Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells.

Stewart, Alastair G.; Dubbin, Philip N.; Harris, Trudi; Dusting, Gregory J.

doi:10.1073/pnas.87.8.3215

Cited by 115 publications

(58 citation statements)

References 35 publications

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“…17,18 Indeed, PAF regulates the interaction between endothelial cells and neutrophils by facilitating, together with LTB 4 , the margination and adhesion of neutrophils to the vascular wall. 19 Furthermore, PAF and LTB 4 contribute to neutrophil recruitment and activation, including the generation of bactericidal components (oxygen radicals and antibiotic proteins) and the release of a wide variety of intracellular constituents (lysosomal enzymes).…”

Section: Discussionmentioning

confidence: 99%

Impaired mesenteric leukocyte recruitment in experimental portal hypertension in the rat

et al. 1999

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Increased incidence of septic complications in human and experimental portal hypertension has been documented. Because development of an inflammatory response is essential in defense against infectious agents, the aim of this study was to assess leukocyte-endothelial cell interactions in an experimental model of portal hypertension. Intravital microscopy studies showed that under baseline conditions, leukocyte rolling, adhesion, and emigration in mesenteric venules were similar in control, sham operated (SO), and partial portal vein ligated (PPVL) rats. Compared with either control or SO rats, PPVL animals exhibited a markedly reduced recruitment of rolling, adherent, and emigrated leukocytes in response to leukotriene B 4 (LTB 4 ) stimulation. Similarly, platelet-activating factor (PAF) superfusion, which induced a large increment in leukocyte rolling and adherence in control and SO rats, was without any effect in PPVL animals. Endothelial P-selectin expression in control rats, as measured by the double radio-labeled monoclonal antibody (mAb) technique, was not modified by LTB 4 , but significantly increased in response to PAF. PPVL rats had a significantly lower expression of P-selectin after stimulation with PAF. Neutrophils isolated from PPVL rats exhibited increased L-selectin shedding and CD11b up-regulation in response to PAF and LTB 4 , compared with neutrophils isolated from SO rats. These observations indicate that portal hypertension is associated with a defective inflammatory response, which is manifested as a decreased recruitment of rolling leukocytes, and subsequently reduced adhesion/emigration. This defect appears to result from a reduced endothelial P-selectin up-regulation and increased L-selectin shedding. (HEPATOLOGY 1999;30:445-453.)Patients with liver disease and portal hypertension are predisposed to develop spontaneous infections by enteric bacteria. These infective sequelae are responsible for serious and often fatal complications; however, the mechanism(s) underlying this high incidence of infection-related complications is not completely understood. One potential contributing factor is impaired neutrophil function. Neutrophilic superoxide anion production and the generation of both platelet-activating factor (PAF) and leukotriene B 4 (LTB 4 ) are reduced in alcohol-related 1 and non-alcohol-related cirrhosis. 2 In addition, demonstration of bacterial translocation to mesenteric ganglia in animal models of portal hypertension without liver disease 3,4 and the appearance of a unique septic complication such as spontaneous bacterial peritonitis in human cirrhosis with portal hypertension 5 suggest that there is a deficient host immune response in the mesenteric circulation directly related to portal hypertension.The adhesion of leukocytes to vascular endothelial cells is a critical early step in the development of an inflammatory response. This process is essential in isolating and eliminating infectious agents and in tissue repair. The inflammatory response involves sequential leukocyte...

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Section: Discussionmentioning

confidence: 99%

Impaired mesenteric leukocyte recruitment in experimental portal hypertension in the rat

et al. 1999

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“…However, unlike other lipid mediators (e.g., prostaglandins and lipoxygenase products), once formed, PAF is often retained in cells (4)(5)(6). This cellular retention is a prominent feature of stimulus-evoked PAF and may underlie intracellular functions (4,7,8). When PAF is added to cells (e.g., washed rabbit platelets), it is rapidly internalized (9).…”

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confidence: 99%

Platelet-activating factor and retinoic acid synergistically activate the inducible prostaglandin synthase gene.

Bazán

Fletcher

Herschman

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

139

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Platelet-activating factor (PAF), a potent lipid mediator generated in cell injury and in the inflammatory and immune responses, promotes transcriptional activation of several primary response genes. TIS10/PGS-2 is a primary response gene encoding the inducible form of prostaglandin synthase. The inductive effects of PAF and retinoic acid (RA), alone and in combination, were studied with the regulatory region of TIS10/PGS-2 transfected into an exponentially growing glioblastoma-neuroblastoma NG108-15 hybrid in the human SH-SY5Y neuroblastoma or in the NIH 3T3 cell. RA alone exhibited only a small inductive effect. However, in the presence of RA (100 nM), a PAF-dependent (1-50 nM) synergistic activation of luciferase reporter constructs driven by regulatory regions of the TIS10/PGS-2 gene was found. The hetrazepine BN-50730, an antagonist selective for intracellular PAF binding sites, inhibited PAF and RA induction of luciferase from the TIS10/PGS-2 promoter. Thus, the intracellular PAF binding site is involved in TIS10/PGS-2 expression. Induction is rapid, suggesting that the combination of PAF and RA activates a preexisting latent transcription factor(s). Deletion studies restrict the major PAF and RA cis-acting response element of the TIS10/PGS-2 gene to a 70-nucleotide sequence as an intracellular inducer of TIS10/PGS-2 expression. The synergistic effect of RA and PAF represents an unusual convergence of nuclear signaling pathways by which, through the modulation of preexisting transcription factors, specific gene expression can be upregulated. PAF-dependent induction of TIS10/PGS-2 expression may play a role in cell injury, differentiation, inflammation, and immune responses.

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“…31 Furthermore, PAF induces release of proteases, such as elastase, from macrophages 35 ; such enzymes may degrade components of the extracellular matrix of the intima. PAF also induces release of active oxygen species from monocytes, 36 macrophages, 37 endothelial cells, 38 and lymphocytes 39 ; in the subintimal space, active oxygen species may induce tissue damage and equally contribute to LDL oxidation (reviewed in Reference 1).…”

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confidence: 99%

PAF-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cell-mediated oxidation.

Dentan

Lesnik

Chapman

et al. 1994

Arterioscler Thromb

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In peripheral blood, native low-density lipoprotein (LDL) is a major carrier of acetylhydrolase, the enzyme that hydrolyzes the sn-2 acetate of PAF-acether, converting it to lyso PAF-acether. By controlling the level of PAF-acether, the acetylhydrolase may regulate the biologic effects of this potent inflammatory and thrombotic mediator. The biologic oxidation of LDL appears to underlie its atherogenicity. We report here that oxidative modification of LDL led to progressive loss of associated acetylhydrolase activity. Reductions of approximately 90% and 40% of acetylhydrolase activity occurred respectively in LDL oxidized for 24 hours by copper ions (2.5 /xmol/L) in phosphate-buffered saline and in LDL incubated with human monocyte-like THP, cells in Ham's F-10 medium. Acetylhydrolase activity decreased as a function of the degree of LDL oxidation and was correlated with an increase in net negative charge and in the content of thiobarbituric acid-reactive substances (r=-.94 and r=-.88, respectively; Fs.001). The acetylhydrolase of mildly oxidized LDL displayed a similar K m for PAF-acether compared with native

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Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells.

Cited by 115 publications

References 35 publications

Impaired mesenteric leukocyte recruitment in experimental portal hypertension in the rat

Impaired mesenteric leukocyte recruitment in experimental portal hypertension in the rat

Platelet-activating factor and retinoic acid synergistically activate the inducible prostaglandin synthase gene.

PAF-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cell-mediated oxidation.

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