title: Mechanisms of toxic smoke inhalation and burn injury: role of neutral endopeptidase and vascular leakage in mice.
abstract: The effects of neutral endopeptidase (NEP) in acute inflammation in the lung were studied using a newly developed murine model of smoke and burn (SB) injury. C57BL/6 mice were pretreated with an i.v. dose of a specific NEP antagonist CGS-24592 (10 mg/Kg) 1 h prior to SB injury (n = 5-8/group). Mice were anesthetized with i.p. ketamine/xylazine, intubated, and exposed to cooled cotton smoke (2 x 30 s). After s.c. injection of 1 ml 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphene (2 mg/kg) was given i.p. and resuscitated by saline. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were analyzed for their levels of EB dye and myeloperoxidase (MPO). In mice pretreated with CGS-24592 followed by SB injury the EB levels were significantly higher (61%, p = 0.043) than those with SB injury alone. There was a significant increase (144%, p = 0.035) in EB dye in animals with SB injury alone as compared to shams. In mice pretreated with CGS-24592 prior to SB injury wet/dry weight ratios were significantly (27%, p = 0.042) higher compared to animals with SB injury alone. CGS-24592 pretreatment also caused a significant increase in MPO (29%, p = 0.026) as compared to mice with SB injury alone. In conclusion the current study indicates that specific NEP inhibitor CGS 24592 exacerbates the SB-induced lung injury and inflammation in mice.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77550, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Jacob
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Deyo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D002056:Burns / Q000201:enzymology / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011654:Pulmonary Edema / Q000201:enzymology / Q000503:physiopathology*; D015208:Smoke Inhalation Injury / Q000201:enzymology / Q000503:physiopathology*
chemical_list: C086164:CGS 24592; D063065:Organophosphonates; D011480:Protease Inhibitors; D010649:Phenylalanine; D015260:Neprilysin