Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach

Abstract

Lethality of coronavirus disease (COVID-19) during the 2020 pandemic, currently still in the exponentially accelerating phase in most countries, is critically driven by disruption of the alveolo-capillary barrier of the lung, leading to lung edema as a direct consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We argue for inhibition of the transient receptor potential vanilloid 4 (TRPV4) calcium-permeable ion channel as a strategy to address this issue, based on the rationale that TRPV4 inhibition is protective in various preclinical models of lung edema and that TRPV4 hyperactivation potently damages the alveolo-capillary barrier, with lethal outcome. We believe that TRPV4 inhibition has a powerful prospect at protecting this vital barrier in COVID-19 patients, even to rescue a damaged barrier. A clinical trial using a selective TRPV4 inhibitor demonstrated a benign safety profile in healthy volunteers and in patients suffering from cardiogenic lung edema. We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for lung edema. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. Successful protection of the alveolo-capillary barrier will not only reduce COVID-19 lethality but will also preempt a distressing healthcare scenario with insufficient capacity to provide ventilator-assisted respiration.

Keywords: COVID-19; SARS-CoV-2; TRPV4; TRPV4 inhibitor; pulmonary edema.

Fig. 1.

Medical regimen based on three pillars, targeting the alveolo-capillary barrier of the lung feasible off the shelf. We favor a complementary approach to effectively manage coronavirus disease (COVID-19) and future coronavirus respiratory infections with high infectivity and significant lethality due to respiratory failure. Possibly a complimentary medical regimen could support a partially effective vaccine.

Fig. 2.

Alveolo-capillary barrier, transient receptor potential vanilloid 4 (TRPV4) expression, and proposed treatment with GSK2798745 in coronavirus disease (COVID-19). Note that TRPV4 expression and function might differ under lung infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As we argue, we believe that the benefits outweigh the risks, making possibly transformative therapeutic inroads against COVID-19 (at the individual patient and especially at the population health level) by protecting the alveolo-capillary barrier by inhibiting TRPV4. In clinical trials with early COVID-19 patients, daily oral dosing will be preferred. Injecting the compound will be reserved for more severely ill patients, with inhalatory application as additional treatment once a deterioration of lung barrier function has become clinically apparent. AT1 and AT2, alveolar type I and type II cells.