Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets

Abstract

The lung is highly sensitive to chemical injuries caused by exposure to threat agents in industrial or transportation accidents, occupational exposures, or deliberate use as weapons of mass destruction (WMD). There are no antidotes for the majority of the chemical threat agents and toxic inhalation hazards despite their use as WMDs for more than a century. Among several putative targets, evidence for transient receptor potential (TRP) ion channels as mediators of injury by various inhalational chemical threat agents is emerging. TRP channels are expressed in the respiratory system and are essential for homeostasis. Among TRP channels, the body of literature supporting essential roles for TRPA1, TRPV1, and TRPV4 in pulmonary chemical injuries is abundant. TRP channels mediate their function through sensory neuronal and nonneuronal pathways. TRP channels play a crucial role in complex pulmonary pathophysiologic events including, but not limited to, increased intracellular calcium levels, signal transduction, recruitment of proinflammatory cells, neurogenic inflammatory pathways, cough reflex, hampered mucus clearance, disruption of the integrity of the epithelia, pulmonary edema, and fibrosis. In this review, we summarize the role of TRP channels in chemical threat agents-induced pulmonary injuries and how these channels may serve as medical countermeasure targets for broader indications.

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

“…It has been proposed that morbidity, severity of the disease, and underlying physiological events leading to mortality are closely linked with the TRPV1-expressing neuronal system (afferent/efferent neurons) in the lungs [73]. TRVP1 and TRPV4 are involved in pulmonary chemical injuries [74]. In mouse acute lung injury models, the bacterial endotoxin LPS involves both TRPV1 and TRPA1 [31, 73, 75].…”

Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential

“…TRP channels are nonspecific cationic channels located throughout the respiratory system ( Clapham et al, 2001 ), where TRPA1, TRPV1 and TRPV4 are the most abundant TRP subtypes ( Kaneko and Szallasi, 2014 ; Steinritz et al, 2018 ). Evidences for TRPs as medium of lung injury are emerging from studies on various inhalational chemical threats ( Achanta and Jordt, 2020 ). TRPs regulate their functions through sensory neuronal and nonneuronal pathways and play an important role in complicated pulmonary pathophysiologic events, such as increased intracellular calcium levels, recruitment of pro-inflammatory cells, cough reflex, blocked mucus clearance, epithelia integrity disruption, pulmonary edema, fibrosis and so on ( De Logu et al, 2016 ).…”

“…Inhibiting these TRPs may benefit the treatment of pulmonary edema. A recent review has summarized the effects of TRPs in pulmonary chemical injuries, which includes the representative TRPA1, TRPV1 and TRPV4 antagonists which have participated in preclinical and clinical studies ( Achanta and Jordt, 2020 ) ( Supplementary Tables S1–S3 ).…”

Development of chlorine-induced lung injury in the anesthetized, spontaneously breathing pig

“…The establishment of a clinically relevant large animal model of chlorine-induced lung injury will enable potential therapies to be investigated in a species which more closely resembles man, and help translate animal efficacy studies, as well as enabling more direct extrapolation of clinical effects. As part of the development of new treatments to be approved for human use, two promising compounds R-107 (Radikal Therapeutics 2016;Fukuda et al 2016) andTRPV4 inhibitors (Global-Biodefense 2017;Achanta and Jordt 2020) are now in advanced development in large animal species for treatment of chlorineinduced lung injury (Summerhill et al 2017).…”