title: Conceptual approaches for treatment of phosgene inhalation-induced lung injury.
abstract: Toxic industrial chemicals are used throughout the world to produce everyday products such as household and commercial cleaners, disinfectants, pesticides, pharmaceuticals, plastics, paper, and fertilizers. These chemicals are produced, stored, and transported in large quantities, which poses a threat to the local civilian population in cases of accidental or intentional release. Several of these chemicals have no known medical countermeasures for their toxic effects. Phosgene is a highly toxic industrial chemical which was used as a chemical warfare agent in WWI. Exposure to phosgene causes latent, non-cardiogenic pulmonary edema which can result in respiratory failure and death. The mechanisms of phosgene-induced pulmonary injury are not fully identified, and currently there is no efficacious countermeasure. Here, we provide a proposed mechanism of phosgene-induced lung injury based on the literature and from studies conducted in our lab, as well as provide results from studies designed to evaluate survival efficacy of potential therapies following whole-body phosgene exposure in mice. Several therapies were able to significantly increase 24h survival following an LCt50-70 exposure to phosgene; however, no treatment was able to fully protect against phosgene-induced mortality. These studies provide evidence that mortality following phosgene toxicity can be mitigated by neuro- and calcium-regulators, antioxidants, phosphodiesterase and endothelin receptor antagonists, angiotensin converting enzymes, and transient receptor potential cation channel inhibitors. However, because the mechanism of phosgene toxicity is multifaceted, we conclude that a single therapeutic is unlikely to be sufficient to ameliorate the multitude of direct and secondary toxic effects caused by phosgene inhalation.
authors.affiliation: Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States. Electronic address: wesley.w.holmes.civ@mail.mil.
authors.forename: Wesley W
authors.initials: WW
authors.lastname: Holmes
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Keyser
authors.affiliation: Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Paradiso
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Radharaman
authors.initials: R
authors.lastname: Ray
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Devon K
authors.initials: DK
authors.lastname: Andres
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Betty J
authors.initials: BJ
authors.lastname: Benton
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Cristin C
authors.initials: CC
authors.lastname: Rothwell
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Hoard-Fruchey
authors.affiliation: Research Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Dillman
authors.affiliation: Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
authors.affiliation: Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States. Electronic address: dana.r.anderson.civ@mail.mil.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D002619:Chemical Warfare Agents; D004195:Disease Models, Animal; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010705:Phosgene; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D010705:Phosgene
keywords: Exposure; Inhalation; Mechanism; Mice; Phosgene; Survival; Toxicity; Treatment; Whole-body