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Early Protection from Burn-induced Acute Lung Injury by Deletion of Preprotachykinin-A Gene

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and ² Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore

Correspondence and requests for reprints should be addressed to Madhav Bhatia, Ph.D., Department of Pathology, University of Otago, PO Box 4345, Christchurch 8140, New Zealand. E-mail: madhav1{at}hotmail.com or madhav1245{at}gmail.com.

Rationale: Burn-induced acute lung injury (ALI) is a common clinical disorder associated with high mortality even in the absence of inhalational injury. Identification of endogenous triggers that mediate the early onset of remote ALI after burn represents an important goal but remains poorly defined.

Objectives: We investigated the role of proinflammatory neuropeptide, substance P (SP), in instigating remote ALI and its effects on respiratory function early after severe local burn injury.

Methods: A 30% total body surface area full-thickness burn was induced in wild-type (WT) mice, preprotachykinin-A (PPT-A) gene deficient mice, which encodes for SP, and PPT-A^–/– mice challenged with exogenous SP, followed by ALI and lung function analysis.

Measurements and Main Results: Endogenous SP production was heightened in burn-injured WT mice, which induced significant elevation of proinflammatory cytokines, chemokines, and endothelial adhesion molecules concurrent with disruption of pulmonary permeability barrier, excessive neutrophil infiltration, and severe ALI. Additionally, decreased neutral endopeptidase and elevated matrix metalloproteinase-9 were evident. Notably, disruption of respiratory function demonstrates a critical role of SP in lungs after burn. These effects were significantly attenuated in PPT-A^–/– mice, whereas the exogenous administration of SP to PPT-A^–/– mice restored the inflammatory response and ALI. Furthermore, analysis of neurokinin-1-receptor (NK1R), to which SP binds preferentially, revealed that SP in conjunction with burn injury regulates NK1R expression.

Conclusions: We show that the absence of a single endogenous factor, SP, significantly provides early protection against burn-induced ALI in mice with marked improvement in respiratory function. Thereby, the blockade of SP may be beneficial in preventing early inflammation and ALI in patients with critical burn injuries.

Key Words: neuropeptide • respiratory function • substance P • thermal

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The prominent occurrence of acute lung injury (ALI) is a major problem in burn patients even in the absence of inhalational injury. However, the early triggers of remote ALI following severe local burn injury are not well understood. What This Study Adds to the Field The neuropeptide, substance P, encoded by preprotachykinin-A (PPT-A) gene, is an early and critical endogenous mediator to the pathophysiology of remote ALI and disruption of respiratory function after severe local burn injury.