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

摘要

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 pretreated with an i.v. dose of a specific NK-1 receptor antagonist, CP9635, or its inactive enantiomer, CP96344, (10 mg/Kg) 1 hr prior to SB injury per protocol (n = 5). Mice were anesthetized and exposed to cooled cotton smoke, 2X 30 sec, followed by a 40% total body surface area flame burn per protocol. At 48 hr 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 pretreatment 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 pretreatment 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 hr following SB injury alone compared to respective sham animals. In conclusion, the current study indicates that pretreatment with specific NK-1R antagonist CP-96345 attenuates the lung injury and inflammation induced by SB injury in mice.