Human
urinary trypsin inhibitor (UTI), a
serine protease inhibitor, has been widely used in Japan as a drug for patients with acute inflammatory disorders such as
septic shock and
pancreatitis.
Lipopolysaccharide (LPS) triggers the
sepsis syndrome by activating monocytes to produce proinflammatory
cytokines, including
tumor necrosis factor alpha (
TNFalpha), which potently stimulate the activation of neutrophils. The inhibitory mechanism of UTI on the systemic inflammatory response induced by the
intraperitoneal injection of LPS in the kidney is unclear. This study was undertaken to examine the inhibitory effects of UTI on renal injury associated with the systemic inflammatory response induced by LPS stimulation, with emphasis on systemic
TNFalpha and the activation of neutrophils in rat kidney. The
systemic inflammatory response syndrome was induced by LPS treatment. Serum and renal
TNFalpha, renal
cytokine-induced neutrophil chemoattractant-1 (CINC-1) and
myeloperoxidase (MPO) levels, as well as renal function after LPS stimulation, were evaluated. UTI (50,000 U/kg) inhibited LPS-induced increases in the serum and renal tissue levels of
TNFalpha, as well as the renal tissue levels of CINC-1 and MPO after LPS stimulation. UTI (50,000 U/kg) also inhibited the production of serum
TNFalpha associated with the
systemic inflammatory response syndrome induced by LPS stimulation, thereby attenuating neutrophil infiltration into renal tissues and subsequent neutrophil-mediated renal injury. These findings may have important implications in understanding the biologic functions of UTI. UTI may prove useful in protecting against
acute renal injury associated with a systemic inflammatory response.