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A more recent version of this article appeared on February 1, 2008

Published online before print November 12, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807575

Received for publication August 27, 2007.
Revised October 9, 2007.
Accepted for publication October 11, 2007.

Article

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

Siaw Wei Ng , Huili Zhang , Akhil Hegde , and Madhav Bhatia @

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

@ To whom correspondence should be addressed. 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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Copyright © 2007 by the Society for Leukocyte Biology.