Enterogenous Endotoxemia In Experimental Hepatopulmonary Syndrome Pathogenesis

The liver disease may develop severe influence on the other organs in the human body. Clinically, chronic liver diseases exert a great influence on the function of lungs that manifests mainly hepatopulmonary syndrome (HPS). The clinical signs and symptoms most closely linked to HPS in liver patients include dilatation of the pulmonary microcirculation and hypoxemia. The latter may be ascribed to diffuse dilatation of pulmonary arterioles and alveolar capillaries leading to a diminished oxygenated arterial blood. Therefore, the hepatopulmonary syndrome substantially is a triplet that consists of liver disease, dilatation of the pulmonary microcirculation, and hypoxemia. The increasing attention has been paid to the relationship between the intestinal endotoxemia (IETM) and the liver diseases. The clinical observations have shown that there is an increased content of endotoxin at a different level in patients with various acute and chronic hepatitis, cirrhosis and fulminant hepatitis. And a close relation is present between the extent of increased plasma endotoxin and the gravity of hepatic diseases. These clinical findings have been demonstrated in many animal experiments as well. The investigations show that endotoxin is a potent activator of kuppfer cells. Endotoxin can stimulate kupffer cells to produce and release a variety of cytokines, such as TNF-α, lipid inflammatory mediators, nitric oxide, endothelin, and free radicals to inevitably lead to impairment of liver. These bioactive mediators play an important role in hepatitis, hepatic fibrosis, cirrhosis, decompensation of cirrhosis or failure. This may not only aggravate original hepatic injury, but induce various disorders of metabolic and hemodynamics. What's worse, it may result in the development of more complications and thereby jeopardize the prognosis of the patients with hepatic diseases gravely. We have successfully induced hepatic encephalopathy and hepatorenal syndrome in rats with cirrhosis by means of employing a small dosage of LPS peritoneally, and have demonstrated intestinal endotoxemia accompanied by rats with cirrhosis automatically is a key factor in their occurrence. Meanwhile, a variety of cytokines associated with intestinal endotoxemia also have a major effect on them. Therefore, on the basis of previous researches, we continuously employed the rat model of cirrhosis in our laboratory and explore the effect of IETM and its accompanying cytokines (TNF-α, lipid inflammatory mediators, NO, ET-1 and free radicals, etc.) on the pathogenesis of HPS. We further probed into the signal mechanism that lipopolysaccharide (LPS) mediates the alterations of KCs phagocytosis and secretion in vitro. As regard the research on a relationship between the pathogenesis of HPS and IETM, it is scarcely reported so far. The scientific research was carried out in three parts. The first part: the occurrence of HPS in the course of IETM formation in rats with cirrhosis. The second part: the effect of IETM on pathogenesis of HPS in rats with cirrhosis. The third part: the effect of LPS, glycine and other agents on the function of cultured KCs in vitro. Part One The occurrence of HPS in the course of IETM formation in rats with cirrhosis There are three experiments in this part. Experiment 1 The changes of pulmonary respiratory function and morphology The rat model of cirrhosis developed by our laboratory was reconstructed. The duration of rat cirrhosis in this model undergo several stages. The first stage is mainly degeneration and necrosis of hepatic cells within 1-2 weeks. The second stage is hepatic fibrosis within 3-4 weeks. The third stage is the formation of early cirrhosis within 5-6 weeks. The fourth stage is the occurrence of advanced cirrhosis within 7-10 weeks. Our experiment is aiming at the exploration of pulmonary respiratory function and morphology at the end of eighth week. The experimental animals were randomly divided into sevengroups: normal control, normal animals + a small dosage of LPS, cirrhosis, cirrhosis + a small dosag...