Neurokinin‐1 Receptor antagonist treatment alleviates CLP‐induced polymicrobial sepsis in mice, acting via NFkappaB

Abstract

We have earlier shown a beneficial effect of substance P (SP) receptor blocking on lung inflammation in sepsis by using SP receptor antagonist SR140333. To further understand the mechanism, we evaluated the effect of SR140333 on plasma SP levels and lung nuclear transcription factor NFκB in sepsis. Sepsis was induced in male Swiss mice by cecal ligation and puncture (CLP). Sham operated animals received the same surgical procedure except cecal ligation and puncture. Vehicle or SR140333 (1 mg/kg; s.c.) was administered to CLP mice either 30 min before or 1 h after the CLP. 8 h after surgery, plasma SP levels were estimated and lung tissue was analyzed for binding activity of NFκB. CLP induced sepsis resulted in a significant increase in plasma SP levels in vehicle treated mice compared to the corresponding levels in sham mice. Prophylactic and therapeutic administration of SR140333 showed a significant reduction in plasma SP levels. NFκB is known to be responsible for the gene regulation of various mediators in lung inflammation. We observed a significant increase in the binding activity of NFκB in lung in CLP operated mice. SR140333 treatment lowered the binding activity of NFκB indicating a role for this transcription factor downstream of SP in inducing lung inflammation. These results show that SR140333 therapy may be beneficial in the treatment of lung inflammation in sepsis by acting via NFκB. Hegde A et al J Leukoc Biol 2007, 82:678–85.