Mechanisms of toxic smoke inhalation and burn injury: Role of neutral endopeptidase and vascular leakage in mice

Sam Jacob, Donald J. Deyo, Robert A. Cox, Daniel L. Traber, David N. Herndon, Hal K. Hawkins

Research output: Contribution to journalArticle

7 Scopus citations

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 58/group). Mice were anesthetized with i.p. ketamine/xylazine, intubated, and exposed to cooled cotton smoke (2 × 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.

Original languageEnglish (US)
Pages (from-to)191-196
Number of pages6
JournalToxicology Mechanisms and Methods
Volume19
Issue number3
DOIs
StatePublished - Nov 4 2009

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Keywords

  • Acute lung injury
  • NEP
  • Neurogenic inflammation
  • Neutral endopeptidase activity
  • Plasma extravasation
  • Vascular permeability

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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