Impact of antithrombin III on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation: an in vivo analysis.

AIM: To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin III (ATIII) on leukocyte kinetics and liver damage. METHODS: Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis, animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATIII. RESULTS: Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91+/-0.28 sticker/microm vs 0.5+/-0.5 sticker/microm in controls, P<0.05). The effect enhanced in animals with cirrhosis and IBD (5.4+/-1.65 sticker/microm), but reversed after ATIII application (3.97+/-1.04 sticker/microm, P<0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3+/-0.31 nL/min vs 5.4+/-0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49+/-0.6 nL/min). This effect was normalized in the treatment group (5.13+/-0.4 nL/min, P<0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATIII application (P<0.05). CONCLUSION: Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATIII.

Enhancement of leukocyte adhesion after percutaneous irradiation in rats with hepatocellular carcinoma.

AIM: To evaluate the effects of percutaneous radiation on leukocyte-endothelium interaction (LEI) in experimental hepatocellular carcinoma (HCC). METHODS: Twelve ACI rats underwent HCC-inoculation, six of which on day 12 received low-dose external radiation and six did not. After 12 h intravital microscopy was performed. RESULTS: LEI was significantly reduced in tumor tissue. However, irradiation of liver sinusoids and tumor tissue with 6 Gy led to a significant activation of leukocyte adhesion in the tumor with a marked increase of the proinflammatory cytokine TNF-alpha. CONCLUSION: The findings indicate that the immunological tumor-endothelial barrier can be overcome by external irradiation.

Disturbance of hepatic and intestinal microcirculation in experimental liver cirrhosis.

AIM: To analyze hepatic, mesenteric and mucosal microcirculation and leukocyte-endothelium interaction (LEI) in a rat model with liver cirrhosis. METHODS: Hepatic cirrhosis was induced in Wistar rats by gavage with carbon tetrachloride, and intravital videomicroscopy was performed in liver, mesentery and small intestine mucosa. Special emphasis is given on microcirculatory and morphometric changes during cirrhotic portal hypertension. RESULTS: LEI was influenced significantly in the cirrhotic liver but not in the gut. Blood flow measurement showed significant differences among liver, main mesenteric vessels and the mucosa. The results of our study indicate that liver cirrhosis leads to alterations in hepatic and mesenteric blood flow but not in mucosal blood flow. CONCLUSION: The enhanced inflammatory response in hepatic microvessels may be caused by a decrease of antithrombin III levels and could be responsible for disturbances of organ pathology.

Expansion of endothelial surface by an increase of vessel diameter during tumor angiogenesis in experimental and hepatocellular and pancreatic cancer.

AIM: A low vessel density is a common feature of malignant tumors. We suggested that the expansion of vessel diameter might reconstitute the oxygen and nutritient's supply in this situation. The aim of the present study was to compare the number and diameter of blood vessels in pancreatic and liver carcinoma with normal tissue. METHODS: Tumor induction of pancreatic (DSL6A) or hepatocellular (Morris-hepatoma) carcinoma was performed in male Lewis (pancreatic cancer) and ACI (hepatoma) rats by an orthotopic inoculation of solid tumor fragments (pancreatic cancer) or tumor cells (hepatoma). Six weeks (pancreatic cancer) or 12 d (hepatoma) after tumor implantation, the tumor microvasculature as well as normal pancreatic or liver blood vessels were investigated by intravital microscopy. The number of perfused blood vessels in tumor and healthy tissue was assessed by computer-assisted image analysis. RESULTS: The vessel density in healthy pancreas (565+/-89 n/mm(2)) was significantly higher compared to pancreatic cancer (116+/-36 n/mm(2)) (P<0.001). Healthy liver showed also a significantly higher vessel density (689+/-36 n/mm(2)) compared to liver carcinoma (286+/-32 n/mm(2)) (P<0.01). The comparison of diameter frequency showed a significant increase of vessel diameter in both malignant tumors compared to normal tissue (P<0.05). CONCLUSION: The expansion of endothelial cells during tumor angiogenesis is accompanied to a large extent by an increase of vessel diameter rather than by formation of new blood vessels. This may be a possible adaptive mechanism by which experimental pancreatic and hepatocellular cancers expand their endothelial diffusion surface of endothelium to compensate for inadequate neoangiogenesis.

Immune escape mechanism: defective resting and stimulated leukocyte-endothelium interaction in hepatocellular carcinoma of the rat.

Hepatocellular carcinoma represents an increasing therapeutic challenge due to its high incidence and early metastasis. Numerous studies have demonstrated the influence of the vascular system on tumor growth and development. In addition, the role of leukocyte-endothelium interaction in tumor vessels is of particular significance with regard to immunological tumor therapy. In this study we used an experimental in vivo animal model that allows a quantitative analysis on vessel morphology, microcirculation, and leukocyte-endothelium interaction. The vessel architecture in tumor tissue was found to be extremely heterogeneous, with a consecutively variable blood flow velocity. Following superfusion with chemotactic factors (fMLP, LB4), the leukocyte-endothelium interaction in tumor tissue with respect to leukocyte sticking was significantly reduced in comparison to healthy liver tissue. In conclusion, one of the main mechanisms for the reduced leukocyte-endothelium interaction in tumor tissue seems to be a decreased expression of adhesion molecules such as ICAM-1, indicating an effective immune escape mechanism for this tumor.

Reduction in mortality with delayed surgical therapy of severe pancreatitis.

The indications for surgery in acute pancreatitis have changed significantly in the past two decades. Medical charts of patients with acute pancreatitis treated at our institution were analyzed to assess the effects of changes in surgical treatment on patient outcomes. A total of 136 patients with radiologically defined severe pancreatitis were primarily treated or referred to our institution between 1980 and 1997. Severity of the disease (Ranson score), indications for surgical intervention, timing of surgery, and mortality rates were compared during three study periods: 1980 to 1985 (period I), 1986 to 1990 (period II), and 1991 to 1997 (period III). In period I patients underwent exploratory laparotomy if their clinical status did not improve markedly within 72 hours of admission to the hospital, whereas during period II surgery was reserved for patients who had secondary organ failure together with pancreatic necrosis seen on CT scan. During period III the aim was to operate as late as possible in the presence of pancreatic necrosis or when infected necrosis was suspected. The policy of limiting the indications for surgery resulted in a decrease in surgically treated patients from 68% to 33% (P < 0.001). Likewise, surgical intervention was performed later. In period I, 73% of operations were performed within 72 hours of admission, compared to 32% in period III (P = 0.008). The mortality rate for patients who underwent early surgery (within 72 hours) was higher than for those who underwent late surgical exploration of the abdomen (P = 0.02). Overall, the mortality rate for patients with severe pancreatitis was reduced from 39% to 12% (P = 0.003). Mortality among patients treated nonoperatively did not change significantly. The present study supports the policy of delayed surgery in severe acute pancreatitis. Early surgical intervention often results in unnecessary procedures with an increase in the number of deaths. Whenever possible, prolonged observation allows selection of patients who are likely to benefit from delayed surgery or nonoperative treatment.