Intestinal pathology frequently accompanies experimental endotoxic shock and is mediated by proinflammatory cytokines. Our hypotheses are that hepatobiliary factors operating from the luminal side of the gut make a major contribution to this damage and that tumor necrosis factor alpha (TNF-␣) is involved in the pathology. We treated rats with lipopolysaccharide (LPS) intravenously and found that external drainage of bile totally protected the gastrointestinal tract, macroscopically and microscopically, 4 h after LPS administration and dramatically improved survival of the animals for 48 h after LPS administration. The concentration of TNF-␣ in bile increased markedly after LPS administration and was over 30 times higher in bile than in serum. Tissue damage and the biliary TNF-␣ response were abrogated when animals were pretreated with gadolinium chloride to eliminate Kupffer cells. TNF-␣ infusion into the duodenal lumen caused intestinal damage similar to that elicited by intravenous LPS. In rats treated with LPS, survival was significantly increased during the first 36 h in animals given an infusion of anti-TNF-␣ antibody into the duodenum. These results demonstrate that in endotoxemia, intestinal damage is mediated by factors derived from the bile. The findings indicate that luminally acting TNF-␣ contributes to the intestinal damage.Septic shock associated with infection by gram-negative bacteria is a common problem in hospitalized patients. Intestinal lesions, including hemorrhage and diarrhea, are a prominent feature of endotoxemia. Several bacterial species can cause such lesions, and lipopolysaccharide (LPS) is an important bacterial product that initiates these effects (19). Antibiotics are not highly effective, and this has driven investigations on the mechanisms of pathogenesis. The major features of LPSmediated shock are now considered to be elicited by a range of endogenous proinflammatory mediators released in response to LPS. Most attention has focused on tumor necrosis factor-␣ (TNF-␣) (35), interleukin 1 (IL-1) (25), and platelet-activating factor (9). How these agents might network to produce the various effects is not known. TNF-␣ has attracted particular attention because neutralizing antibodies to TNF-␣ inhibit the toxic effects of LPS, and administration of TNF-␣ alone elicits the features of endotoxemia (2, 34). Furthermore, in mice lacking functional genes for TNF-␣ or for the 55-kDa TNF receptor, endotoxic shock was attenuated (26, 30).It is implicit in studies on the intestinal effects of proinflammatory cytokines that these agents are derived from the interstitial aspect of the epithelium (32). However, there are indications that biliary molecules (other than bile salts) have functional activity in the gut. For instance, epidermal growth factor has been shown to be present in bile (36) and to be functional from within the lumen (15). Also, hepatobiliary delivery of immunoglobulins has an important role in the protection of the gut (11,18). Recently, we have reported that factors in bile...
In this study, the role of the hepatobiliary system in the early pathogenesis of Salmonella enteritidis infection was investigated in a rat model. Intravenous (i.v.) challenge with lipopolysaccharide (LPS) has previously been shown to enhance the translocation of normal gut flora. We first confirmed that LPS can similarly promote the invasion of S. enteritidis. Oral infection of outbred Australian Albino Wistar rats with 10 6 to 10 7 CFU of S. enteritidis led to widespread tissue invasion after days. If animals were similarly challenged after intravenous administration of S. enteritidis LPS (3 to 900 g/kg of body weight), significant invasion of the livers and mesenteric lymph nodes (MLN) occurred within 24 h, with invasion of the liver increasing in a dose-dependent fashion (P < 0.01). If bile was prevented from reaching the intestine by bile duct ligation or cannulation, bacterial invasion of the liver and MLN was almost totally abrogated (P < 0.001). As i.v. challenge with LPS could induce the delivery of inflammatory mediators into the bile, biliary tumor necrosis factor alpha (TNF-␣) concentrations were measured by bioassay. Biliary concentrations of TNF-␣ rose shortly after LPS challenge, peaked with a mean concentration of 27.0 ng/ml at around 1 h postchallenge, and returned to baseline levels (3.1 ng/ml) after 2.5 h. Although TNF-␣ cannot be directly implicated in the invasion process, we conclude that the invasiveness of the enteric pathogen S. enteritidis is enhanced by the presence of LPS in the blood and that this enhanced invasion is at least in part a consequence of the delivery of inflammatory mediators to the gastrointestinal tract by the hepatobiliary system.
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