title: 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 Ca(2+) concentration ([Ca(2+)]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16ppm, 8min), using an air/liquid interface exposure system. CG increased [Ca(2+)]i (p<0.05) in both cell types, The CG-induced [Ca(2+)]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 24h lethality from whole body CG inhalation exposure in mice (8-10ppm×20min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity.
authors.affiliation: Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. Electronic address: devon.k.andres.ctr@mail.mil.
authors.forename: Devon
authors.initials: D
authors.lastname: Andres
authors.affiliation: Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Keyser
authors.affiliation: Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Benton
authors.affiliation: Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Melber
authors.affiliation: Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Dorian
authors.initials: D
authors.lastname: Olivera
authors.affiliation: Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Holmes
authors.affiliation: Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Paradiso
authors.affiliation: Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. Electronic address: radharaman.ray.civ@mail.mil.
authors.forename: Radharaman
authors.initials: R
authors.lastname: Ray
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002619:Chemical Warfare Agents / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019570:Inhalation Exposure; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D051379:Mice; D058990:Molecular Targeted Therapy; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010705:Phosgene / Q000633:toxicity*; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D007093:Imidazoles; D049990:Membrane Transport Modulators; D050051:Transient Receptor Potential Channels; D010705:Phosgene; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium
keywords: Calcium signaling; Inhalation; Phosgene; Respiratory toxicology; SKF; TRP channels; Therapeutic