Neurokinin-1 Receptor Antagonist Treatment in Polymicrobial Sepsis: Molecular Insights

Author:

Hegde Akhil12,Koh Yung-Hua1,Moochhala Shabbir M.13,Bhatia Madhav12

Affiliation:

1. Cardiovascular Biology Program, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, MD 11, No. 05-09, 10 Medical Drive, Singapore 117597

2. Department of Pathology, University of Otago, Christchurch, 2 Riccarton Avenue, P.O. Box 4345, Christchurch 8140, New Zealand

3. DSO National Laboratories, DSO@DMERI, Kent Ridge, 27 Medical Drive, Singapore 117510

Abstract

Neurokinin-1 receptor blocking has been shown to be beneficial against lung injury in polymicrobial sepsis. In this paper, we evaluated the possible mediators and the mechanism involved. Mice were subjected to cecal ligation and puncture (CLP-) induced sepsis or sham surgery. Vehicle or SR140333 [1 mg/kg; subcutaneous (s.c.)] was administered to septic mice either 30 min before or 1 h after the surgery. Lung tissue was collected 8 h after surgery and further analyzed. CLP alone caused a significant increase in the activation of the transcription factors, protein kinase C-α, extracellular signal regulated kinases, neurokinin receptors, and substance P levels in lung when compared to sham-operated mice. SR140333 injected pre- and post surgery significantly attenuated the activation of transcription factors and protein kinase C-αand the plasma levels of substance P compared to CLP-operated mice injected with the vehicle. In addition, GR159897 (0.12 mg/kg; s.c.), a neurokinin-2 receptor antagonist, failed to show beneficial effects. We conclude that substance P acting via neurokinin-1 receptor in sepsis initiated signaling cascade mediated mainly by protein kinase C-α,led to NF-κB and activator protein-1 activation, and further modulated proinflammatory mediators.

Funder

National Medical Research Council

Publisher

Hindawi Limited

Subject

Immunology and Allergy

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