Preliminary studies of an acid-labile factor (ALF) in human sera that inactivates platelet-activating factor (PAF)

Farr, Richard S.; Cox, Charles P.; Wardlow, M.L.; Jorgensen, Richard

doi:10.1016/0090-1229(80)90044-6

Cited by 234 publications

(98 citation statements)

References 19 publications

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“…Potentially, PAF could be increased by a decrease in the activity of plasma PAF-acetylhydrolase, an enzyme predominantly responsible for hydrolysis of PAF to lyso-PAF. 44 45 However, plasma PAF-acetylhydrolase activity is similar in normal individuals and in patients with alcohol induced liver cirrhosis 46 while patients with primary and secondary biliary cirrhosis have elevated levels both of circulating PAF and of serum PAF-acetylhydrolase activity. 47 This suggests that increased synthesis of PAF, and not decreased metabolism by plasma PAF-acetylhydrolase, is the mechanism by which circulating levels of PAF are elevated.…”

Section: Discussionmentioning

confidence: 99%

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Yang

Nemoto²,

Harvey³

et al. 2004

Gut

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Background and aims: The liver is a major site for the synthesis and actions of platelet activating factor (PAF), a potent hepatic vasoconstrictor and systemic vasodilator. As PAF is implicated in portal hypertension and hyperdynamic circulation associated with liver cirrhosis, we characterised changes in the hepatic PAF system in experimental cirrhosis. Methods: In rats made cirrhotic by carbon tetrachloride (CCl 4 ) administration for eight weeks, we determined hepatic levels of PAF and its cognate receptor, and the effects of PAF and PAF antagonist (BN52021) on portal and arterial pressure. Results: Compared with control rats, cirrhotic rats had higher hepatic PAF levels, higher apparent hepatic efflux of PAF, and higher PAF levels in arterial blood (p,0.01, p,0.01, p,0.05, respectively). Relative to controls, cirrhotic livers had elevated hepatic PAF receptors (by mRNA and protein levels and [ 3 H]PAF binding), higher (p,0.01) baseline hepatic portal pressure, and an augmented (p = 0.03) portal pressure response to PAF infusion (1 mg/kg). Portal infusion of BN52021 (5 mg/kg) showed that elevated endogenous PAF was responsible for 23% of the cirrhotic portal pressure increase but made no contribution to systemic hypotension. Finally, increased PAF receptor density was observed in the contractile perisinusoidal stellate cells isolated from cirrhotic livers relative to those from control livers. Conclusions: In cirrhosis, increased hepatic release of PAF elevates systemic PAF; in combination with upregulated hepatic PAF receptors in stellate cells, this contributes to portal hypertension.

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Section: Discussionmentioning

confidence: 99%

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Yang

Nemoto²,

Harvey³

et al. 2004

Gut

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“…Before the structure of PAF was identified, it was reported that human and rabbit serum contained an acid-labile factor that inactivated PAF (25,26). Later, it was clarified that this PAF-inactivating factor in serum was acetylhydrolase, which hydrolyzes the sn-2-acetyl moiety of PAF to inactive lyso PAF (27,28).…”

Section: Introductionmentioning

confidence: 99%

Characterization of serum platelet-activating factor (PAF) acetylhydrolase. Correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children.

Miwa¹,

Miyake²,

Yamanaka³

et al. 1988

J. Clin. Invest.

282

116

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Platelet-activating factor (PAF) acetylhydrolase has been recognized as an enzyme that inactivates PAF. We developed a convenient and reproducible method for determining human serum PAF acetyihydrolase activity. The assay was based on measurement of 1I4Clacetate produced from 1-O-alkyl-2-1'4C]-acetyl-sn-glycero-3-phosphocholine upon precipitation of the complex of radioactive substrate and albumin with TCA. The apparent Km value of PAF acetylhydrolase (near the physiological concentration of serum protein) was 1.5 X 10-4 M PAF. 32 subjects with serum PAF acetylhydrolase deficiency were found among 816 healthy Japanese adults. The low PAF acetylhydrolase activity in the deficient serum might not be due to the presence of enzyme inhibitor. Both the sensitivity to PAF and the metabolism of PAF in platelets from PAF acetylhydrolase-deficient subjects were almost the same as those of normal subjects. Deficiency in serum PAF acetylhydrolase appeared to be transmitted by autosomal recessive heredity among five Japanese families. Among healthy adults, healthy children, and asthmatic children, who were grouped into five classes on the basis of respiratory symptoms (remission, wheezy, mild, moderate, and severe groups), the probability of PAF acetylhydrolase deficiency was significantly higher in groups with severe symptoms (moderate and severe) (P < 0.01). These results suggest that deficiency of serum PAF acetylhydrolase might be one of the factors leading to severe respiratory symptoms in asthmatic children.

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“…PAF is rapidly degraded to the inactive metabolite lysoPAF by acetylhydrolase (8), a 43-kD acid-labile enzyme critical to PAF regulation. We have shown that serum acetylhydrolase is decreased in NEC patients compared with controls (7) and that newborn infants have lower acetylhydrolase activity than older children and adults (9).…”

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confidence: 99%

Endotoxin and Hypoxia-Induced Intestinal Necrosis in Rats: The Role of Platelet Activating Factor

1992

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ABSTRACT. We have previously shown that intravascular platelet activating factor (PAF) causes ischemic bowel necrosis in rats morphologically similar to neonatal necrotizing enterocolitis (NEC). Because endotoxin (LPS) and hypoxia are risk factors for NEC, we studied their effect on PAF metabolism and the development of intestinal injury. Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1 ) control, 2) LPS alone (2 mglkg), 3) hypoxia alone (5% 04, 4) LPS + hypoxia, 5) WEB 2086 (PAF antagonist) + LPS + hypoxia, and 6) SRI 63-441 (PAF antagonist) + LPS + hypoxia. Evaluations included blood pressure recording, superior mesenteric artery blood flow, arterial blood gas, white blood cell count, hematocrit, plasma PAF, plasma acetylhydrolase, plasma tumor necrosis factor, intestinal perfusion, and intestinal injury at 3 h.We found that LPS + hypoxia synergistically contributed to hypotension (mean blood pressure 27 f 5.6% baseline versus 101 f 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 f 0.3 mL/min versus 5.8 f 0.2 mL/min control), and intestinal injury.The morbidities resulting from LPS + hypoxia were partially or completely prevented by PAF antagonists. In addition, animals treated with LPS + hypoxia had neutropenia, elevated plasma acetylhydrolase, and elevated plasma TNF. These results suggest that endogenous PAF may contribute to LPS + hypoxia-induced intestinal hypoperfusion and necrosis. (Pediatr Res 31: 428-434,1992) Abbreviations PAF, platelet activating factor LPS, lipopolysaccharide, endotoxin WBC, white blood cell count TNF, tumor necrosis factor NEC, necrotizing enterocolitis SMA, superior mesenteric artery NEC is a common gastrointestinal disease of premature infants that has a high incidence of morbidity and mortality (1). Alto the development of the disease (2, 3). We have previously shown that intravascular administration of PAF (PAF-acether), an endogenous phospholipid inflammatory mediator, produces intestinal injury in an animal model (4). In addition, it is known that endotoxin (LPS)-induced shock and intestinal injury can be prevented by PAF receptor antagonists (5, 6). Because we have recently reported increased plasma PAF concentrations in newborns afflicted with NEC (7), it is possible that, in addition to causing experimental intestinal injury, PAF is an important endogenous mediator of the human disease.Additional factors related to PAF metabolism may play a role in the development of intestinal injury. PAF is rapidly degraded to the inactive metabolite lysoPAF by acetylhydrolase (8), a 43-kD acid-labile enzyme critical to PAF regulation. We have shown that serum acetylhydrolase is decreased in NEC patients compared with controls (7) and that newborn infants have lower acetylhydrolase activity than older children and adults (9). Because the majority of NEC cases occur in the neonatal period, suppressed PAF degradation may contribut...

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Preliminary studies of an acid-labile factor (ALF) in human sera that inactivates platelet-activating factor (PAF)

Cited by 234 publications

References 19 publications

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Characterization of serum platelet-activating factor (PAF) acetylhydrolase. Correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children.

Endotoxin and Hypoxia-Induced Intestinal Necrosis in Rats: The Role of Platelet Activating Factor

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