Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene

Abstract

Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca2+ concentration ([Ca2+]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16 ppm, 8 min), using an air/liquid interface exposure system. CG increased [Ca2+]i (p<0.05) in both cell types, The CG-induced [Ca2+]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24 hr lethality from whole body CG inhalation exposure in mice (8-10 ppm × 20 min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity.

Transient Receptor Potential Ion Channel–Dependent Toxicity of Silica Nanoparticles and Poly(amido amine) Dendrimers

“…Transient receptor potential (TRP) ion channels are a superfamily of polymodal cellular sensors located on the plasma membranes of many mammalian cell types that nanoparticles can potentially interact with. Different TRPs are involved in different physiologic processes, such as the regulation of local and cellular calcium levels and associated signaling, control of Na 21 and Mg 21 levels, transduction of sensory signals, cell proliferation, cell death, migration, and general homeostasis (Fleig and Penner, 2004;Nilius, 2007;Venkatachalam and Montell, 2007;Gees et al, 2010;Andres et al, 2016;Markó et al, 2017). The TRP superfamily can be divided into seven subfamilies: TRP vanilloid (TRPV), TRP ankyrin (TRPA), TRP canonical, TRP melastatin (TRPM), TRP mucolipin, and TRP polycystin (Polycystic Kidney Disease [PKD] and polycystic kidney disease 2-like [PKDL]) (Fleig and Penner, 2004;Gees et al, 2010;Khalil et al, 2018).…”

Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury

“…The calcium channels are now receiving more attention as novel therapeutic targets of lung injury [ 5 , 31 , 32 ]. In general, Ca 2+ channels can be classified based on their activation pattern and are divided into voltage-dependent calcium channels (VDCC) and non-VDCC.…”

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity—A Structured Review

“…Here, chemical induced vascular leakage and airway hyperreactivity were suppressed, while blood oxygenation was significantly improved [ 100 ]. In vivo experiments conducted by Andres et al point in the same direction: phosgene-induced pulmonary injury and lethality in mice were partially improved by post-exposure treatment with ruthenium red (RR), an unspecific TRP channel blocker [ 101 ]. Although the experimental design did not allow the identification of the distinct TRP channel, the authors speculate that TRPV4 may be one of the possible candidates.…”