English

Abstract

Introduction Urinary trypsin inhibitor, a serine protease inhibitor, has been widely used, particularly in Japan, as a drug for patients with acute inflammatory disorders such as pancreatitis, shock and disseminated intravascular coagulation. Previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties beyond their inhibition of neutrophil elastase at sites of inflammation. However, the therapeutic effects of urinary trypsin inhibitor in vivo remain unclarified. In this review, we introduce the roles of urinary trypsin inhibitor in experimental systemic inflammatory responses induced by both the intraperitoneal and intratracheal administration of lipopolysaccharide using urinary trypsin inhibitor-deficient (–/–) and corresponding wild-type mice. Conclusion Urinary trypsin inhibitor may provide an attractive ‘rescue’ therapeutic option for systemic inflammatory response syndromes such as disseminated intravascular coagulation, acute lung injury and acute liver injury. Introduction Urinary trypsin inhibitor (UTI) is a multivalent Kunitz-type serine protease inhibitor synthesized and released in human urine and blood1. Various serine proteases such as trypsin, chymotrypsin, neutrophil elastase and plasmin are reportedly inhibited by UTI2. Based on the multivalent nature of protease inhibition, UTI appears to prevent organ injury by inhibiting the activity of these proteases3,4. Although the therapeutic effects of UTI on circulatory shock have been recognized, especially in Japan, current understanding regarding the target mechanisms/pathways remains limited. The aim of this review was to discuss UTI as a therapeutic option for inflammatory disorders. Discussion The authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964), and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies. General characteristics of UTI UTI is a multivalent Kunitz-type serine protease inhibitor found in human urine and blood. 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. It is composed of 143-amino acid residues and its sequence includes two Kunitz-type domains. UTI is produced by hepatocytes as a precursor in which UTI is linked to α1-microgloblin. 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, through a chondroitin sulphate chain7; these proteins comprise inter-α-inhibitor (IαI) family members, including IαI, pre-α-inhibitor (pαI), inter-α-like inhibitor (IαLI) and free UTI. IαI, pαI and IαLI are composed of HC1 + HC2 + UTI, HC3 + UTI and HC2 + UTI, respectively8,9. During inflammation, UTI is cleaved from IαI family proteins through proteolytic cleavage by neutrophil elastase in the peripheral circulation or at the inflammatory site10–13. Therefore, plasma UTI has been considered to be one of the acute-phase reactions, and indeed, the plasma UTI level and its gene expression alter in severe inflammatory conditions11. Further, UTI is rapidly released into urine when infection occurs and is an excellent inflammatory marker, constituting most of the urinary anti-trypsin activity14. Various serine proteases such as trypsin; thrombin; chymotrypsin; kallikrein; plasmin; elastase; cathepsin and factors IXa, Xa, XIa and XlIa are inhibited by UTI2,15. Furthermore, UTI can reportedly suppress urokinase-type plasminogen activator (uPA) expression through the inhibition of protein kinase C16,17. Clinical utility of UTI Although its precise physiological role in normal subjects has not been fully clarified, clinically, UTI is widely used, especially in Japan, to treat acute pancreatitis including post-endoscopic retrograde cholangiopancreatography pancreatitis and septic shock, in which several proteases are considered to play a pathophysiological role18,19. Also, in gynaecological * Corresponding author Email: kinoue@iuhw.ac.jp Center for Medical Science, International University of Health and Welfare, 2600-1, Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan