Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Palomo, Jesús Jurado; Caballero, Teresa

doi:10.5772/67704

Cited by 10 publications

(12 citation statements)

References 77 publications

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“…[42] Furthermore, the kallikrein-kinin system is regulated by ACE and ACE2. Increased activity of the kallikrein-kinin system occurs under proinflammatory conditions, [59] specifically bradykinin and des-Arg-BK 9 , which can lead to vascular leakage when unchecked by ACE and ACE2, respectively. This mechanism has been posited to be, at least in part, a cause of cough [60] and pulmonary edema, [61] independent of proposed Ang II induced hydrostatic pressure.…”

Section: Aceis and Arbsmentioning

confidence: 99%

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

et al. 2020

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ImportanceCoronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin–angiotensin–aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin–angiotensin–aldosterone–SARS-CoV (RAAS–SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS–SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner.ObservationsThis review discusses the role of the RAAS–SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS–SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited.ConclusionProposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS–SCoV axis on acute lung injury in COVID-19.

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Section: Aceis and Arbsmentioning

confidence: 99%

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

et al. 2020

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“…The kinin-kallikrein system is a zymogen system that after activation leads to the release of the nona-petide bradykin that after binding to the B2-receptor on endothelial cells leads to capillary leakage and thus angioedema. The prototype diseases of local peripheral transient increased bradykinin release are hereditary or acquired angio-edema 5 . The clinical picture of COVID-19 is in line with a single-organ failure of the lung that is due to edema at the site of inflammation.…”

Section: Bradykinin-induced Local Pulmonary Angioedemamentioning

confidence: 99%

“…Plasma kallikrein processes highmolecular-weight kininogen (HMWK produced by the liver 8 ) into bradykinin, while tissue kallikrein processes low-molecular-weight kininogen (LMWK produced by the liver 8 ) and results in Lys-BK ( Figure 1). These are the ligands for the constitutively expressed bradykinin receptor B2 on endothelial cells 5 . In addition, the enzymes (carboxypeptidase M (CPM) and carboxypeptidase N (CPN)) can further process BK and Lys-BK into des-Arg9-BK and Lys-des-Arg9-BK respectively, which are ligands for bradykinin receptor B1, a receptor on endothelial cells that is upregulated under proinflammatory conditions 5 .…”

Section: Bradykinin-induced Local Pulmonary Angioedemamentioning

confidence: 99%

“…These are the ligands for the constitutively expressed bradykinin receptor B2 on endothelial cells 5 . In addition, the enzymes (carboxypeptidase M (CPM) and carboxypeptidase N (CPN)) can further process BK and Lys-BK into des-Arg9-BK and Lys-des-Arg9-BK respectively, which are ligands for bradykinin receptor B1, a receptor on endothelial cells that is upregulated under proinflammatory conditions 5 . These kinins have strong vasopermeable and vasodilatory capacity and need to be tightly controlled to prevent excessive angioedema.…”

Section: Bradykinin-induced Local Pulmonary Angioedemamentioning

confidence: 99%

“…However, for ACE inhibitors and ARBs it is a much more complicated story. Since most of the attention was focused on the RAS system and its interaction with modulating the vascular system and inflammation, the other major role of ACE and ACE2 for the regulation of the kinin-kallikrein system was lacking attention 4,5 .…”

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confidence: 99%

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

Veerdonk¹,

Netea²,

Deuren³

et al. 2020

Preprint

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

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Snake venom‐derived bradykinin‐potentiating peptides: A promising therapy forCOVID‐19?

Gouda¹,

Mégarbane

2020

Drug Development Research

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The severe acute respiratory syndrome coronavirus‐2 (SARS‐COV‐2), a novel coronavirus responsible for the recent infectious pandemic, is known to downregulate angiotensin‐converting enzyme‐2 (ACE2). Most current investigations focused on SARS‐COV‐2‐related effects on the renin–angiotensin system and especially the resultant increase in angiotensin II, neglecting its effects on the kinin–kallikrein system. SARS‐COV‐2‐induced ACE2 inhibition leads to the augmentation of bradykinin 1‐receptor effects, as ACE2 inactivates des‐Arg9‐bradykinin, a bradykinin metabolite. SARS‐COV‐2 also decreases bradykinin 2‐receptor effects as it affects bradykinin synthesis by inhibiting cathepsin L, a kininogenase present at the site of infection and involved in bradykinin production. The physiologies of both the renin–angiotensin and kinin–kallikrein system are functionally related suggesting that any intervention aiming to treat SARS‐COV‐2‐infected patients by triggering one system but ignoring the other may not be adequately effective. Interestingly, the snake‐derived bradykinin‐potentiating peptide (BPP‐10c) acts on both systems. BPP‐10c strongly decreases angiotensin II by inhibiting ACE, increasing bradykinin‐related effects on the bradykinin 2‐receptor and increasing nitric oxide‐mediated effects. Based on a narrative review of the literature, we suggest that BPP‐10c could be an optimally effective option to consider when aiming at developing an anti‐SARS‐COV‐2 drug.

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Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

Cited by 10 publications

References 77 publications

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

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

Snake venom‐derived bradykinin‐potentiating peptides: A promising therapy forCOVID‐19?

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