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Originally published online as doi:10.1189/jlb.0407217 on June 12, 2007

Published online before print June 12, 2007
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(Journal of Leukocyte Biology. 2007;82:678-685.)
© 2007 by Society for Leukocyte Biology

Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis

Akhil Hegde*, Huili Zhang*, Shabbir M. Moochhala*,{dagger} and Madhav Bhatia*,1

* Cardiovascular Biology Program, Department of Pharmacology, National University of Singapore, Singapore; and
{dagger} Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore

1 Correspondence: A/P Madhav Bhatia, Centre for Life Sciences, #03-06, 28 Medical Drive, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456. E-mail: mbhatia{at}nus.edu.sg

Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP). Sham-operated animals received the same surgical procedure, except CLP. Vehicle or SR140333 (1 mg/kg, s.c.) was administered to CLP mice 30 min before or 1 h after the CLP. Eight hours after surgery, lung tissue was collected and analyzed for myeloperoxidase (MPO) activity, chemokines, cytokines, and adhesion molecules. The CLP procedure alone caused a significant increase in the lung levels of MIP-2, MCP-1, IL-1ß, IL-6, ICAM-1, E- and P-selectin, and MPO activity when compared with sham-operated mice. SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1ß, IL-6, ICAM-1, and E- and P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of SR140333 on lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial sepsis, and this effect is brought about via reduction in leukocyte recruitment.

Key Words: SR140333 • cecal ligation and puncture • substance P • NK-1






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