The Metabolic Effects of Platelet-Activating Factor Antagonism in Endotoxemic Man

Thompson, W. A.; Coyle, Susette M.; Zee, Kimberly Van; Oldenburg, Hester S. A.; Trousdale, Rhonda K.; Rogy, Michael A.; Felsen, Diane; Moldawer, Lyle L.; Lowry, Stephen F.

doi:10.1001/archsurg.1994.01420250084011

Cited by 38 publications

(6 citation statements)

References 33 publications

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“…The extracellular, soluble fragments of both receptors released into the circulation by proteolytic shedding [27] can be detected in biological fluids by monoclonal antibodies. A monophasic peak of soluble receptors similar to TNF occurs 2 to 3 h after endotoxin administration [13,28]. Elevated levels of soluble receptors correlating with the severity of the disease are found in sepsis patients compared to healthy controls in this study.…”

Section: Discussionmentioning

confidence: 67%

Pattern of soluble TNF receptors I and II in sepsis

et al. 1995

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The serum levels of soluble TNF receptors I (sTNFR I) and sTNFR II were measured frequently in 14 patients with sepsis to evaluate the pattern of these TNF antagonists in relation to TNF alpha, Soluble TNFR I and II could be detected in all samples with significantly higher levels (p < 0.001) compared to healthy controls. The concentration of sTNFR I as well as sTNFR II was significantly higher in nonsurvivors compared to survivors during the first 36 h of sepsis (p < 0.001). Levels remained elevated throughout the evaluation with maximal values in patients who died. A positive correlation exists between both receptors and between soluble receptors and simultaneously obtained sepsis score (p < 0.01) while TNF immunoreactivity detected in 80% of all samples did not correlate to soluble receptor levels or sepsis score. Soluble receptors were constantly found in the circulation representing the inflammatory state throughout the evaluation even when TNF activity was undetectable.

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Section: Discussionmentioning

confidence: 67%

Pattern of soluble TNF receptors I and II in sepsis

et al. 1995

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“…In humans administered LPS, treatment with the PAF receptor antagonist Ro 24 -4736 resulted in fewer symptoms, such as rigor and myalgia, than those with a placebo (47). These reports suggest the clinical significance of PAF in sepsis.…”

Section: Discussionmentioning

confidence: 84%

Priming Effect of Lipopolysaccharide on Acetyl-Coenzyme A:Lyso-Platelet-Activating Factor Acetyltransferase Is MyD88 and TRIF Independent

Shindou

Ishii

Yamamoto

et al. 2005

The Journal of Immunology

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LPS has a priming effect on various stimuli. For instance, LPS priming enhances the production of platelet-activating factor (PAF), a proinflammatory lipid mediator that is induced by PAF itself. Among various enzymes responsible for PAF biosynthesis, acetyl-coenzyme A:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase is one of the enzymes activated by PAF receptor stimulation. In this study we investigated the priming effect of LPS on the acetyltransferase activation by PAF in TLR4-knockout (KO) mice, MyD88-KO mice, and Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF)-KO mice. This enzyme was biphasically activated by LPS. Although the first peak occurred within 30 min in wild-type (WT), but not TLR4-KO or MyD88-KO, macrophages, the second phase reached a maximum within hours in WT, MyD88-KO, and TRIF-KO, but not in TLR4-KO, macrophages. Only in the second phase was the increase in acetyltransferase activity upon PAF receptor activation remarkably enhanced in WT, MyD88-KO, and TRIF-KO cells, but not in TLR4-KO cells. These data demonstrated that LPS exerted a priming effect on PAF receptor-mediated acetyltransferase activation through the TLR4-dependent, but MyD88- and TRIF-independent, pathway.

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“…To complicate the matter even further, there is evidence against the involvement of the PAF receptor in the T b responses to LPS, at least when it comes to fever, as LPS fever was only marginally affected by a PAF antagonist in a study in horses 21 and not affected at all by another PAF antagonist in a study in humans. 22 …”

Section: Introductionmentioning

confidence: 99%

Platelet-activating factor is a potent pyrogen and cryogen, but it does not mediate lipopolysaccharide fever or hypothermia

Steiner

Romanovsky

2015

Temperature

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We examined whether platelet-activating factor (PAF) and its receptor mediate lipopolysaccharide (LPS)-induced fever and hypothermia in rats. Two highly potent, structurally distinct antagonists of the PAF receptor, CV6209 and WEB2086, were used. At a neutral ambient temperature (Ta) of 30ºC, administration of LPS at a low (10 μg/kg, i.v.) or high (1,000 μg/kg, i.v.) dose resulted in fever. The response to the high dose was turned into hypothermia at a subneutral Ta of 22ºC. Neither LPS-induced fever nor hypothermia was affected by pretreatment with CV6209 (5 mg/kg, i.v.) or WEB2086 (5 mg/kg, i.v.). However, both PAF antagonists were efficacious in blocking the thermoregulatory response caused by PAF (334 pmol/kg/min, 1 h, i.v.), regardless of whether the response was a fever (at 30ºC) or hypothermia (at 22ºC). Additional experiments showed that the thermoregulatory responses to LPS and PAF are also distinct in terms of their mediation by prostaglandins. Neither PAF fever nor PAF hypothermia was affected by pretreatment with the cyclooxygenase-2 inhibitor SC236 (5 mg/kg, i.p.), which is known to abrogate LPS fever. The responses to PAF were also unaffected by pretreatment with the cyclooxygenase-1 inhibitor SC560 (5 mg/kg, i.p.), which is known to attenuate LPS hypothermia. In conclusion, PAF infusion at a picomolar dose causes fever at thermoneutrality but hypothermia in a subthermoneutral environment, both responses being dependent on the PAF receptor and independent of prostaglandins. However, the PAF receptor does not mediate LPS-induced fever or hypothermia, thus challenging the dogma that PAF is an upstream mediator of responses to LPS.

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The Metabolic Effects of Platelet-Activating Factor Antagonism in Endotoxemic Man

Cited by 38 publications

References 33 publications

Pattern of soluble TNF receptors I and II in sepsis

Pattern of soluble TNF receptors I and II in sepsis

Priming Effect of Lipopolysaccharide on Acetyl-Coenzyme A:Lyso-Platelet-Activating Factor Acetyltransferase Is MyD88 and TRIF Independent

Platelet-activating factor is a potent pyrogen and cryogen, but it does not mediate lipopolysaccharide fever or hypothermia

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