Yu Kimura

Non-Occlusive Mesenteric Ischemia and Its Associated Intestinal Gangrene in Acute Pancreatitis

Background/Aims: Non-occlusive mesenteric ischemia (NOMI) has been defined as diffuse intestinal ischemia that often results in intestinal gangrene in the presence of a patent arterial trunk. The prevalence and nature of NOMI in acute pancreatitis was investigated. Methods: A total of 120 consecutive patients with acute pancreatitis managed in the Department of Surgery II, Kumamoto University Medical School, from April 1992 through December 2002, were investigated retrospectively. Among them, 60 patients had the severe form. Results: The overall mortality of acute pancreatitis patients was 8.3% (10/120). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. The mortality of patients with severe acute pancreatitis who did not develop NOMI was 10% (5/52). All patients with NOMI-associated intestinal gangrene quickly progressed and subsequently died of multiple organ failure. Plasma creatine phosphokinase (CPK) and lactate levels were elevated significantly in patients with NOMI. Conclusion: Acute pancreatitis associated with NOMI was extremely severe. If the plasma CPK and lactate levels are extremely high, NOMI should be suspected.

Further Evidence for Endothelin as an Important Mediator of Pancreatic and Intestinal Ischemia in Severe Acute Pancreatitis

Introduction Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Mesenteric vasoconstriction is one of the most probable types of pathogenesis of these complications. Aim To investigate the involvement of endothelin-1 (ET-1), a potent vasoconstrictor. Methodology and Results Plasma ET-1 concentrations were extremely high in patients with pancreatic and/or diffuse intestinal necrosis. ET-1 mRNA was demonstrated in the rat pancreas, and the production of ET-1 protein by human umbilical vein endothelial cells was enhanced by tumor necrosis factor-&agr;, thrombin, and protease-activated receptor-2–activating peptide. Administration of ET-1 in vivo induced mesenteric arterial spasm and decreased pancreatic and intestinal blood flow. Conclusion These results suggest the following: ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; in the inflammatory setting, cytokines, activated thrombin and trypsin, may stimulate ET-1 production in a paracrine fashion; produced ET-1 may exaggerate the splanchnic microcirculation; and progressive ischemia may lead to necrosis of the pancreas and intestine.

Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis.

Objectives: The pathophysiology of acute pancreatitis is strongly associated with autoactivation of trypsin. The biologic activity of trypsin on cells is attributed to the activation of protease-activated receptor-2 (PAR-2). We hypothesize that trypsin may activate acinar cells or inflammatory cells through PAR-2 signals in acute pancreatitis. Methods: We immunochemically analyzed the expression of PAR-2 in the rat acinar cell line, ARIP, and the rat pancreas, using anti-rat PAR-2 cleavage site (PCS) and anti-rat PAR-2 N-terminal fragment (PNF) antibodies. Plasma levels of PNF were determined. Furthermore, the effects of the anti-rat PCS antibody and nafamostat mesylate, a potent trypsin inhibitor, on PAR-2 activation during acute pancreatitis were also analyzed. Results: ARIP cells expressed PAR-2, which was activated by exogenous trypsin activity. We also showed that PAR-2 is strongly expressed in pancreatic acinar and duct cells and that it is activated in rat cerulein-induced acute pancreatitis. The anti-rat PCS antibody and nafamostat mesylate reduced interleukin-6 and interferon γ production and alleviated distant organ injury. Conclusions: These results suggest that trypsin and its specific receptor, PAR-2, play an important role in cytokine production and the resultant development of distant organ injury during rat acute pancreatitis.

Visualization of the heterogeneous internal structure of so-called "pancreatic necrosis" by magnetic resonance imaging in acute necrotizing pancreatitis.

Introduction Contrast-enhanced computed tomography (CT) is the gold standard for assessing the severity of acute pancreatitis, especially for evaluating the presence of pancreatic necrosis (poorly perfused area). However, the contrast medium used for CT is potentially toxic to the pancreas and kidney. Therefore, medical institutions without facilities for hemodialysis hesitate to acquire contrast-enhanced CT images. Diagnostic values of magnetic resonance imaging (MRI) in pancreatic diseases have been shown. Aim To evaluate the usefulness of MRI in the assessment of the severity of acute pancreatitis. Results All necrotic regions in the pancreas were visualized by gadolinium-enhanced MRI. Furthermore, MRI can discriminate the poorly perfused pancreatic area, namely so-called “pancreatic necrosis” judged on CT, into three parts: 1) necrotic area of the pancreatic parenchyma, 2) perinecrotic fluid collection, and 3) hemorrhagic foci. Inflammatory changes that were required for severity grading were also evaluated sufficiently by MRI. Conclusion These results suggest that MRI is useful for the assessment of severity of acute pancreatitis.

Dynamic Aspects of Granulocyte Activation in Rat Severe Acute Pancreatitis

We demonstrated 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. This decrease occurred simultaneous to induction of systemic hypercytokinemia and granulocyte migration into the lung. Overall results imply that: (1) circulating granulocytes are activated by induction of mild pancreatitis; (2) activation of granulocytes is mediated by factors other than systemic cytokinemia, such as locally produced cytokines; (3) those priming granulocytes immediately and significantly migrate from the circulation into the extravascular space by induction of endotoxemia; and (4) migration of granulocytes, in turn, may be mediated by systemic cytokinemia.

PDGFRβ and HIF-1α inhibition with imatinib and radioimmunotherapy of experimental prostate cancer

The clinical application of radioimmunotherapy (RIT) as a single modality in the treatment of prostate cancer is held back because of poor tumor responses to RIT and unacceptable normal tissue toxicities. The purpose of reported here studies was to develop a multimodality approach to RIT of prostate cancer that includes imatinib, a potent PDGFR-β inhibitor, and in the course of these studies to define the mechanism of imatinib effects on RIT. Hypothesized interactions between these two modalities depend on the reduction of tumor interstitial fluid pressure with the subsequent increase of 131ICC49 uptake into the tumor, and the inhibition of HIF-1α resulting in the improved tumor radiosensitivity. Levels of HIF-1α, IGF-1, PDGF-BB, phospho-PDGFR-β, and VEGF in response to imatinib were examined in PC-3 human prostate adenocarcinoma cells in vitro and in xenografts. RIT was based on 131ICC49 and it was augmented with imatinib. Although PDGFR-β appears to be functional in PC-3 tumors, the effect of imatinib on the tumor interstitial fluid pressure was insignificant. PC-3 cells and PC-3 xenografts express constitutive HIF-1α, which was significantly inhibited by imatinib. Reduced levels of HIF-1α were accompanied by the notable suppression of IGF-1. Simultaneously the increase in tumor levels of mouse and human PDGF-BB was observed. Improved PC-3 responses to RIT+imatinib treatment were significant and lasted approximately two weeks. Tumor doubling times in mice treated with 131ICC49+imatinib were 21.6±0.7 days compared to 17.2±0.5 days in 131ICC49+PBS-treated control mice. Imatinib alone had no effect on the tumor growth. In conclusion, imatinib inhibits HIF-1α expression in PC-3 tumors and improves RIT, but it has no effect on VEGF indicating absence of anti-angiogenic effects. There is a significant time- and dose-dependent reduction in the expression of IGF-1 suggesting an alternative pathway of imatinib-regulated HIF-1α expression leading to the improved PC-3 responses to RIT.

Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2'-deoxyuridine, 5-iodo-3'-fluoro-2',3'-dideoxyuridine, and 3'-fluorothymidine for molecular radiotherapy of cancer: synthesis and biological evaluation.

Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC(50) values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.

The effect of TNF-α converting enzyme inhibitors on cytokine response in acute pancreatitis

Abstract 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.

Dynamic aspects of granulocyte activation in acute pancreatitis

Abstract 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.

Endothelin is involved in pancreatic and intestinal ischemia during severe acute pancreatitis

Abstract Introduction: Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Vasoconstriction of the abdominal artery is one of the most probable pathogeneses of these complications. Hence, we investigated the involvement of endothelin-1 (ET-1), a potent vasoconstrictor, in the pathogenesis of acute pancreatitis. Materials and methods: (1) Plasma samples from patients with acute pancreatitis were analyzed. (2) Production of ET-1 mRNA in rat pancreas and ET-1 protein by human umbilical vein endothelial cells (HUVECs) in vitro was analyzed. (3) After the administration of ET-1, pancreatic and intestinal blood flow was analyzed in rat. Results: (1) Plasma ET-1 concentrations were extremely high in patients with pancreatic and diffuse intestinal necrosis. (2) ET-1 mRNA was demonstrated in rat pancreas after the induction of pancreatitis, and the production of ET-1 protein by HUVECs was enhanced by TNF-α, thrombin, and trypsin receptor-activating peptide. (3) Administration of ET-1 induced mesenteric arterial spasm and resultant decreased splanchnic blood flow. Conclusions: These results suggest that (1) ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; (2) in the inflammatory setting, cytokines, thrombin, and trypsin may stimulate ET-1 production through paracrine fashion; (3) produced ET-1 may exaggerate the splanchnic microcirculation; and (4) progressive ischemia may lead to necrosis of the pancreas and intestine.