1. ¹Division of Environmental Health Sciences, National Institute for Environmental Studies, Tsukuba, Japan
2. ²Department of Gastroenterology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
3. ³Department of Veterinary Pathology, Faculty of Agriculture, Tottori University, Tottori, Japan
4. ⁴Research Center, Mochida Pharmaceutical Company Ltd., Shizuoka, Japan

Correspondence: Dr K-i Inoue, MD, PhD, Division of Environmental Health Sciences, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan. E-mail: inoue.kenichirou@nies.go.jp

⁵These authors contributed equally to this work.

Received 29 August 2008; Revised 10 November 2008; Accepted 21 November 2008; Published online 27 April 2009.

Abstract

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used for patients with inflammatory disorders including disseminated intravascular coagulation, shock, and pancreatitis in Japan. Our recent studies using UTI-null (-/-) mice have shown that UTI protects against systemic inflammatory responses and acute lung injury. However, the role of UTI in liver injury has not been elucidated. This study determined the contribution of UTI to liver injury and coagulatory disturbance induced by lipopolysaccharide and D-galactosamine (LPS/D-GalN) using UTI (-/-) and wild-type (WT) mice. LPS/D-GalN treatment caused severe liver injury characterized by neutrophilic inflammation, hemorrhagic change, necrosis, and apoptosis, which was more prominent in UTI (-/-) than in WT mice. In both genotypes of mice, LPS/D-GalN challenge caused elevations of aspartate amino-transferase and alanine amino-transferase, prolongation of the prothrombin and activated partial thromboplastin time, and decreases in fibrinogen and platelet counts, as compared with vehicle challenge. These changes, however, were significantly greater in UTI (-/-) than in WT mice. Circulatory levels of tumor necrosis factor (TNF)- (P<0.05) and interferon (IFN)- were also greater in UTI (-/-) than in WT mice after LPS/D-GalN challenge. These results suggest that UTI protects against severe liver injury and subsequent coagulatory disturbance induced by LPS/D-GalN, which was mediated, at least partly, through the suppression of TNF- production along with its antiprotease activity.