CELL-SPECIFIC REGULATION OF EXPRESSION OF PLASMA-TYPE PLATELET-ACTIVATING-FACTOR ACETYLHYDROLASE IN THE LIVER

Platelet-activating factor (PAF) is a potent proinflammatory phospholi pid mediator that causes hypotension, increases vascular permeability, and has been implicated in anaphylaxis, septic shock and several othe r inflammatory responses. PAF is hydrolyzed and inactivated by the enz yme PAF-acetylhydrolase. In the intact rat, a mesenteric vein infusion of lipopolysaccharide (LPS) served as an acute, liver-focused model o f endotoxemia, Plasma PAF-acetylhydrolase activity increased 2-fold by 24 h following LPS administration. Ribonuclease protection experiment s demonstrated very low levels of plasma-type PAF-acetylhydrolase mRNA transcripts in the livers of saline-infused rats; however, 24 h follo wing LPS exposure, a 20-fold induction of PAF-acetylhydrolase mRNA was detected. In cells isolated from endotoxin-exposed rat Livers, Northe rn blot analyses demonstrated that Kupffer cells but not hepatocytes o r endothelial cells were responsible for the increased PAF-acetylhydro lase mRNA levels, In Kupffer cells, plasma-type PAF-acetylhydrolase mR NA was induced by 12 h, peaked at 24 h, and remained substantially ele vated at 48 h, Induction of neutropenia prior to LPS administration ha d no effect on the increase in PAF-acetylhydrolase mRNA seen at 24 h. Although freshly isolated Kupffer cells contain barely detectable leve ls of plasma-type PAF-acetylhydrolase mRNA when Kupffer cells were est ablished in culture, PAF-acetylhydrolase expression became constitutiv ely activated concomitant with cell adherence to the culture plates, A lterations in plasma-type PAF-acetylhydrolase expression may constitut e an important mechanism for elevating plasma PAF-acetylhydrolase leve ls and an important component in minimizing PAF-mediated pathophysiolo gy in livers exposed to endotoxemia.