Ursodeoxycholic acid modifies gut-derived endotoxemia in neonatal rats.
We developed a model for the translocation of intraluminal endotoxin in the neonatal animal and used it to examine the capacity of a nonhepatotoxic bile acid, ursodeoxycholic acid (UDCA), to modify endotoxin translocation and cytokine response. Three-d-old Sprague-Dawley rats were randomized to receive enterally either no drug, lipopolysaccharide (LPS, 1 mg/animal), or UDCA (400 micrograms/animal) alone, or UDCA followed by LPS 1 h later. One h after LPS administration, the rats were killed and plasma endotoxin and tumor necrosis factor (TNF) were measured. Control animals had low circulating endotoxin (21.2 +/- 7.6 endotoxin units) and TNF (0.06 +/- 0.02 ng/mL). Enteral administration of LPS 1 h before the rats were killed resulted in significant elevation of endotoxin (249.5 +/- 71.3, p = 0.008) and TNF (3.6 +/- 1.3, p = 0.019). UDCA alone did not alter endotoxin levels (8.7 +/- 2.1). UDCA 1 h before LPS prevented the rise in endotoxin (38.9 +/- 11.2 endotoxin units) and TNF (0.2 +/- 0.05) significantly. Chenodeoxycholic acid was studied in a similar group of experiments and prevented neither the translocation of LPS nor the development of increased TNF levels in animals receiving LPS. In conclusion, LPS can cross the intestinal barrier in the normal neonatal rat. UDCA, administered before LPS, can decrease the translocation of LPS and prevent the cytokine response as measured by TNF levels. We speculate that UDCA, administered prophylactically, might reduce morbidity in clinical conditions leading to gut-derived endotoxemia.
Schwarzenberg
S J
SJ
Department of Pediatrics, University of Minnesota, Minneapolis 55455.
Bundy
M
M
D000818:Animals; D000831:Animals, Newborn; D001693:Biological Transport, Active / Q000187:drug effects; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008070:Lipopolysaccharides / Q000097:blood / Q000493:pharmacokinetics; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014115:Toxemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014580:Ursodeoxycholic Acid