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We demonstrated the dynamic aspects of granulocyte activation in rat severe acute pancreatitis which was induced by cerulein and aggravated following lipopolysaccharide (LPS) injection. Pancreatitis induced by cerulein increased intracellular elastase activity of granulocytes in the blood. However, significant systemic cytokinemia was not provoked under such conditions. After induction of severe pancreatitis by LPS, intracellular elastase activity of circulating granulocytes decreased markedly and immediately. The timing of this decrease was concomitant with induction of systemic hypercytokinemia and granulocytes migration into the lung. Overall results provide the following implications: (1) circulating granulocytes are activated by the induction of mild pancreatitis; (2) the activation of granulocytes is mediated by other factors than systemic cytokinemia, such as locally produced cytokine; (3) those priming granulocytes immediately and significantly migrate from the circulation into extravascular space by the induction of endotoxemia; (4) the migration of granulocytes, in turn, may be mediated by systemic cytokinemia. [Copyright &y& Elsevier]

Background: Interleukin-18 (IL-18) production is the main mechanism of hepatic injury in several animal models via further gamma interferon (IFN-γ) release. IL-18 also functions as an inducer of proinflammatory cytokines as TNF-α, which are also shown to induce organ injuries in many severe inflammatory conditions. To clarify the mechanism of hepatic injury developed in acute pancreatitis, plasma concentrations of IL-18 and its related cytokines were analyzed. Patients and methods: Plasma levels of IL-18, IL-12, IFN-γ, TNF-α, soluble TNF receptor (sTNF-R) and soluble Fas ligand (sFas-L) were measured by ELISA. Results: Plasma concentrations of IL-18 in patients with hepatic injury increased during the first few days apparently and remained so to some extent thereafter. However, IFN-γ showed no apparent increase in plasma concentrations. Those of TNF-α and sTNF-R remained increased in the hepatic injury group. Conclusion: These results suggest that IL-18 may act as a pro-inflammatory cytokine, which provokes the cytokine storm and eventually hepatic injury. [Copyright &y& Elsevier]

Tumor necrosis factor-α (TNF-α) is known to play a central part in the pathogenesis of acute pancreatitis. TNF-α and its two receptors (p55 and p75 TNF receptors) have shown to be expressed at various sites in the body. TNF-α is initially expressed as a 26-kDa membrane-associated perform, which is proteolytically processed to a 17-kDa secreted mature form. Recently, TNF-α converting enzyme (TACE) has been identified as a membrane-bound TNF-α activating enzyme. Hence, it is expected that the newly devised TACE inhibitor, Y39083, will be a useful candidate for the treatment of inflammatory disorders provoked by TNF-α, including acute pancreatitis. Y39083 suppressed TNF-α production in vitro and in vivo significantly. However, the production of other cytokines, such as IL-1β, IFNγ and IL-6, in vivo were not. The blockade of secreted TNF-α production by Y39083 could not improve the organ injury.These results suggest that the blockade of activities of secreted TNF-α production is not sufficient to suppress systemic cytokine reaction and distant organ injury. [Copyright &y& Elsevier]

Hepatectomy is one of the most effective means of managing hepatic neoplasms. However, some patients are still susceptible to hepatic failure after the procedure. In patients with hepatic failure after surgery, plasma concentrations of IL-18 increased gradually after 1 week. Interestingly, the increase in the plasma IL-18 correlated with that in serum bilirubin. Because IL-18 is metabolized in the liver and excreted in bile, the increase in plasma IL-18 in patients with hepatic failure reflects the decreased metabolism in the liver. [Copyright &y& Elsevier]