Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets

Abstract

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.

Keywords: COVID-19; Kallikrein–Kinin System; acute lung injury; cytokine release storm; endothelin; hypoxic-adenosinergic response; renin angiotensin system; respiratory viral infection.

Figure 1

The renin–angiotensin system (RAS) including bradykinin in coronavirus disease 2019 (COVID-19). (1) To infect cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2), resulting in a functional loss of enzyme due to internalization and reduced expression of ACE2. This results in an imbalance of the angiotensin (Ang, 1–7, yellow triangles) and Ang (II, purple hexagons), favoring the accumulation of Ang II. Then, Ang II is able to bind to angiotensin receptor 1 (AT1) to mediate pulmonary vasoconstriction and inflammation. (2) Depletion of ACE2 activity following SARS-CoV-2 infection results in an increased a Des-Arg9-Bradykinin (BK, green squares) that can activate the bradykinin (B)2 receptor to promote vasoconstriction. (3) High-molecular-weight-kallikrein (HMWK) is converted to bradykinin (BK, blue squares) that in turn is metabolized to BL (1–7) and other metabolites by ACE1. Increased levels of AngII in COVID-19 reduce the enzymatic capacity of ACE1 resulting in an accumulation of BK that can also activate B2 receptors to promote pulmonary vasoconstriction. Clinically tested agents are shown in black boxes with white font. Captopril can inhibit the effect of ACE2, resulting in lower functional receptors for SARS-Cov-2. Losartan, an angiotensin receptor blocker (ARB), antagonizes the AT1 receptor inhibiting the effects of Ang II. Lanadelumab is a monoclonal antibody against HMWK, preventing its cleavage into BK. Icatibant is a B2 antagonist blocking the effects of both Des-Arg9-BK and BK.

Figure 2

The link between pulmonary vasoconstriction, high altitude-induced pulmonary edema (HAPE) and the cytokine release storm (CRS) in COVID-19. (1) Following SARS-Cov-2 infection, reduced PO₂ and resulting hypoxia can promote sustained pulmonary vasoconstriction, resulting in pulmonary edema akin to HAPE. This in turn results in reduced PO₂ that can itself further promote vasoconstriction, resulting in a vicious circle. (2) The cytokine release storm (CRS) in COVID-19 results in an increased in inflammatory cytokines including interleukin (IL)-1 (yellow triangles) IL-6 (brown circles) and tumor-necrosis factor alpha (TNF-A green squares). IL-6 and TNF-A are capable of promoting pulmonary vasoconstriction and vascular remodeling, which are important hallmarks of PH. TNF-A and IL-1 can promote increased hyaluronan levels that also stimulate vascular remodeling and pulmonary vasoconstriction. Clinically tested agents are shown in black boxes with white font. Nitric oxide can promote vasodilation reversing pulmonary vasoconstriction. Tocilizumab is a monoclonal antibody against IL-6, and 4-methylumbelliferone (4MU) inhibits hyaluronan synthesis.

Figure 3

Endothelin receptors, the hypoxic-adenosinergic response, and thrombotic processes in COVID-19 that impact pulmonary contractility. (1) The endothelin receptor antagonists (ERA) bosentan and macitentan inhibit endothelin receptor (ET)A and ETB activity. The activation of ETA is known to induce pulmonary vasoconstriction. ERAs can also reduce inflammatory cytokines such as interleukin (IL)-2,6,8 and cause reduced viral RNA counts. (2) Hypoxemia and resulting low PO₂ levels in COVID-19 lead to the stabilization of hypoxia inducible factor (HIF)-A, which in turn leads to increased ATP levels (yellow squares). The activation of P2Y-receptors (R) by ATP can promote pulmonary vasoconstriction. ATP can also be converted to adenosine (Ado, green triangles), which can then activate adenosine A1 (Adora1) or Adenosine A2B (Adora2B) receptors. The activation of Adora1 promotes pulmonary vasoconstriction, and the activation of Adora2B results in increased hyaluronan levels through the upregulation of hyaluronan synthase 2 (HAS2). (3) Viral-induced endothelial injury initiates the coagulation cascade in COVID-19 through the upregulation of tissue factor and Factor X that promote thrombosis. The degradation of fibrils during thrombosis leads to increased thromboxane A2 (TXA2), which is a potent vasoconstrictor that can be inhibited by ifetroban.