title: Ethyl pyruvate protects rats from phosgene-induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression.
abstract: Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 µm) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2).
authors.affiliation: Department of Toxicology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Hong-li
authors.initials: HL
authors.lastname: Chen
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.forename: Miao-miao
authors.initials: MM
authors.lastname: Xi
authors.forename: Riu
authors.initials: R
authors.lastname: Liu
authors.forename: Xu-jun
authors.initials: XJ
authors.lastname: Qin
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao-di
authors.initials: XD
authors.lastname: Zhang
authors.forename: Wen-li
authors.initials: WL
authors.lastname: Li
authors.forename: Chun-xu
authors.initials: CX
authors.lastname: Hai
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D002619:Chemical Warfare Agents / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010705:Phosgene / Q000633:toxicity*; D020011:Protective Agents / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002619:Chemical Warfare Agents; D020011:Protective Agents; D011773:Pyruvates; C046522:ethyl pyruvate; D010705:Phosgene; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases