COVID-19: urgent reconsideration of lung edema as a preventable outcome Inhibition of TRPV4 as a promising and feasible approach

Summary:

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.

At this point (early April, 2020), true lethality of SARS-CoV-2 infections is unknown because the accurate number of infected remains undetermined (1). Any effective reduction in lethality of severe Covid-19 is urgently needed on a global scale. In particular, interventions to reduce the numbers of patients requiring assisted ventilation is critical since their numbers threaten to exceed the available ventilator capacity, a potentially catastrophic perspective (2, 3).

Here we propose the calcium-permeable TRPV4 ion channel as a currently underappreciated yet promising target for efforts to reduce respiratory complications, morbidity and mortality of severe Covid-19. Clinically feasible inhibition of TRPV4 should be seriously and urgently considered as a rapidly implementable new treatment for this purpose.

The case for TRPV4 is based on these 3 lines of evidence

1. Fortunately, the severity of the majority of Covid-19 cases is not amounting to a level of critically ill. However, once SARS-CoV-2 infection progresses to the stage of pneumonia, then alveolo-capillary barrier failure and ensuing formation of permeability-type lung edema become key pathogenic drivers toward critically-ill SARS. This clinical stage shows characteristic symptoms of the acute respiratory distress syndrome (ARDS) and can readily lead to lethal outcome. This clinical path of manifest SARS transitioning to critically-ill SARS via alveolo-capillary barrier failure is a shared hallmark of SARS-CoV-1, SARS-MERS and SARS-CoV-2 caused diseases (4–9).

2. TRPV4 channels are multimodally-activated calcium-permeable cation channels that have been identified as important regulators of alveolo-capillary barrier integrity, with expression in all relevant cell types of the alveolo-capillary unit, namely alveolar type I and type II cells as well as alveolar capillary endothelial cells (10–13). In addition, TRPV4 is expressed in and regulates the activation of innate immune cells such as alveolar macrophages and neutrophil granulocytes which contribute to alveolo-capillary barrier disruption via the release of proteases, cytokines, and reactive oxygen species (11, 14–21). The critical role of TRPV4 in alveolo-capillary barrier integrity was first documented in 2006 in a study demonstrating that selective TRPV4 activation results in rapid loss of alveolo-capillary barrier function and subsequent formation of alveolar edema (22), also see our Figure. Since then, the particular role of TRPV4 in alveolo-capillary barrier regulation has been corroborated and extended in a series of preclinical studies showing protective effects of TRPV4 inhibition in models of permeability-type lung edema following e.g. mechanical overventilation, acid aspiration, or chlorine inhalation (11, 13, 15, 17, 18, 23). It was also demonstrated that TRPV4 regulates alveolo-capillary barrier integrity in a human lung-on-a-chip model (24). In several preclinical studies including one in primates, selective TRPV4 inhibitors were shown to prevent or attenuate cardiogenic lung edema following acute left ventricular failure (25). On the other hand, a nano-molar potency TRPV4 selective activator caused lethality in several experimental animal species upon systemic injection by causing endothelial barrier failure with subsequent acute circulatory collapse and pulmonary edema (26). Recently, a gene-therapeutic approach was employed to suppress TRPV4 function via a co-expressed protein, the CD98 high-homology domain (27). Using AAV gene-therapy viral vectors for transduction of human lung cells, this approach proved effective to attenuate alveolo-capillary barrier failure in a lung-on-a-chip model. Finally, exosomes derived from human adipocytes have been found to protect mice against ventilator-induced lung injury via inhibition of TRPV4-mediated calcium influx (28). Taken together, there is ample evidence for a protective effect of TRPV4 inhibition on alveolo-capillary barrier function, and different pharmacological and genetic approaches have been developed for effective targeting of TRPV4.

3. Inhibition of TRPV4 in Covid-19 patients is clinically feasible with inhibitor compounds available for clinical testing and implementation now. One particular inhibitor, GSK2798745, has been tested in Phase-I trials in human healthy volunteers, also in patients with cardiogenic lung edema and chronic cough, and was found to be safe in all cohorts (29–33).

Figure:

Alveolo-capillary barrier, TRPV4 expression and proposed treatment with GSK2798745 in Covid-19.

Note that TRPV4 expression and function might differ under lung infection with SARS-CoV-2. As we argue, we believe that the benefits outweigh the risks, from 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.

Importantly, compared to classic ARDS which develops acutely and as such, does not allow for preventive measures, Covid-19 is characterized by a gradual onset of symptoms which progress in a slow-crescendo from flu-like symptoms to pneumonia and ultimately, respiratory failure (3). As such, the Covid-19 scenario is ideally suited for adjunctive therapies such as inhibition of TRPV4. A TRPV4 inhibitor can be introduced into patients early after the onset of respiratory symptoms before their progression to a SARS-like clinical picture with the aim to stabilize the alveolo-capillary barrier prior to its failure. Early protection of the alveolo-capillary barrier prior to overt alveolar flooding may prove to be particularly life-saving in regions where the needed medical infrastructure (number of ventilator beds, operated by competent intensive care teams) is insufficient vs number of patients in need with critically-ill SARS. As such, TRPV4 inhibition appears as an attractive and feasible strategy to alleviate the global burden of deaths from Covid-19 which otherwise could rapidly become highly challenging. With development of Covid-19 countermeasures focusing on antivirals, vaccines, protease-inhibitory and immunomodulatory drugs, treatment with a TRPV4 inhibitor has an encouraging outlook to achieve additive or even synergistic effects (34–39).

Commentary and caveats

We argue for rapid consideration of TRPV4 inhibitory therapy that can be implemented essentially NOW for effective protection of the alveolo-capillary barrier of Covid-19 patients.

Despite its clear promise, some potential restrictions and caveats should not go unmentioned: First, systemic inhibition of TRPV4 could prove problematic due to potential effects on hepatic function, a concern that is particularly relevant in the critically ill (40), yet a hepato-protective role of TRPV4 inhibition has also been postulated in acetaminophen toxicity (41). Notably, phase-I clinical trials using a selective TRPV4 inhibitor did not detect increased liver enzymes in healthy volunteers or patients with congestive heart failure (30). In regards to respiratory infections, recent studies report that TRPV4 inhibition may reduce bacterial clearance of Pseudomonas aeruginosa by macrophages (42). However, TRPV4 inhibition seems beneficial in lung infection with Streptococcus pneumoniae, the most frequent microbial cause of community-acquired pneumonia (43). In addition, an earlier study documenting the role of TRPV4 in alveolar barrier integrity in-vivo demonstrated that ventilator-induced lung injury depended on TRPV4 function in macrophages (17, 18).

While these potential caveats, rooted in preclinical studies with divergent results, need to be subjected to scrutiny in future studies, we believe that they are outweighed by the urgent need for alveolo-capillary barrier-stabilizing drugs in the present Covid-19 pandemic.

Rapid clinical trials will be daunting, but do-able as the example of currently ongoing clinical trials with remdesivir in Covid-19 illustrates (44).

Taken together, we reiterate the global and urgent priority to reduce Covid-19-associated lethality and potentially disastrous burden on health care systems due to the need for ventilator-assisted respiration. We identify TRPV4 as a worthy target to protect and rescue the integrity of the alveolo-capillary barrier as an achievable milestone to avoid extremely unfortunate outcomes. Addressing this task under normal circumstances would perhaps take years. We do not have this time now and need to adapt regulatory schedules to our unprecedented current situation.