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The Neuropeptide Substance P Is a Critical Mediator of Burn-Induced Acute Lung Injury¹

Selena Wei Shan Sio^*, Manoj Kumar Puthia, Jia Lu, Shabbir Moochhala^*, and Madhav Bhatia^2,*

^* Department of Pharmacology, National University of Singapore, Singapore; and Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore

The classical tachykinin substance P (SP) has numerous potent neuroimmunomodulatory effects on all kinds of airway functions. Belonging to a class of neuromediators targeting not only residential cells but also inflammatory cells, studying SP provides important information on the bidirectional linkage between how neural function affects inflammatory events and, in turn, how inflammatory responses alter neural activity. Therefore, this study aimed to investigate the effect of local burn injury on inducing distant organ pulmonary SP release and its relevance to lung injury. Our results show that burn injury in male BALB/c mice subjected to 30% total body surface area full thickness burn augments significant production of SP, preprotachykinin-A gene expression, which encodes for SP, and biological activity of SP-neurokinin-1 receptor (NK1R) signaling. Furthermore, the enhanced SP-NK1R response correlates with exacerbated lung damage after burn as evidenced by increased microvascular permeability, edema, and neutrophil accumulation. The development of heightened inflammation and lung damage was observed along with increased proinflammatory IL-1β, TNF-, and IL-6 mRNA and protein production after injury in lung. Chemokines MIP-2 and MIP-1 were markedly increased, suggesting the active role of SP-induced chemoattractants production in trafficking inflammatory cells. More importantly, administration of L703606, a specific NK1R antagonist, 1 h before burn injury significantly disrupted the SP-NK1R signaling and reversed pulmonary inflammation and injury. The present findings show for the first time the role of SP in contributing to exaggerated pulmonary inflammatory damage after burn injury via activation of NK1R signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by bridging funds (Grant R-184-000-139-101) and Cardiovascular Research Programme (Grant R-184-000-074-712).

² Address correspondence and reprint requests to Dr. Madhav Bhatia, Cardiovascular Biology Research Programme, Department of Pharmacology, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, No. 03-02, Singapore 117456. E-mail address: mbhatia{at}nus.edu.sg

³ Abbreviations used in this paper: SP, substance P; MPO, myeloperoxidase; NK1R, neurokinin-1 receptor; PPT-A, preptotachykinin-A.