Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is a systemic inflammatory response that results from the inability of the immune system to limit bacterial spread during an ongoing infection. Recently, we have documented an impaired neutrophil migration toward the infectious focus in severe sepsis. This impairment seems to be mediated by circulating cytokines, chemokines, and NO. Platelet-activating factor (PAF) plays an important role in the orchestration of different inflammatory reactions, including the release of cytokines, chemokines, and free radicals. Using a PAFR antagonist, PCA-4248, and PAFR-deficient mice, we investigated whether signaling via PAFR was relevant for the failure of neutrophils to migrate to the site of infection after lethal sepsis caused by cecum ligation and puncture in mice. In PAFR-deficient mice or mice pretreated with PCA-4248 (5 mg/kg) and subjected to lethal sepsis, neutrophil migration failure was prevented, and bacterial clearance was more efficient. There was also reduced systemic inflammation (low serum cytokine levels), lower nitrate levels in plasma, and higher survival rate. Altogether, the results firmly establish a role for PAFR in mediating the early impairment of neutrophil migration toward the infectious focus. Blockade of PAFR may prevent the establishment of severe sepsis.
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PMID:Signaling via platelet-activating factor receptors accounts for the impairment of neutrophil migration in polymicrobial sepsis. 1681 86

Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In PAFR(-/-) mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar (PAFR(-/-)) or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are disease-modifying agents in experimental dengue infection.
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PMID:Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection. 1966 57