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

Abstract

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.

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

“…The dysregulated kallikrein-kinin system's role remains theoretical in COVID-19; however, if true, AT 1 receptor blockade may be favored (over ACE inhibition) in an attempt to preserve the regulatory mechanisms of this system. [61] While there may still be a key role for ACE inhibition in the context of the current disease that we will elucidate in the following sections, these observations support our decision to narrow the focus of this review to the downstream RAAS modifiers, ARBs.…”

“…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. The dysregulated kallikrein-kinin system's role remains theoretical in COVID-19; however, if true, AT 1 receptor blockade may be favored (over ACE inhibition) in an attempt to preserve the regulatory mechanisms of this system.…”

Histopathology and genetic susceptibility in COVID‐19 pneumonia

“…This spectrum of abnormalities is highly reminiscent of changes seen in the context of the chronic lung allograft rejection (CLAD) of the restrictive phenotype (restrictive allograft syndrome (RAS)), which we have recently described, and which is presumed to occur secondary to antibody-mediated endothelial damage and complement activation of humoral rejection episodes 13 . Such vascular changes are likely to play a central role in the pathogenesis of COVID-19, and may in part be attributable to dysregulation of the endothelial ACE2 receptor with ensuing bradykinin-dependent local lung edema 14 , as well as a highly pro-thrombotic state, which can manifest itself in the lung as well as in extra-pulmonary tissues 15 . Direct…”

A Review: Does Complement or the Contact System Have a Role in Protection or Pathogenesis of COVID-19?

“…A recent manuscript by van de Veerdonk et al notes that as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [15]. They further propose that blocking the B1 and B2 receptors may be beneficial in reducing the pulmonary edema noted in COVID-19.…”

“…Unfortunately, though B2 receptor antagonists (icatibant) exist, there are presently no B1 receptor antagonists. It would be anticipated that dual B1 and B2 receptor inhibition would be ideal; however, the possibility that inhibiting the kallikreinkinin pathway could be of benefit needs to be excluded [14,15].…”