Neuroprotective Effect of Urinary Trypsin Inhibitor against Focal Cerebral Ischemia–Reperfusion Injury in Rats

Yano, Toshiyuki; Anraku, Sakiko; Nakayama, Ryosuke; Ushijima, Kazuo

doi:10.1097/00000542-200302000-00028

Cited by 83 publications

(72 citation statements)

References 41 publications

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“…We did not confirm whether exogenous UTI administration abrogates the changes to clearly show that LPS/D-GalN is acting in concert with UTI, and not independently. In previous studies, UTI experimentally ameliorated several inflammatory models such as ischemia-reperfusion injury, 5 septic shock, 6 hemorrhagic shock, 7 and glomerulonephritis 33 in vivo. In these models, however, the animals were treated with human-derived UTI as a foreign protein.…”

Section: Uti In Liver Injury With Coagulatory Disturbancementioning

confidence: 90%

“…Furthermore, UTI reportedly exhibits anti-inflammatory properties aside from its blocking of the protease pathway in vitro [2][3][4] and in vivo. [5][6][7] In fact, we demonstrated earlier that UTI can protect against systemic inflammatory responses 8 and acute lung injury 9 induced by lipopolysaccharide (LPS) using UTI-null (À/À) mice. However, the role of UTI in the other inflammatory conditions and/or organ injury has not been elucidated using gene-knockout mice.…”

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confidence: 98%

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

Takano

Inoue

Shimada

et al. 2009

Laboratory Investigation

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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.

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Section: Uti In Liver Injury With Coagulatory Disturbancementioning

confidence: 90%

mentioning

confidence: 98%

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

Takano

Inoue

Shimada

et al. 2009

Laboratory Investigation

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“…The rectal (core) temperature was measured and maintained at 37.0±0.5 °C with a heating pad and a heating lamp during the surgery. Percent changes in the regional cerebral blood flow (rCBF) over the middle cerebral arterial (MCA) territory (2 mm in diameter; 6 mm lateral and 2 mm caudal to bregma) were recorded as described [21] using a laser Doppler flowmeter (ML191, AD Instruments, Bella Vista, New South Wales, Australia), and the steady baseline value of rCBF before ischemia was 100%.…”

Section: Measurements Of Physiological Variablesmentioning

confidence: 99%

Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats

Chu

Fang

Zhou

et al. 2007

Acta Pharmacologica Sinica

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Aim: To determine whether the anti-inflammatory effect of minocycline on postischemic brain injury is mediated by the inhibition of 5-lipoxygenase (5-LOX) expression and enzymatic activation in rats. Methods: Focal cerebral ischemia was induced for 30 min with middle cerebral artery occlusion, followed by reperfusion. The ischemic injuries, endogenous IgG exudation, the accumulation of neutrophils and macrophage/microglia, and 5-LOX mRNA expression were determined 72 h after reperfusion. 5-LOX metabolites (leukotriene B 4 and cysteinyl leukotrienes) were measured 3 h after reperfusion. Results: Minocycline (22.5 and 45 mg/kg, ip, for 3 d) attenuated ischemic injuries, IgG exudation, and the accumulation of neutrophils and macrophage/microglia 72 h after reperfusion. It also inhibited 5-LOX expression 72 h after reperfusion and the production of leukotrienes 3 h after reperfusion. Conclusion: Minocycline inhibited postischemic brain inflammation, which might be partly mediated by the inhibition of 5-LOX expression and enzymatic activation.

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“…UTI inhibits the enhanced production of proinflammatory molecules such as prostaglandin H2 synthase-2 (Zaitsu et al, 2000), thromboxane B2 (Aibiki and Cook, 1997), interleukin (IL)-8 (Nakamura et al, 1997), and tumor necrosis factor (TNF)-␣ (Aosasa et al, 2001) induced by LPS in vitro. In addition, UTI ameliorates several inflammatory models such as ischemiareperfusion injury (Yano et al, 2003), septic shock (Tani et al, 1993), hemorrhagic shock (Masuda et al, 2003), and glomerulonephritis (Koizumi et al, 2000) in vivo. In these models, however, the animals have been treated with human-derived UTI as a foreign protein; thus, the direct contribution of UTI to inflammatory diseases, including systemic inflammatory response syndrome, has never been examined in knockout mice.…”

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confidence: 99%

Urinary Trypsin Inhibitor Protects against Systemic Inflammation Induced by Lipopolysaccharide

Inoue¹,

Takano²,

Shimada³

et al. 2004

Mol Pharmacol

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Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (Ϫ/Ϫ) mice and corresponding wild-type (WT) mice. After LPS (1 mg/kg) challenge, UTI (Ϫ/Ϫ) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (Ϫ/Ϫ) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1␤, macrophage inflammatory protein-2, MCP-1, and KC in the liver, were significantly greater in UTI (Ϫ/Ϫ) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.

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Neuroprotective Effect of Urinary Trypsin Inhibitor against Focal Cerebral Ischemia–Reperfusion Injury in Rats

Abstract: Intravenous pretreatment with 300,000 U/kg UTI reduces focal ischemia-reperfusion injury in the rat brain, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia.

Cited by 83 publications

References 41 publications

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

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

Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats

Urinary Trypsin Inhibitor Protects against Systemic Inflammation Induced by Lipopolysaccharide

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