Cell-specific Regulation of Expression of Plasma-type Platelet-activating Factor Acetylhydrolase in the Liver

Abstract

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that causes hypotension, increases vascular permeability, and has been implicated in anaphylaxis, septic shock and several other inflammatory responses. PAF is hydrolyzed and inactivated by the enzyme PAF-acetylhydrolase. In the intact rat, a mesenteric vein infusion of lipopolysaccharide (LPS) served as an acute, liver-focused model of endotoxemia. Plasma PAF-acetylhydrolase activity increased 2-fold by 24 h following LPS administration. Ribonuclease protection experiments demonstrated very low levels of plasma-type PAF-acetylhydrolase mRNA transcripts in the livers of saline-infused rats; however, 24 h following LPS exposure, a 20-fold induction of PAF-acetylhydrolase mRNA was detected. In cells isolated from endotoxin-exposed rat livers, Northern blot analyses demonstrated that Kupffer cells but not hepatocytes or endothelial cells were responsible for the increased PAF-acetylhydrolase mRNA levels. In Kupffer cells, plasma-type PAF-acetylhydrolase mRNA was induced by 12 h, peaked at 24 h, and remained substantially elevated at 48 h. Induction of neutropenia prior to LPS administration had no effect on the increase in PAF-acetylhydrolase mRNA seen at 24 h. Although freshly isolated Kupffer cells contain barely detectable levels of plasma-type PAF-acetylhydrolase mRNA, when Kupffer cells were established in culture, PAF-acetylhydrolase expression became constitutively activated concomitant with cell adherence to the culture plates. Alterations in plasma-type PAF-acetylhydrolase expression may constitute an important mechanism for elevating plasma PAF-acetylhydrolase levels and an important component in minimizing PAF-mediated pathophysiology in livers exposed to endotoxemia.

Platelet‐activating factor and liver metastasis of colorectal cancer

“…Liver is thus a potentially PAF target since PAF, lyso-PAF, AHA and PAF-R are found in normal liver. 14,15 As reported in Figure 1(a), investigation of 30 patients revealed a 7-fold increase (p ϭ 0.0008) of PAF levels in the tumor tissue (7.30 Ϯ 1.98 pg/mg protein) as compared to the adjacent tissue (0.88 Ϯ 0.24 pg/mg protein). Elevated levels of PAF can result from a lower PAF degradation or a higher PAF production.…”

Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

“…24 Endotoxin infusion in vivo has been shown to induce a dramatic increase in pPAF-AH mRNA levels in Kupffer cells but not in hepatocytes isolated from LPS-treated rats. 25 The induction of pPAF-AH mRNA was not detected before 12 hours after LPS exposure and attained maximal levels at 24 hours indicating a somewhat delayed response of these sinusoidal cells to LPS in the circulation.…”

“…24,25,[29][30][31] We have shown that freshly isolated rat Kupffer cells as well as hepatocytes contain a preformed pool of pPAF-AH, which is secreted by these cells after their establishment in primary culture. 24 Endotoxin infusion in vivo has been shown to induce a dramatic increase in pPAF-AH mRNA levels in Kupffer cells but not in hepatocytes isolated from LPS-treated rats.…”

“…In in vivo studies, Kupffer cells isolated from endotoxin-exposed rat livers, but not hepatocytes or endothelial cells, expressed a 20-fold increase in pPAF-AH messenger RNA (mRNA) levels. 25 This observation is particularly important, because Kupffer cells rapidly generate a large amount of PAF in response to endotoxin exposure. 26,27 Hence, although the liver may substantially promote an inflammatory response to endotoxin via generating of PAF and oxidized PAF analogs, hepatic release of PAF-AH and potentially LCAT may be an important response designed to counteract the inflammatory attributes of PAF.…”

Regulating inflammation through the anti-inflammatory enzyme platelet-activating factor-acetylhydrolase

“…Recently, Asano et al (1999) analyzed subjects who had received an allogeneic bone marrow transplant and demonstrated that PAF-AH activity in plasma depended on the donor's, but not on the recipient's genotype, confirming that PAF-AH activity in plasma originates from hematopoietic stem cell-derived cells such as macrophages, but not from hepatocytes. The expression of plasma PAF-AH mRNA and production of plasma PAF-AH protein are increased in the resident macrophages of the liver in response to LPS exposure (Howard et al 1997). Up-regulation of the plasma PAF-AH expression appears to be an important mechanism for elevating the local and systemic ability to inactivate PAF and oxidized phospholipids in order to minimize PAF-mediated pathophysiology resulting from exposure to LPS (Howard & Olson 2000).…”