Circulating Plasma Platelet Activating Factor in Persistent Pulmonary Hypertension of the Newborn

Caplan, Michael S.; Hsueh, Wei; Sun, Xiaoming; Gidding, Samuel S.; Hageman, Joseph R

doi:10.1164/ajrccm/142.6_pt_1.1258

Cited by 47 publications

(32 citation statements)

References 14 publications

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“…The level of plasma PAFacetylhydrolase activity also can be altered by acquired factors. Changes in the activity of plasma acetylhydrolase have been found in conjunction with asthma (38,45), systemic lupus erythematosus (46), hypertension (47,48), chronic cholestasis (49), and necrotizing entercolitis (50,51). In the case of clinical sepsis, two conflicting reports have been published.…”

Section: Discussionmentioning

confidence: 99%

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

Howard

Miller

Miwa

et al. 1997

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

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

Howard

Miller

Miwa

et al. 1997

Journal of Biological Chemistry

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“…Neonates with PPHN have high PAF levels (Caplan et al, 1990), showing that persistence of high PAF levels postnatally leads to abnormal perinatal pulmonary adaptation. We speculate that inhibition of PKG and PKA activities by high PAF levels and the inability of cyclic nucleotides to downregulate PAFr-mediated effects postnatally will also contribute to development of PPHN.…”

Section: Paf and Regulation Of Pkg And Pka Activities In Perinatal Pumentioning

confidence: 99%

“…We recently showed that acute hypoxia up-regulates PAFr-mediated intracellular signaling in ovine fetal pulmonary vascular smooth muscle (Ibe et al, 2005). Therefore, chronic hypoxia in the perinatal period may result in abnormal up-regulation of PAFr protein expression, PAFr binding, and PAFr-mediated cell signaling, leading to increased pulmonary vasomotor tone and vascular remodeling, a key event in the onset of clinical disorders such as persistent pulmonary hypertension of the newborn (PPHN) (Caplan et al, 1990).…”

mentioning

confidence: 99%

Platelet-Activating Factor Modulates Activity of Cyclic Nucleotides in Fetal Ovine Pulmonary Vascular Smooth Muscle

Ibe

Ameer

Portugal

et al. 2006

J Pharmacol Exp Ther

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At birth, release of endogenous vasodilators such as nitric oxide and prostacyclin facilitate pulmonary vasodilation via the cyclic nucleotides, cGMP and cAMP. Interaction of cyclic nucleotides and platelet-activating factor (PAF)-mediated responses in pulmonary vascular smooth muscle is not known. We studied the effects of cGMP and cAMP on PAF-mediated responses in ovine fetal intrapulmonary venous smooth muscle cells. Studies were done in hypoxia or normoxia with buffer with 8-Br-cGMP (BGMP) and 8-Br-cAMP (BAMP), as well as cGMPdependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA) inhibitors. All groups were treated with 1 nM PAF and incubated for 30 min for the binding assay or 20 min for measurement of inositol 1,4,5-phosphate (IP 3 ) production. BGMP and BAMP decreased PAF binding in normoxia by 63 and 14%, respectively. Incubations with the PKG inhibitor Rp-8-(4-chlorophenylthio)-guanosine-3Ј,5Ј-cyclic monophosphorothioate sodium and the PKA inhibitor Rp-adenosine-3Ј,5Ј-cyclic monophosphorothioate abrogated the inhibitory effects of BGMP and BAMP. PAF-stimulated IP 3 production was 8565 Ϯ 314 dpm/10 6 cells in hypoxia and 5418 Ϯ 118 dpm/10 6 cells in normoxia, a 40% decrease. BGMP attenuated PAFstimulated IP 3 production by 67 and 37% in hypoxia and normoxia, respectively; the value for BAMP was 44% under both conditions. Pretreatment with PKG or PKA inhibitor abrogated BGMP and BAMP inhibition of IP 3 release. PAF receptor (PAFr) protein expression decreased in normoxia, but pretreatment with 10 nM PAF up-regulated PAFr expression. Pretreatment with PAF decreased expression and activities of PKG or PKA proteins in normoxia and hypoxia. Our data demonstrate the existence of cGMP/cAMP-PAF cross-talk in pulmonary vascular smooth muscle cells, which may be one mechanism by which PAFr-mediated vasoconstriction is down-regulated at birth.

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“…Additionally, IFN-␥ and LPS decreased the human PAF acetylhydrolase promoter activity by 35% and 50% respectively in monocyte-derived macrophages and various established macrophage cell lines (11). However, changes in the in vivo activity of plasma PAF acetylhydrolase have been documented in conjunction with asthma (12), systemic lupus erythematosus (13), hypertension (14,15), chronic cholestasis (9), and necrotizing enterocolitis (16,17). In most cases, the levels of circulating PAF acetylhydrolase activity are increased as a physiological response to inflammatory stimuli.…”

mentioning

confidence: 99%

The Expression and Localization of Plasma Platelet-activating Factor Acetylhydrolase in Endotoxemic Rats

Howard

Olson

2000

Journal of Biological Chemistry

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The production of platelet-activating factor (PAF) and PAF-like phospholipids that also bind the PAF receptor are implicated in numerous pathological situations including bacterial endotoxemia and injury-induced oxidative damage. PAF and PAF-like phospholipids are hydrolyzed and inactivated by the enzyme PAF acetylhydrolase. In the intact rat, infusion of lipopolysaccharide (LPS) into a mesenteric vein served as an acute, liver-focused model of endotoxemia. We determined that the liver responds to LPS exposure with the production of plasma-type PAF acetylhydrolase mRNA and protein expression specifically in the resident macrophages of the liver. Liver macrophages, defined immunohistochemically using antibodies against ED1, present in livers from saline-treated animals contained no detectable PAF acetylhydrolase. Twenty-four hours following in vivo LPS administration, immunohistochemistry detected a slight increase in the number of ED1 staining cells and the ED1-positive cells now contained an abundance of PAF acetylhydrolase. The systemic administration of LPS resulted in increased expression of PAF acetylhydrolase in several tissues. Of the tissues examined, the greatest increase in PAF acetylhydrolase expression was observed in lung followed by increases in spleen, liver, kidney, and thymus. Additionally, the expression of PAF acetylhydrolase mRNA increased in circulating leukocytes and in peritoneal macrophages in response to systemic exposure to LPS. We examined the regulation of PAF acetylhydrolase expression and demonstrated the administration of the PAF receptor antagonists, BN 50739 and WEB 2170, inhibited by 50% the increase in PAF acetylhydrolase expression in response to LPS. The up-regulation of the plasma-type PAF acetylhydrolase expression constitutes an important mechanism for elevating the local and systemic ability to inactivate PAF and oxidized phospholipids in order to minimize PAF-mediated pathophysiology consequent from exposure to endotoxin. The abundance of PAF acetylhydrolase production in the liver lobule likely limits endotoxin-mediated tissue damage due to PAF synthesis.

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Circulating Plasma Platelet Activating Factor in Persistent Pulmonary Hypertension of the Newborn

Cited by 47 publications

References 14 publications

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

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

Platelet-Activating Factor Modulates Activity of Cyclic Nucleotides in Fetal Ovine Pulmonary Vascular Smooth Muscle

The Expression and Localization of Plasma Platelet-activating Factor Acetylhydrolase in Endotoxemic Rats

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