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First published on December 2, 2004; DOI: 10.1124/mol.104.005967

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Received for publication August 17, 2004.
Revised December 1, 2004.
Accepted for publication December 2, 2004.

Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide

Ken-ichiro Inoue 1, Hirohisa Takano 2*, Akinori Shimada 3, Rie Yanagisawa 2, Miho Sakurai 2, Shin Yoshino 4, Hiroyuki Sato 5, Toshikazu Yoshikawa 6

1 Inhalation Toxicology & Pathophysiology Research Team 2 Inhalation Toxicology & Pathophysiology Research Team, National Institute for Environmental Studies 3 Department of Vaterinary Pathology, Faculty of Agriculture, Tottori University 4 Department of Pharmacology, Kobe Pharmaceutical University 5 Research Center, Mochida Pharmaceutical Company, Ltd 6 Inflammation and Immunology, Kyoto Prefectural University of Medicine

* Address correspondence to: E-mail: htakano{at}nies.go.jp

Abstract

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (-/-) mice and corresponding wild type (WT) mice. After LPS (1 mg/kg) challenge, UTI (-/-) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts as compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (-/-) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1{beta}, macrophage inflammatory protein-2, MCP-1, and KC in the livers, were significantly greater in UTI (-/-) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly, through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.


Key words: Interleukins, Leukocytes/Mast cells, Knockout


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K.-i. Inoue, H. Takano, T. Yoshikawa, and J.H.J. Vernooy
Protease-Antiprotease Imbalance in Inflammatory Diseases in the Lung
Chest, August 1, 2005; 128(2): 1069 - 1069.
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