Urinary trypsin inhibitor protects against liver injury and coagulation pathway dysregulation induced by lipopolysaccharide/D-galactosamine in mice

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 (À/À) 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 (À/À) 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 (À/À) 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 (À/À) than in WT mice. Circulatory levels of tumor necrosis factor (TNF)-a (Po0.05) and interferon (IFN)-g were also greater in UTI (À/À) 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-a production along with its antiprotease activity.

The therapeutic efficacy of Ulinastatin for rats with smoking inhalation injury

“…Numerous investigators have described that UTI had the ability to inhibit the enhanced production of pro-inflammatory cytokines [33][34][35][36][37][38]. Therefore, we investigated the role of UTI in the lung expression of proinflammatory cytokines in the rat model of smoke inhalation.…”

Urinary Trypsin Inhibitor, an Alternative Therapeutic Option for Inflammatory Disorders

“…Circulatory levels of TNF-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 anti-protease activity [71]. Furthermore, after LPS/D-GalN challenge, protein levels of IL-1 , TNF-, IFN-, MIP-1 , and MCP-1 in the lung homogenates were elevated in both genotypes, but to a greater extent in UTI (-/-) than in WT mice.…”

“…Further, the plasma UTI level is reportedly correlated with the degree of liver damage in patients with chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma [70]. In a liver inflammation and coagulatory disturbance model induced by LPS (3μg/kg) and D-galactosamine (800 mg/kg: LPS/D-GalN), 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 [71]. In both genotypes of mice, interestingly, 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.…”

Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway

“…Mice were injected intraperitoneally with LPS (60 mg/kg) and D-GalN (800 mg/kg) to establish the mice liver injury model [35]. ADH (2.5, 5, and 10 mg/kg) were administered intraperitoneally 1 h after LPS/GalN treatment.…”