ABSTRACT
During periods of periodontal attachment loss, one of the most significant cellular changes is a decrease in the number of fibroblasts. We previously demonstrated that LPS induces apoptosis of fibroblastic cells in vivo, largely through TNF-alpha. We conducted in vivo experiments by subcutaneous inoculation of LPS in wild-type, TNFR1-/-R2-/-, TNFR1-/-, and TNFR2-/- mice to identify which TNF receptors are involved and the specific caspase pathway activated. LPS stimulated apoptosis through TNFR1 but not TNFR2, which was accompanied by the induced expression of 12 apoptotic genes. Fluorometric studies demonstrated that LPS in vivo significantly increased caspase-8 and caspase-3 activity, which was also dependent on TNF receptor signaling. By the use of specific caspase inhibitors, caspases-3 and -8 were shown to play an important role in LPS-induced apoptosis in vivo. Thus, LPS acts through TNFR1 to modulate the expression of apoptotic genes and activate caspases-3 and -8.
Subject(s)
Antigens, CD/drug effects , Apoptosis/drug effects , Fibroblasts/drug effects , Lipopolysaccharides/pharmacology , Receptors, Tumor Necrosis Factor/drug effects , Animals , Antigens, CD/physiology , Apoptosis/genetics , Caspase 3 , Caspase 8 , Caspase 9 , Caspase Inhibitors , Caspases/drug effects , Cells, Cultured , Enzyme Activation/drug effects , Enzyme Precursors/antagonists & inhibitors , Enzyme Precursors/drug effects , Escherichia coli , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Receptors, Tumor Necrosis Factor/physiology , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , Signal Transduction/drug effectsABSTRACT
In this study the severity of aspirin-induced gastric mucosal damage was investigated in rats with obstructive cholestasis. Cholestasis was induced by ligation and resection of the bile duct under general anesthesia. Two weeks after operation, the rats were fasted for 24 hours. Aspirin was administered orally in doses of 0, 128, 192, 266 and 335 mg/kg, and the animals were killed four hours after dosing. The dose of 266 mg/kg was chosen for a study of the time-dependency; other groups of animals were killed at time intervals of one, three, five, seven and nine hours after aspirin administration. The results showed that aspirin induces more severe gastric damage in bile duct resected rats compared with sham-operated and control animals. Salicylate levels of serums were also measured but there was no significant difference in serum salicylate levels between bile duct resected, sham-operated and control rats. It can be concluded that cholestasis can potentiate aspirin-induced gastric damage in rats.
