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

Wolfgang M Kuebler, Sven-Eric Jordt, Wolfgang B Liedtke, Wolfgang M Kuebler, Sven-Eric Jordt, Wolfgang B Liedtke

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.

Conflict of interest statement

W. B. Liedtke cofounded TRPblue, a biotechnology start-up company that is aiming to commercialize TRPV4/TRPA1 dual-inhibitory compounds for treatment of chemotherapy-associated nerve pain and chronic allergic skin inflammation. Of note, none of TRPblue’s compounds would be suitable for the advocated approach because they await testing in humans and are intended for topical application to skin. S.-E. Jordt was supported by cooperative agreement U01ES015674 by the National Institutes of Health Countermeasures Against Chemical Threats (CounterACT) program to investigate the efficacy of TRPV4 inhibitors in models of chlorine inhalation injury. He received TRPV4 inhibitors from GlaxoSmithKline Pharmaceuticals for these studies. W. M. Kuebler does not have any conflicts of interest, financial or otherwise, to disclose.

Figures

Fig. 1.
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.
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.

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