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Originally published online as doi:10.1189/jlb.0807575 on November 12, 2007

Published online before print November 12, 2007
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(Journal of Leukocyte Biology. 2008;83:288-295.)
© 2008 by Society for Leukocyte Biology

Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia

Siaw Wei Ng, Huili Zhang, Akhil Hegde and Madhav Bhatia1

Cardiovascular Biology Research Group, Department of Pharmacology, National University of Singapore, Singapore

1 Correspondence: Cardiovascular Biology Group, Department of Pharmacology c/o Centre for Life Sciences, #03-02, National University of Singapore, 28 Medical Drive, Singapore 117456. E-mail: mbhatia{at}nus.edu.sg

ABSTRACT

Endotoxemia is a life-threatening, inflammatory condition that involves multiple organ injury and dysfunction. Preprotachykinin-A (PPT-A) gene products, substance P (SP), and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products on multiple organ injury in LPS-induced endotoxemia, endotoxemia was induced by LPS administration (10 mg/kg, i.p.) in PPT-A gene-deficient mice (PPTA–/–) and the wild-type (WT) control mice (PPT-A+/+). I.p. administration of LPS to WT mice caused a significant increase in circulating levels of SP as well as in liver, lung, and kidney. PPT-A gene deletion significantly protected against liver, pulmonary, and renal injury following LPS-induced endotoxemia, as evidenced by tissue myeloperoxidase activities, plasma alanine aminotransferase, aspartate aminotransferase levels, and histological examination. Furthermore, PPT-A–/– mice had significantly attenuated chemokines, proinflammatory cytokines, and adhesion molecule levels in the liver, lung, and kidney. These results show that PPT-A gene products are critical proinflammatory mediators in endotoxemia and the associated multiple organ injury. In addition, the data suggest that deletion of the PPT-A gene protected mice against organ damage in endotoxemia by disruption in neutrophil recruitment.

Key Words: substance P • endotoxin shock • neutrophils • inflammation




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