title: Lipopolysaccharide Cross-Tolerance Delays Platelet-Activating Factor-Induced Sudden Death in Swiss Albino Mice: Involvement of Cyclooxygenase in Cross-Tolerance.
abstract: Lipopolysaccharide (LPS) signaling through Toll-like receptor-4 (TLR-4) has been implicated in the pathogenesis of many infectious diseases. Some believe that TLR-mediated pathogenicity is due, in part, to the lipid pro-inflammatory mediator platelet-activating factor (PAF), but this has been questioned. To test the direct contribution of PAF in endotoxemia in murine models, we injected PAF intraperitoneally into Swiss albino mice in the presence and absence of LPS. PAF alone (5 μg/mouse) caused death within 15-20 min, but this could be prevented by pretreating mice with PAF-receptor (PAF-R) antagonists or PAF-acetylhydrolase (PAF-AH). A low dose of LPS (5 mg/kg body wt) did not impair PAF-induced death, whereas higher doses (10 or 20 mg/kg body wt) delayed death, probably via LPS cross-tolerance. Cross-tolerance occurred only when PAF was injected simultaneously with LPS or within 30 min of LPS injection. Tolerance does not appear to be due to an abundant soluble mediator. Histologic examination of lungs and liver and measurement of circulating TNF-α and IL-10 levels suggested that the inflammatory response is not diminished during cross-tolerance. Interestingly, aspirin, a non-specific cyclooxygenase (COX) inhibitor, partially blocked PAF-induced sudden death, whereas NS-398, a specific COX-2 inhibitor, completely protected mice from the lethal effects of PAF. Both COX inhibitors (at 20 mg/kg body wt) independently amplified the cross-tolerance exerted by higher dose of LPS, suggesting that COX-derived eicosanoids may be involved in these events. Thus, PAF does not seem to have a protective role in endotoxemia, but its effects are delayed by LPS in a COX-sensitive way. These findings are likely to shed light on basic aspects of the endotoxin cross-tolerance occurring in many disease conditions and may offer new opportunities for clinical intervention.
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India.
authors.forename: Shancy Petsel
authors.initials: SP
authors.lastname: Jacob
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India.
authors.forename: Chikkamenahalli Lakshminarayana
authors.initials: CL
authors.lastname: Lakshmikanth
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India.
authors.forename: Vyala Hanumanthareddy
authors.initials: VH
authors.lastname: Chaithra
authors.affiliation: Department of Zoology, St. Philomena's College, Bannimantap, Mysuru, 570015, Karnataka, India.
authors.forename: Titus Ruth Shantha
authors.initials: TR
authors.lastname: Kumari
authors.affiliation: Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas, 77225-0345, United States of America.
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, 44195, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India.
authors.forename: Gopal Kedihitlu
authors.initials: GK
authors.lastname: Marathe
mesh_terms: D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003645:Death, Sudden / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019446:Endotoxemia / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000633:toxicity*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015996:Survival Rate
chemical_list: D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D020011:Protective Agents; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D011451:Prostaglandin-Endoperoxide Synthases