Substance P antagonist CP-96345 blocks lung vascular leakage and inflammation more effectively than its stereoisomer CP-96344 in a mouse model of smoke inhalation and burn injury

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

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The recently developed murine model of smoke inhalation and burn (SB) injury was used to study the effect of the substance-P antagonist CP96345. C57BL/6 mice were pre-treated with an i.v. dose of a specific NK-1 receptor antagonist, CP9635, or its inactive enantiomer, CP96344, (10 mg/Kg) 1 h prior to SB injury per protocol (n = 5). Mice were anesthetized and exposed to cooled cotton smoke, 2X 30 s, followed by a 40% total body surface area flame burn per protocol. At 48 h after SB injury Evans Blue (EB) dye and myeloperoxidase (MPO) were measured in lung after vascular perfusion. Lungs were also analyzed for hemoglobin (Hb) and wet/dry weight ratio. In the current study, CP96345 pre-treatment caused a significant decrease in wet/dry weight ratio (23%, p = 0.048), EB (31%, p = 0.047), Hb (46%, p = 0.002), and MPO (54%, p = 0.037) levels following SB injury compared to animals with SB injury alone. CP-96344 pre-treatment caused an insignificant decrease in wet/dry weight ratio (14%, p = 0.18), EB (16%, p = 0.134), Hb (9%, p = 0.39), and an insignificant increase in MPO (4%, p = 0.79) as compared to mice that received SB injury alone. As expected, levels of EB, Hb, MPO, and wet/dry weight ratios were all significantly (p < 0.05) increased 48 h following SB injury alone compared to respective sham animals. In conclusion, the current study indicates that pre-treatment with a specific NK-1R antagonist CP-96345 attenuates the lung injury and inflammation induced by SB injury in mice.

Original languageEnglish (US)
Pages (from-to)197-203
Number of pages7
JournalToxicology Mechanisms and Methods
Volume20
Issue number4
DOIs
StatePublished - May 1 2010

Keywords

  • Acute lung injury
  • Burn injury
  • CP-96344
  • CP-96345
  • Myeloperoxidase
  • NK-1 receptor antagonist
  • Neurogenic inflammation
  • Plasma extravasation
  • Smoke inhalation
  • Substance P
  • Vascular permeability

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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