The neuropeptide substance P is a critical mediator of burn-induced acute lung injury

Research output: Contribution to journalArticle

Abstract

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-1beta, TNF-alpha, and IL-6 mRNA and protein production after injury in lung. Chemokines MIP-2 and MIP-1alpha 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.

Details

Authors
External organisations
  • National University of Singapore
  • DSO (Defence Science Organisation) National Laboratories
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area

Keywords

  • Acute Disease, Adjuvants, Immunologic/biosynthesis, Animals, Blood Platelets/pathology, Burns/blood, Capillary Permeability/immunology, Chemokines/biosynthesis, Cytokines/biosynthesis, Disease Models, Animal, Inflammation Mediators/blood, Lung/immunology, Lymphocytes/pathology, Male, Mice, Mice, Inbred BALB C, Monocytes/pathology, Neutrophils/pathology, RNA, Messenger/biosynthesis, Receptors, Neurokinin-1/blood, Signal Transduction/immunology, Substance P/biosynthesis
Original languageEnglish
Pages (from-to)8333-41
Number of pages9
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume180
Issue number12
Publication statusPublished - 2008 Jun 15
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes