In vivo data suggest a role of LTD4 in mediating endotoxin (LPS)-inducible liver injury in galactosamine-sensitized mice. Leukotriene D4 (LTD4) was shown to synergize in this model with subtoxic amounts of LPS in inducing hepatitis. Mice challenged i.v. with a subtoxic dose of LPS [50 ng/kg] showed significant TNF serum levels 90 min later which were sixfold increased by coadministration of 50 μg/kg LTD4. When rat Kupffer cells were challenged with LPS, TNF-α measured in the supernatant was significantly increased by LTD4 [100 pg-100 ng/ml]. Addition of LTD4 alone did not result in any detectable TNF formation. Since Kupffer cells are known producers of small amounts of LTD4, it seems feasible that LTD4 represents an autocrine stimulus of nonparenchymal liver cells. In fact, different LTD4 synthesis inhibitors and receptor antagonists attenuated LPS-inducible TNF release of rat Kupffer cells supporting the conclusion that LTD4 acts as an endogenous autocrine enhancer of liver macrophage TNF release.
ASJC Scopus subject areas
- Pharmacology (medical)