Lys-Bradykinin, BM: Bradykinin, ACE: Angiotensin-converting enzyme

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Moreover, AT1 receptor outlines a heterodimer with B2 receptor and augments B1 receptor in the induction of oxidative stress and endothelial dysfunction.[35]

In SARS-CoV-2 infection, BK and its metabolites are augmented due to downregulation of ACE2 by SARS-CoV-2, therefore dysregulation of this pathway may lead to acute pulmonary damage, fluid extravasation, leukocyte recruitment, and the development of ARDS via activation of B1 receptors, which are overexpressed by the pro-inflammatory conditions. Activation of BK system in the acute viral respiratory infection increases the risk of capillary permeability and development of multiple organ failure (MOF). Therefore, BK antagonists are effective in the prevention of MOF through attenuation hemodynamic instability in the experimental sepsis. Though BK pathway is not suppressed by corticosteroid or catecholamine, inhibitors of this pathway are necessary. Icatibant is a selective B2 receptor blocker used for hereditary angioedema, and nowadays there is no any B1 receptor blocker.[36],[37] Besides, exposure to SARS-CoV-2 infection reduces the expression of ACE2 and increases the activity and level of Des-Arg973-BK (DABK). Enhanced signaling through DABK/BKB1R system leads to vascular–alveolar fluid extravasation, leukocyte extravasation, and ARDS development. Ecallantide, a 60 amino-acid recombinant protein, binds to PK selectively and inhibits BK generation from high-molecular-mass kininogen,[36] and might of value in the reduction of upregulated BK in SARS-CoV-2 infection. Therefore, ACEIs may have deleterious effect through increasing BK and beneficial effect through upregulation of ACE2, which metabolizes BK metabolites and prevents the activation of B1 receptor-induced acute lung injury (ALI).[38]

As a consequence, there is a noteworthy interaction between kallikerin–kinnogen system and RAS in SARS-CoV-2 infection [Figure 3], and modulation of each arm of this system might be of an immense value in the attenuation of SARS-CoV-2 infection-induced ARDS.
Figure 3: Interactions between kallikerin–kinnogen system and renin–angiotensin system . BKB1R: Bradykinin B1 receptor (Des-Arg973)-BK or DABK: Metabolically active form of bradykinin, ACE2: Angiotensin-converting enzyme 2, Ang: Angiotensin, KKS: The kallikrein–kinin system, RAS: The renin–angiotensin system. ARDS: Acute respiratory distress syndrome, NO: Nitric oxide

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Sanchis-Gomar et al. found that ARBs despite similar efficacy with ACEIs had a lower adverse effect and were recommended in hypertensive patients with SARS-CoV-2 infection due to upregulation of ACE2 without BK increment effect. An Italian retrospective study which involved hypertensive patients with SARS-CoV-2 pneumonia on either ACEIs or ARBs shows that the mortality rate was 36% for ACEIs as compared with 16% for ARBs (odds ratio 2.26 and 1.66–3.09, respectively, 95% confidence interval). Indeed, as there are 96% similarity between SARS-Co-V and SARS-CoV-2, a previous study illustrated that irbesartan improves the transcription of solute carrier family 10 member 1 which suppresses the nonstructural protein 10 of SARS-Co-V and prevents it replication.[39]

  Fibrinolytic System and Covid-19 Top

FP is involved in the lysis of forming thrombus, through secretion of plasminogen activators (PAs) from the intact endothelial cells. There are two types of PA, tissue type PA (t-PA) and urokinase type PA (u-PA), that bind fibrin surface to generate plasmin. Besides, u-PA increases body fluid plasmin, whereas t-PA increases plasmin in the plasma. In the absence of fibrin, plasmin formation depends on the expressed plasminogen and t-PA receptors. Indeed, the endothelium controls fibrinolysis through releasing PAI-1. FP is also stimulated by kallikrein and activated factor XII (XIIa).[40]

Recently, Ji et al. found that SARS-CoV-2 infection is associated with hyperfibrinolysis as evident with high circulating fibrin degradation products, high plasmin, and presence of hemorrhagic spots in multiple organs. Hence, patients with elevated plasminogen levels as in hypertension, type 2 diabetes mellitus, and cardiometabolic complications are at a higher risk for SARS-CoV-2 infection.[7] The envelope proteins of different viruses such as SARS, MERS, and respiratory syncytial virus are cleaved by cellular furin-like proteases that increase the ability of viruses to enter ACE2-containing host cells.[41] Furin proteases are highly expressed in pulmonary alveolar type 2 cells together with kallikrein and plasminogen. Plasmin together with furin protease and TMPRSS cleaves SP of CoV and enhances its entry.[42] It has been reported that bronchial plasmin and kallikrein potentiate the replication of influenza via cleaving HA protein, and thereby plasmin increases the virulence of SARS-CoV-2 via cleaving its SP. Hence, the inhibition of plasmin or TMPRSS by camostat mesylate may be of great worth in the management of kallikrein in Japan.[43],[44] Zhang et al. show that high plasmin levels are present in 97% of patients with SARS-CoV-2 infection; this percentage is augmented in severely ill patients prior to death. Moreover, 71.4% of patients with SARS-CoV-2 infection had disseminated intravascular coagulopathy, suggesting coagulation activations. Therefore, D-dimer is regarded as an independent risk factor for mortality in SARS-CoV-2 infection, and so normalization of FP is of value in this management.[45] On the other hand, α2-anti-plasmin is also increased by 2% compared with 50-fold of plasmin; this increment induces the formation of soluble plasmin–antiplasmin complex which deposits on the luminal surface of alveoli that initiates ARDS.[46] Therefore, these findings document that plasmin is involved in facilitating SARS-CoV-2 entry and replication, thus suppression of plasmin activity may reduce poor clinical outcomes in SARS-CoV-2 infection. Despite these robust evidences, Moore et al. show that administration of t-PA in SARS-CoV-2 infection with ARDS patients leads to significant improvement of respiratory functions via dissolution of peri-alveolar fibrin depositions.[47] Nevertheless, the author missed plasmin/infectivity axis and ignored that plasmin is an independent risk factor in mortality in SARS-CoV-2 infection. Han et al. establish that antithrombin plasma levels are significantly reduced in patients with SARS-CoV-2 infection compared with healthy controls, suggesting that coagulation pathway is deranged and together with abnormal FP may cause abnormal homeostatic activation in ARDS.[48] Furthermore, mechanical ventilation in the management of ARDS may cause ventilator-associated lung injury which per se leads to bronchoalveolar coagulopathy with significant reduction of t-PA activity.[49]

  The Interactions of Ras, Bradykinin, and Fibrinolytic Pathway in Covid-19 Top

The activity of FP is mainly determined by the balance between the levels of t-PA and PAI-1. ACEIs improve fibrinolysis via inhibition of PAI-1, whereas ARBs have a neutral effect on both fibrinolysis and PAI-1. The positive effect of ACEIs on the FP relates to the induction of the release of BK and inhibition of AngII-mediated PAI-1. As well, the release of t-PA from endothelium is also stimulated by BK.[50] Moreover, ACEIs increase the function of B2 receptor as allosteric enhancers via conformational changes in ACE. However, ARBs increase PAI-1 through the elevation of AngII-mediated AT1R.[51]

Therefore, these findings show ACEIs, but not ARBs, as a potential risk for the development of SARS-CoV-2 infection as both plasmin and BK facilitate the pathogenesis of SARS-CoV2 and augment the development of ARDS in SARS-CoV-2 pneumonia.[52] Up to date, Kickbusch and Leung show that impaired ACE2 in SARS-CoV-2 infection leads to a high BK metabolite level, which activates IL-6. Both BK and IL-6 cause vasodilation and augmentation of capillary permeability that are hallmarks of ARDS in SARS-CoV-2 infection.[36] It has been reported that high AngII level and induced oxidative stress play a crucial role in the development and progression of ARDS, therefore a renin inhibitor, aliskiren, prevents ALI through the reduction of AngII levels, IL-6, TNF-α, and IL-1β which together participate in lung inflammation and injury.[53] Besides, a BK receptor antagonist, deltibant, reduces septic shock-induced ALI, however, its role in viral-induced acute lung damage is limited.[54] Similarly, a leukotriene receptor antagonist, montelukast, attenuates ALI through inhibition of IL-6, TNF-α, and oxidative stress, thus it reduces systemic inflammatory reactions and ALI.[55] As well, olmesartan activates ACE2 directly and increases Ang 1-7 that activates Mas receptors.[56] Thus, this drug exerts renoprotective and pulmoprotective effects in hypertensive patients with SARS-CoV-2 infection. Moreover, ARBs, but not ACEIs, increase plasminogen via activation of PAI-1. Plasminogen improves ALI and ARDS, thus plasminogen therapy might be of worth in the management of SARS-CoV-2 infection.[57]

Therefore, different studies document the interactions between RAS, FP and bradykinine pathway in COVID-19 [Table 1]. Therefore, this study concludes that ACEIs, but not ARBs, in hypertensive patients are implicated in facilitating the pathogenesis of SARS-CoV-2 infection through their impact on the BK and FP. Depending on these observations, hypertensive patients with SARS-CoV-2 infection on ACEIs should be switched to ARBs, which have similar efficacy with a neutral effect on the BK and FPs.
Table 1: The interactions between RAS , FP and bradykinine pathway in COVID-19

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