A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications

Abstract

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation → injury → inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.

Keywords: bradykinin; bradykinin receptor; coronavirus; icatibant; inflammation; injury.

FIGURE 1

Hypothesized role for dysregulated bradykinin signaling in COVID‐19 respiratory complications and the potential benefit of bradykinin receptor blockers. SARS coronavirus‐2 (SARS‐CoV‐2), the virus that causes coronavirus disease 19 (COVID‐19), is known to enter host cells in the respiratory system via the transmembrane protein, angiotensin converting enzyme 2 (ACE2), (Panel A). SARS‐CoV infection depletes ACE2 at the plasma membrane of infected cells (Panel B). In the extracellular environment of both infected cells as well as neighboring bystander cells, ACE2 depletion increases the levels of des‐Arg(9)‐bradykinin (DABK), which is a bioactive metabolite of bradykinin (BK) that is associated with airway inflammation (Panels B, C). SARS‐CoV infection severely affects host cell homeostasis, by triggering endoplasmic reticulum stress, mitochondrial death signaling, downregulation of ACE2, upregulation of pro‐inflammatory genes, and nuclear death signals, which ultimately lead to cell death (Panels D, E). Cellular injury and inflammation induces BK‐B1‐receptor (B1R) upregulation and trafficking to the plasma membrane, which amplifies DABK‐mediated inflammation and injury, (Panel D). Tissue injury and inflammation also increases BK levels and BK‐B2‐receptor (B2R) stimulation, (Panels D, E). Our testable hypothesis for dysregulated BK signaling in COVID‐19 respiratory complications is that, ACE2 depletion in SARS‐CoV‐2‐infected cells causes DABK accumulation in the extracellular environment of infected and neighboring bystander cells, which triggers a vicious positive feedback loop of inflammation and injury leading to even greater levels of DABK‐ and BK‐mediated inflammation and injury (Panel E). DABK not only binds strongly to B1Rs, through which it exerts downstream effects, but also binds weakly to B2Rs in certain tissues, and exerts effects that are blocked by the B2R blocker, icatibant, (Panel E). Since there are currently no FDA‐approved drugs that selectively block DABK signaling through B1Rs, we provide a testable prediction that, off‐label use of FDA‐approved icatibant, will at least partially interrupt the positive feedback loop of DABK‐ and BK‐mediated inflammation → injury→inflammation, and improve clinical outcomes in patients with COVID‐19 respiratory complications (Panels E‐H). Bidirectional arrows suggest that, these processes are likely to aggravate each other and be part of smaller positive feedback loops