PROSTAGLANDIN E-2 ALTERATIONS DURING SEPSIS ARE PARTIALLY MEDIATED BYENDOTOXIN-INDUCED INHIBITION OF PROSTAGLANDIN 15-HYDROXYDEHYDROGENASE

Prostaglandin E-2 (PGE(2)) is significantly elevated in the plasma of septic or injured patients and is thought to be a component of the res ultant immune suppression associated with augmented rates of infection and mortality. Many studies have examined the effect of burn injury a nd sepsis on PGE(2) synthesis. However, the effect of sepsis or burn i njury on the expression of prostaglandin 15-hydroxydehydrogenase (PGDH ), the key enzyme responsible for PGE(2) degradation, has not been exp lored. The aim of this study was to examine the effect of endotoxin tr eatment and/or burn injury on the expression of PGDH. Male BDF1 mice w ere assigned to four groups (n = 4/group): sham, lipopolysaccharide (L PS) (2.5 mg/kg, Escherichia coli LPS, IP), burn (15% body surface area scald injury:), and burn + LPS (15% body surface area + 2.5 mg/kg LPS , LP), Lung tissue was harvested at specific time points after treatme nt and subsequently was processed for total RNA and protein, Northern and Western blot analyses were used to examine differences in PGDH pro tein and mRNA expression. Total RNA was probed with the riboprobe for murine PGDH, and the 100,000 g protein fraction was immunoblotted usin g an rabbit antimurine PGDH antibody. PGDH was expressed in lung at t = 0 in both the saline and LPS-treated animals. A decrease in mRNA exp ression was initially observed at 2 hours after LPS treatment. The dec rease was also significant (p < 0.05) at 3 hours after LPS and maximal decrease in mRNA and protein expression was observed at 6 hours. At 2 4 hours after LPS administration, the PGDH mRNA and protein expression was still significantly depressed to 49% of control expression. PGDH expression was similar and not statistically different in both burn an d burn + LPS treatment at t = 0, At 2 hours after LPS, PGDH mRNA expre ssion in the burn + LPS treatment group had significantly decreased to 47% in comparison with the burn alone group, Maximal decrease in PGDH mRNA and protein expression in lung from burn + LPS was observed at 6 hours after LPS treatment. This change represents a 73% decrease in m RNA in comparison with the time-matched burn control. At 24 hours afte r LPS administration, PGDH mRNA but not protein expression in the lung from burn C LPS treated mice was still significantly decreased. In su mmary, LPS treatment alters PGDH mRNA expression at the transcriptiona l and protein levels. Consequently, sepsis-induced increases in PGE(2) levels may not be only due to increased PGE(2) synthesis but also due to decreased PGDH expression and, hence, PGE(2) degradation.