Hiroyuki Yoshidome

Secretory leukocyte protease inhibitor in mice regulates local and remote organ inflammatory injury induced by hepatic ischemia/reperfusion.

BACKGROUND & AIMSnThis study identified and characterized the hepatic expression of secretory leukocyte protease inhibitor (SLPI) during hepatic ischemia and reperfusion in mice. In addition, the effects of exogenously administered and endogenous SLPI on liver and lung injury induced by hepatic ischemia and reperfusion were evaluated.nnnMETHODSnC57BL/6 mice underwent 90 minutes of partial hepatic ischemia and 4 hours of reperfusion in the presence or absence of exogenous SLPI or neutralizing antibodies to SLPI.nnnRESULTSnIntravenous infusion of SLPI reduced liver and lung damage and diminished neutrophil accumulation in both organs. These effects were accompanied by reduced serum levels of tumor necrosis factor (TNF)-alpha and the CXC chemokine macrophage inflammatory protein (MIP)-2. SLPI also suppressed activation of the transcription factor NF-kappaB in liver. Hepatic ischemia and reperfusion caused increased expression of SLPI messenger RNA and SLPI protein, which was found in hepatocytes. Treatment of mice with anti-SLPI enhanced serum levels of TNF-alpha and MIP-2 and increased hepatic neutrophil accumulation and amount of liver injury.nnnCONCLUSIONSnThese data indicate that SLPI has protective effects against hepatic ischemia/reperfusion injury and suggest that endogenous SLPI functions to regulate the hepatic inflammatory response.

Interleukin-10 inhibits pulmonary NF-κB activation and lung injury induced by hepatic ischemia-reperfusion

Hepatic ischemia and reperfusion cause local and remote organ injury. This injury culminates from an integrated cascade of proinflammatory cytokines, chemokines, and adhesion molecules, many of which are regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). The anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to have inhibitory effects on NF-kappaB. The objective of the current study was to determine whether IL-10 could suppress pulmonary NF-kappaB activation and ensuing lung injury induced by hepatic ischemia-reperfusion. C57BL/6 mice underwent partial hepatic ischemia with or without intravenous administration of IL-10. Hepatic ischemia-reperfusion resulted in pulmonary NF-kappaB activation, increased mRNA expression of tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2), as well as increased pulmonary neutrophil accumulation and lung edema. Administration of IL-10 suppressed lung NF-kappaB activation, reduced TNF-alpha and MIP-2 mRNA expression, and decreased pulmonary neutrophil recruitment and lung injury. The data suggest that IL-10 protects against hepatic ischemia and reperfusion-induced lung injury by inhibiting lung NF-kappaB activation and the resulting pulmonary production of proinflammatory mediators.

Reduced hepatic ischemia/reperfusion injury by IL-4: potential anti-inflammatory role of STAT6

Objective and Design: The ability of interleukin-4 (IL-4) to modulate activation of the transcription factors, NF-κB and STAT6, reduce proinflammatory cytokine expression and protect against liver injury induced by ischemia/ reperfusion was assessed.¶Materials and Subjects: C57BL/6 mice underwent 90 minutes of partial hepatic ischemia followed by 1 or 8 h of reperfusion with or without intravenous administration of 1 μg (0.5 μg just prior to ischemia, 0.5 μg at reperfusion) recombinant murine IL-4. Liver expression of TNFα mRNA was determined by RT-PCR. Activation of NF-κB and STAT6 in liver nuclear extracts was assessed by mobility shift assay.¶Results: Hepatic ischemia/reperfusion increased hepatic expression of tumor necrosis factor-α (TNFα), induced significant neutrophil accumulation and liver injury. Treatment with IL-4 greatly suppressed liver TNFα mRNA expression, neutrophil accumulation and liver injury. IL-4 had no effect on liver NF-κB activation, but greatly increased the activation of STAT6.¶Conclusions: The data suggest that STAT6 activation by IL-4 may be responsible for the protective effects of this cytokine.

IL-13 Activates STAT6 and Inhibits Liver Injury Induced by Ischemia/Reperfusion

Hepatic ischemia/reperfusion injury is initiated by the activation of Kupffer cells and their subsequent release of proinflammatory mediators, including tumor necrosis factor-alpha (TNFalpha). These mediators stimulate a cascade of events including up-regulation of CXC chemokines and vascular endothelial adhesion molecules, leading to hepatic neutrophil recruitment and tissue injury. Interleukin-13 (IL-13) is a cytokine that has been shown to suppress macrophage production of proinflammatory mediators. The objective of the current study was to determine whether IL-13 could regulate the liver inflammatory injury induced by ischemia and reperfusion. C57BL/6 mice underwent 90 minutes of partial hepatic ischemia followed by reperfusion with or without intravenous administration of recombinant murine IL-13. Hepatic ischemia/reperfusion increased expression of TNFalpha and macrophage inflammatory protein-2 (MIP-2), leading to hepatic neutrophil recruitment, hepatocellular injury, and liver edema. Administration of IL-13 reduced the production of TNFalpha and MIP-2 mRNA and protein. IL-13 suppressed liver neutrophil recruitment by up to 72% and hepatocellular injury and liver edema were each reduced by >60%. Administration of IL-13 had no effect on liver NFkappaB activation, but greatly increased the activation of STAT6. The data suggest that the hepatoprotective effects of IL-13 may be a result of STAT6 activation.

Regulation of liver inflammatory injury by signal transducer and activator of transcription-6.

Liver injury induced by hepatic ischemia/reperfusion is characterized by activation of the transcription factor NF-kappaB, increased production of tumor necrosis factor-alpha (TNFalpha), liver neutrophil accumulation, and hepatocellular damage. Exogenous administration of interleukin-4 (IL-4) or IL-13 was recently shown to regulate this inflammatory injury in association with activation of signal transducer and activator of transcription-6 (STAT6). The objective of the present study was to determine whether STAT6 was required for the regulation of liver inflammation by IL-4 and IL-13. Wild-type and STAT6 knockout mice underwent 90 minutes of hepatic ischemia followed by 8 hours of reperfusion. Hepatic ischemia/reperfusion in wild-type and STAT6 knockout mice significantly increased (P < 0.05) NF-kappaB activation, serum levels of TNFalpha, liver accumulation of neutrophils [measured by myeloperoxidase (MPO) content], and hepatocellular damage [measured by serum alanine aminotransferase (ALT)] compared to sham controls. In wild-type mice, activation of STAT6 was not observed after ischemia/reperfusion. Administration of 1 microg of IL-4 or IL-13 at reperfusion reduced serum TNFalpha, liver neutrophil accumulation, and hepatocellular injury in wild-type mice. Treatment with IL-4 or IL-13 had no effect on liver NF-kappaB activation but significantly increased activation of STAT6. In STAT6 knockout mice, neither IL-4 nor IL-13 had any effect on TNFalpha, MPO, or ALT values, the regulatory effects of these cytokines being completely abolished. The data suggest that activation of STAT6 may regulate liver inflammatory injury.

An embryological perspective on congenital portacaval shunt: a rare anomaly in a patient with hepatocellular carcinoma

We describe a 42-yr-old woman with hepatocellular carcinoma and a congenital portacaval shunt. A computed tomography (CT) scan of the abdomen showed a prominent left hepatic lobe extending into the lower abdomen. A large encapsulated, necrotic-appearing mass was seen within the right hepatic lobe. The patient underwent hepatic resection, during which the continuation of the confluence of the splenic and superior mesenteric veins was found to empty directly into the inferior vena cava, bypassing the hepatic parenchyma. An extended right hepatic lobectomy was performed with a complete excision of the mass (T3 N0 M0, stage III). The patient had an uneventful postoperative course. To our knowledge, this is the first reported case of this anomaly in a living adult having undergone hepatectomy.

Distinct biological activities of recombinant forms of human interleukin-2 in vivo

Abstractu2003The biological activity of all recombinant forms of interleukin-2 (IL-2) is based upon an in vitro lymphocyte proliferation assay and measured in international units (IU). Numerous in vitro investigations have suggested that there may be different cellular effects of recombinant human IL-2 retaining the natural sequence (nIL-2) as compared to another recombinant form containing a serine substitution at amino acid position 125 ([Ser]IL-2). In the present study we investigated whether nIL-2 and [Ser]IL-2 cause similar patterns of systemic toxicities. C57BL/6 mice were treated with identical doses of either nIL-2 or [Ser]IL-2, as measured in IU, for 3 days and had blood and tissues removed for analysis of lymphocyte activation and organ dysfunction. The administration of nIL-2 had considerably greater effects on lymphocyte activation than did [Ser]IL-2, causing much greater up-regulation of the α subunit of the IL-2 receptor and the adhesion molecule lymphocyte function-associated antigen-1. Furthermore, nIL-2 induced more organ edema than did [Ser]IL-2 and caused hepatocellular injury, which was absent in mice treated with [Ser]IL-2. These data demonstrate that equivalent doses, measured in IU, of nIL-2 and [Ser]IL-2 have profoundly different effects on the induction of organ toxicity, suggesting that the IU standard may not be appropriate for the measurement of many in vivo biological activities.