**Part 1**

**Urinary Trypsin Inhibitor** 

**1** 

 *Japan* 

**Urinary Trypsin Inhibitor, an** 

**for Inflammatory Disorders** 

Ken-ichiro Inoue1 and Hirohisa Takano2

*School of Pharmacy, Kitasato University, Tokyo 2Kyoto University Graduate School of Enginnering, Department of Environmental Engineering, Kyoto* 

**Alternative Therapeutic Option** 

*1Department of Public Health and Molecular Toxicology,* 

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely (and sometimes experiencely) used as a supportive drug for patients with inflammatory disorders such as pancreatitis, shock, and disseminated intravascular coagulation (DIC). Also, previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties at sites of inflammation. However, the therapeutic effects of UTI in vivo remain unclarified, since commercial UTI have been developed to act against human, with the activity and selectivity toward the relevant animal UTI being less characterized. In this review, we introduce the roles of UTI mainly in experimental endotoxin (lipopolysaccharide: LPS)-related inflammatory disorders using UTI-deficient (-/-) and corresponding wild-type (WT) mice. Our experiments employing genetic approach suggest that endogenous UTI can serve protection against the systemic inflammatory response and subsequent organ injury induced by LPS, at least partly, through the inhibition of proinflammatory cytokine and chemokine expression, which provide important in vivo evidence and understanding about a protective role of UTI in inflammatory conditions. Using genetically targeted mice selectively lacking UTI, UTI has been evidenced to provide an attractive "rescue" therapeutic option for endotoxin-related inflammatory disorders such

UTI, also referred to as ulinastatin, HI-30, ASPI, or bikunin, is an acidic glycoprotein with a molecular weight of 30 kDa by SDS-polyacrylamide gel electrophoresis. UTI is a multivalent Kunitz-type serine protease inhibitor found in human urine and blood [1]. It is composed of 143 amino acid residues and its sequence includes two Kunitz-type domains (Fig. 1). UTI is produced by hepatocytes as a precursor in which UTI is linked to α1-microgloblin [2, 3]. In hepatocytes, different types of UTI-containing proteins are formed by the assembly of UTI with one or two of the three evolutionarily related heavy chains (HC) 1, HC 2, and HC 3,

**1. Introduction** 

as DIC, acute lung injury, and acute liver injury.

**2. General characteristics of UTI and clinical utility** 
