Download This PaperCOVID-19: Urgent Reconsideration of Lung Edema as a Preventable Outcome: Inhibition of TRPV4 As a Promising and Feasible Approach
Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: Inhibition of TRPV4 represents a promising and feasible approach.13 May 2020 American Journal of Physiology-Lung Cellular and Molecular Physiology, DOI/10.1152/ajplung.00161.2020
9 Pages Posted: 23 Mar 2020 Last revised: 21 May 2020
Date Written: March 22, 2020
Abstract
Lethality of Covid-19 during the 2020 pandemic, currently 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 SARS-CoV-2 infection. We argue for inhibition of the 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. We note that 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 pre-empt a catastrophic scenario in healthcare with insufficient capacity to provide ventilator-assisted respiration.
Note: Funding: Sven-Eric Jordt was supported by cooperative agreement U01ES015674 by the NIH Countermeasures Against Chemical Threats (CounterACT) program to investigate the efficacy of TRPV4 inhibitors in models of chlorine inhalation injury.
Conflict of Interest: Wolfgang Liedtke co-founded 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. Sven-Eric Jordt was supported by cooperative agreement U01ES015674 by the NIH 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. There is no additional conflict of interest.
Keywords: SARS-CoV-2, Covid-19, TRPV4, lung edema, alveolo-capillary barrier
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