title: Dehydrocostuslactone inhibits LPS-induced inflammation by p38MAPK-dependent induction of hemeoxygenase-1 in vitro and improves survival of mice in CLP-induced sepsis in vivo.
abstract: We investigated the hypothesis that the administration of dehydrocostuslactone (DL), a sesquiterpene lactone found in Saussurea lappa Clarke (Compositae), might reduce organ failure and increase survival in a cecal ligation and puncture (CLP)-induced mouse model of sepsis due to HO-1 induction. Treatment of RAW264.7 cells with DL increased HO-1 expression in a time- and concentration-dependent manner, and this up-regulation of HO-1 by DL was significantly inhibited by silencing either Nrf2 and p38 or treating cells with SB203580 (a p38MAPK inhibitor), but it was not inhibited in the presence of SP600125 (an ERK inhibitor), PD98059 (a JNK inhibitor), or LY294002 (PI3K inhibitor). As expected, DL concentration dependently inhibited the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and the productions of NO and PGE2 in LPS-activated cells, and these inhibitions were reversed by silencing HO-1. Most importantly, administration of DL significantly reduced mortality and reduced serum IL-1β and TNF-α and the infiltration of macrophages into liver tissues of CLP-mice. Inducible NOS expression in lung and liver tissues of CLP-mice was reduced by DL, which was reversed by the co-administration of zinc-protoporphyrin IX (ZnPPIX; a competitive inhibitor of HO-1). Our findings indicate that DL might be useful for the treatment of sepsis.
authors: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors: Eun Jung
authors: EJ
authors: Park
authors: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors: Sang Won
authors: SW
authors: Park
authors: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors: Hye Jung
authors: HJ
authors: Kim
authors: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Jong-Hwan
authors: JH
authors: Kwak
authors: Division of Bioscience, Dongguk University, Gyeongju 780-714, Republic of Korea. Electronic address: dulee@dongguk.ac.kr.
authors: Dong-Ung
authors: DU
authors: Lee
authors: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors: Ki Churl
authors: KC
authors: Chang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002432:Cecum / Q000293:injuries / Q000601:surgery; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015232:Dinoprostone / Q000276:immunology; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use*; D008026:Ligation; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D007783:Lactones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D012717:Sesquiterpenes; D009569:Nitric Oxide; C083030:dehydrocostus lactone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: Dehydrocostuslactone; Heme oxygenase; Inflammation; Mice; Sepsis