Diseases of the intestine are often associated with extraintestinal manifestations including arthritis, dermatitis, and hepatic lesions, but the pathophysiological mechanisms are unknown. The long-term objective of this proposal is to show that bacterial cell wall polymers, which originate from normal endogenous enteric bacteria, participate in the initiation and/or propagation of extraintestinal manifestations of intestinal disease. Recently, the investigator developed an animal model which associates intestinal injury with hepatobiliary injury. Following surgical creation of jejunal self-filling blind loop in rats, small bowel bacterial overgrowth (SBBO) develops causing intestinal mucosal injury which permits enhanced absorption of bacterial cell wall polymers. Susceptible rat strains with SBBO are associated with hepatomegaly; portal tract fibrosis and inflammation; bile duct proliferation and destruction. Cholangiograms show large extrahepatic features resemble sclerosing cholangitis, a liver disease often associated with chronic inflammatory bowel disease, which has a chronic, progressive course often terminating in hepatic failure. The hypothesis states that during SBBO, bacterial cell wall polymers are absorbed from the intestine, enter the liver by the portal vein and are phagocytosed by Kupffer cells causing activation of these macrophages. This proposal will study the role of bacterial cell wall polymers, lipopolysaccharide (LPS) and peptidoglycan-polysaccharide (PG-PS), in causing Kupffer cell activation, release of inflammatory mediators including tumor necrosis factor alpha, interleukin-1, prostaglandins E2 and D2 and leukotriene B4, and hepatic injury. To verify this hypothesis, the first aim will be to characterize Kupffer cell activation by identifying important inflammatory mediators released from isolated perfused livers in rats with and without SBBO after stimulation with LPS and PG-PS. Activation will be further studied by stimulating purified cultures of Kupffer cells, endothelial cells, and hepatocytes isolated from rats without SBBO.
The second aim will be to define differences in Kupffer cell activation between Lewis and Buffalo rats, genetically different rat strains which differ greatly in their susceptibility to hepatic injury after SBBO.
The third aim will be to show that a liver which has been activated by bacterial cell wall polymers is capable of inducing extraintestinal inflammation, namely, arthritis, either by release of bacterial cell wall polymers or by release of inflammatory mediators. This proposal, the investigators believe, is unique because it uses a model which associates intestinal disease with extraintestinal lesions and focuses on the inflammatory potential of endogenous bacterial cell wall polymers which originate from normal enteric flora. Although the liver will be studied in this project, the results they expect will have wider implications explaining the occurrence of extraintestinal manifestations occurring in conjunction with several intestinal diseases including reactive arthritis following enteric infection, arthritis-dermatitis-hepatitis syndrome occurring in morbidly obese patients after jejuno-ileal bypass surgery, and the extraintestinal manifestations of chronic inflammatory bowel disease. Defining the cause of extraintestinal lesions may also add to understanding what initiates and/or perpetuates the underlying intestinal disease, especially chronic inflammatory bowel disease.
| Lichtman, S N; Wang, J; Clark, R L (1995) A microcholangiographic study of liver disease models in rats. Acad Radiol 2:515-21 |
| Reinstein, L J; Lichtman, S N; Currin, R T et al. (1994) Suppression of lipopolysaccharide-stimulated release of tumor necrosis factor by adenosine: evidence for A2 receptors on rat Kupffer cells. Hepatology 19:1445-52 |
| Lichtman, S N; Wang, J; Schwab, J H et al. (1994) Comparison of peptidoglycan-polysaccharide and lipopolysaccharide stimulation of Kupffer cells to produce tumor necrosis factor and interleukin-1. Hepatology 19:1013-22 |
| Lichtman, S N; Bachmann, S; Munoz, S R et al. (1993) Bacterial cell wall polymers (peptidoglycan-polysaccharide) cause reactivation of arthritis. Infect Immun 61:4645-53 |
