title: Single high-dose dexamethasone and sodium salicylate failed to attenuate phosgene-induced acute lung injury in rats.
abstract: Life-threatening acute lung injury potentially occurs following high-level accidental exposures to phosgene gas. This situation was mirrored in rats exposed nose-only at 900-1000 mg phosgene/m(3)min. At this exposure level, previous studies on rats demonstrated sustained reflexively induced cardiopulmonary dysfunction and evidence of vascular fluid redistribution. These findings challenge the currently applied treatment strategies to mitigate the presumed non-cardiogenic lung edema by steroidal or non-steroidal anti-inflammatory drugs. This study investigates whether high doses of curatively administered dexamethasone (DX; 100 mg/kg bw, ip) and sodium salicylate (SS; 200 mg/kg bw, ip), alone or in combination, show efficacy to mitigate the phosgene-induced lung edema. Exhaled nitric oxide (eNO), animal morbidity and mortality, and increased lung weights one day postexposure served as endpoints of lung injury and drug efficacy. When applying this dosing regimen, SS showed minimal (if any) efficacy while DX, alone or in combination with SS, substantially aggravated the emerging lung edema (lung weights) with 40% mortality. The degree of acute lung injury (ALI) was mirrored by increased eNO. Its direct relationship to ALI-severity was evidenced by decreased eNO following NO-synthetase inhibitor administration (aminoguanidine-aerosol) and associated mitigation of ALI. All non-treated phosgene-exposed as well as treated but non-phosgene-exposed rats survived. This experimental evidence suggests that high-dose corticoid treatments may aggravate the pulmonary toxicity of phosgene. Similarly, this outcome supports the supposition that non-inflammatory, cardiogenic and/or neurogenic factors play a role in this type of acute lung injury.
authors.affiliation: Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100069, China; Department of Toxicology, Bayer Pharma AG, D-42096 Wuppertal, Germany.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Bayer Pharma AG, D-42096 Wuppertal, Germany. Electronic address: juergen.pauluhn@bayer.com.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
authors.affiliation: Department of Pharmacology Vascular Diseases, Cardiology & Hematology, Bayer Pharma AG, 42096 Wuppertal, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Trübel
authors.affiliation: Beijing Institute of Respiratory Medicine, Beijing Hospital, Ministry of Health, Beijing 100730, China. Electronic address: cyh-birm@263.net.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010705:Phosgene / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D012720:Severity of Illness Index; D012980:Sodium Salicylate / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002619:Chemical Warfare Agents; D005938:Glucocorticoids; D010705:Phosgene; D009569:Nitric Oxide; D003907:Dexamethasone; D012980:Sodium Salicylate
keywords: Acute lung injury; Dexamethasone; Exhaled nitric oxide; Lung edema; Phosgene; Sodium salicylate