PMID- 27064683 OWN - NLM STAT- MEDLINE DCOM- 20160825 LR - 20181113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 4 DP - 2016 TI - Lipopolysaccharide Cross-Tolerance Delays Platelet-Activating Factor-Induced Sudden Death in Swiss Albino Mice: Involvement of Cyclooxygenase in Cross-Tolerance. PG - e0153282 LID - 10.1371/journal.pone.0153282 [doi] LID - e0153282 AB - 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 mug/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-alpha 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. FAU - Jacob, Shancy Petsel AU - Jacob SP AD - Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India. FAU - Lakshmikanth, Chikkamenahalli Lakshminarayana AU - Lakshmikanth CL AD - Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India. FAU - Chaithra, Vyala Hanumanthareddy AU - Chaithra VH AD - Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India. FAU - Kumari, Titus Ruth Shantha AU - Kumari TR AD - Department of Zoology, St. Philomena's College, Bannimantap, Mysuru, 570015, Karnataka, India. FAU - Chen, Chu-Huang AU - Chen CH AD - Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas, 77225-0345, United States of America. FAU - McIntyre, Thomas M AU - McIntyre TM AD - Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, 44195, United States of America. FAU - Marathe, Gopal Kedihitlu AU - Marathe GK AD - Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160411 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Cyclooxygenase Inhibitors) RN - 0 (Cytokines) RN - 0 (Lipopolysaccharides) RN - 0 (Platelet Activating Factor) RN - 0 (Platelet Membrane Glycoproteins) RN - 0 (Protective Agents) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (platelet activating factor receptor) RN - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases) SB - IM MH - Animals MH - Cyclooxygenase Inhibitors/*pharmacology MH - Cytokines/metabolism MH - Death, Sudden/etiology/pathology/*prevention & control MH - Endotoxemia/etiology/mortality/pathology/*prevention & control MH - Injections, Intraperitoneal MH - Lipopolysaccharides/*pharmacology MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Platelet Activating Factor/administration & dosage/*toxicity MH - Platelet Membrane Glycoproteins/metabolism MH - Prostaglandin-Endoperoxide Synthases/*chemistry/metabolism MH - Protective Agents/pharmacology MH - Receptors, G-Protein-Coupled/metabolism MH - Survival Rate PMC - PMC4827832 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2016/04/12 06:00 MHDA- 2016/08/26 06:00 PMCR- 2016/04/11 CRDT- 2016/04/12 06:00 PHST- 2015/08/13 00:00 [received] PHST- 2016/03/04 00:00 [accepted] PHST- 2016/04/12 06:00 [entrez] PHST- 2016/04/12 06:00 [pubmed] PHST- 2016/08/26 06:00 [medline] PHST- 2016/04/11 00:00 [pmc-release] AID - PONE-D-15-34589 [pii] AID - 10.1371/journal.pone.0153282 [doi] PST - epublish SO - PLoS One. 2016 Apr 11;11(4):e0153282. doi: 10.1371/journal.pone.0153282. eCollection 2016.