One of the early events in physiological shock is the generation of activators for leukocytes, endothelial cells, and other cells in the cardiovascular system. The mechanism by which these activators are produced has remained unresolved. We examine here the hypothesis that pancreatic digestive enzymes in the ischemic intestine may be involved in the generation of activators during intestinal ischemia. The lumen of the small intestine of rats was continuously perfused with saline containing a broadly acting pancreatic enzyme inhibitor (6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfate, 0.37 mM) before and during ischemia of the small intestine by splanchnic artery occlusion. This procedure inhibited activation of circulating leukocytes during occlusion and reperfusion. It also prevented the appearance of activators in portal venous and systemic artery plasma and attenuated initiating symptoms of multiple organ injury in shock. Intestinal tissue produces only low levels of activators in the absence of pancreatic enzymes, whereas in the presence of enzymes, activators are produced in a concentration-and time-dependent fashion. The results indicate that pancreatic digestive enzymes in the ischemic intestine serve as an important source for cell activation and inflammation, as well as multiple organ failure.rat ͉ splanchnic arterial occlusion ͉ shock ͉ multiple organ failure ͉ microcirculation S hock is a life-threatening cardiovascular complication (1). Cellular activation in the circulation is a relatively early event in shock that can be detected by leukocyte or endothelial superoxide production, pseudopod projection, expression of membrane adhesion molecules, and many other cell functions (2, 3). Cell activation fundamentally alters the biomechanics of microvascular blood flow by a shift in rheological, adhesive, and cytotoxic cell properties. The interaction between activated leukocytes and endothelial cells is followed by cell and organ failure (4). The level of activation correlates with survival after the shock (5), but the mechanism for production and the source of activating factors has remained an unresolved problem. Several candidates have been proposed, including endotoxins, lipid-derived products, and cytokines (6-9).Recently, we have demonstrated that the supernatant of the homogenized pancreas, but less so homogenates of other organs, mediates a powerful activation of cardiovascular cells (10). Incubation of homogenates from nonactivating organs, such as the liver or intestine, with low concentration of serine proteases also increases the ability to activate leukocytes. An enzyme inhibitor could block the activation, suggesting that pancreatic enzymes may play a central role in the production of activating factors.Pancreatic enzymes are discharged via the pancreatic duct into the duodenum and intestine as a requirement for digestion. We hypothesize that pancreatic enzymes in the ischemic intestine may be involved in the production of activating factors for circulatory cells in shock. Ischemia ...

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We report herein the case of a 64-year-old man successfully treated by portal venous stent placement for repeated gastrointestinal bleeding associated with jejunal varices. He was admitted to our hospital with melena 8 years after having a pancreatoduodenectomy for carcinoma of the papilla of Vater. From portogram findings showing severe portal vein (PV) stenosis and dilated collaterals through the jejunal vein of the Roux-en-Y loop, jejunal varices resulting from PV stenosis were suspected as the cause of the melena. A metallic stent was placed in the PV following percutaneous transhepatic PV angioplasty. Although the cure of hemorrhagic jejunal varices caused by PV stenosis is difficult in patients who have undergone major abdominal surgery, patency of the stent in this patient has been maintained for 32 months without gastrointestinal hemorrhage. Metallic stent placement is recommended as a useful treatment for PV stenosis that is less invasive than open surgery.

Our recent evidence suggests that pancreatic digestive enzymes in the lumen of the intestine may play a major role in the production of cardiovascular stimulatory factors during splachnic artery occlusion and reperfusion. These stimulators are detected in plasma, but their origin and mechanism of production has remained uncertain. We examine here in the rat the role of pancreatic enzymes with and without administration of a serine protease inhibitor (FOY) into the lumen of the small intestine during splanchnic artery occlusion (90 min) and reperfusion (120 min). In the presence of pancreatic enzyme inhibition in the lumen of the intestine, there is significantly enhanced survival rate, lower levels of inflammatory mediator production, the femoral artery blood pressure is maintained close to control levels, and there are significantly lower levels of cell activators in plasma. These results support the hypothesis that pancreatic enzymes may escape across the brush border barrier during intestinal ischemia and thereby initiate the production of a powerful set of cytotoxic mediators. Blockade of pancreatic enzymes in the lumen of the intestine may be a tool to interfere with inflammation and early indicators of multiorgan failure.

Leukocytes respond to physiological fluid shear stress ( approximately 1.5 dyn/cm(2)) by cytoplasmic reorganization. The cytoplasm is also influenced, however, by glucocorticoids. In this study, we explore how glucocorticoids may affect the leukocyte fluid shear response. Normal leukocytes, exposed to fluid shear in vitro during active migration, retract pseudopods accompanied by modestly decreasing intracellular calcium ions. In contrast, dexamethasone (DX)-treated leukocytes project pseudopods after shear exposure with a significant rise in intracellular calcium ions, an effect that can be blocked by voltage-dependent calcium channel blockers. Although a cyclic adenine monophosphate analog blocks calcium influx and pseudopod projection by DX, inhibition of A-kinase induces reversal of the shear response, as seen with DX treatment. DX also reverses the leukocyte shear response in vivo in the rat circulation. Leukocytes that adhere to the endothelium in postcapillary venules of control rats return into the circulation only after pseudopod retraction, and in DX-treated rats, adherent leukocytes return into the circulation still with projecting pseudopods. The fraction of circulating leukocytes with pseudopods in DX-treated rats is higher than in controls. Thus, the reversal of leukocyte shear response by glucocorticoids may contribute to an enhanced incidence of circulating leukocytes with pseudopods, a process that affects the kinetics of these cells in the microcirculation.

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Of these 51 patients, 21 (41.1%) had systemic disorders, including 4 (7.8%) with malignant diseases. Six patients (11.8%) had deep vein thrombosis (DVT) and five (9.8%) had pulmonary embolism (PE). All of the patients with DVT and/or PE had a thrombus in either the greater saphenous vein or the lesser saphenous vein; however, none of the patients with STP and a thrombus in the distal saphenous branch had either DVT or PE. The levels of coagulofibrinolytic markers such as fibrin degradation product-D dimer, plasmin alpha plasmin inhibitor complex, and thrombin antithrombin III complex were elevated in patients with STP or DVT, compared with those with varicose veins only. The level of C-reactive protein (CRP) was also elevated in the patients with STP or DVT. These findings indicate that STP is not necessarily a localized disease, but may be a symptom of systemic disease. In addition to duplex scanning, the measurement of coagulofibrinolytic markers as well as CRP may be useful for detecting STP and/ or DVT prior to the treatment of varicose veins.