Bile Mediates Intestinal Pathology in Endotoxemia in Rats

Abstract

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...

Apical sodium-dependent bile acid transporter upregulation is associated with necrotizing enterocolitis

“…It is known that accumulation of BA in the intestine can result in damage to the intestinal epithelium (28). Our previously published data strongly suggest that accumulation of BA in the ileum during experimental NEC is a critical component of disease development, a novel concept in experimental NEC pathogenesis (17).…”

Effects of the Flavonoid Chrysin on Nitrofurantoin Pharmacokinetics in Rats: Potential Involvement of ABCG2

“…Bile duct cannulation was carried out as described previously (Jackson et al, 2000) under anesthesia (a combination of 90 mg/kg ketamine and 10 mg/kg xylazine). A dose of 50 mg/kg chrysin (dissolved in dimethyl sulfoxide at a concentration of 20 mg/ml) or vehicle (dimethyl sulfoxide) was first given to rats via i.p.…”

Bile high-mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia

“…This indicates that Kupffer cells, instead of hepatocytes, play an important role in triggering inflammation. LPS challenge not only decreases the rate of bile flow (2, 10), which is important to maintain gut homeostasis, but also stimulates macrophages to release TNF-␣ into the bile (12). It has been shown that TNF-␣ concentration in the bile of LPS-challenged animals is 30 times higher than that in the serum (12).…”