title: Enhanced induction of heme oxygenase-1 suppresses thrombus formation and affects the protein C system in sepsis.
abstract: Heme oxygenase-1 (HO-1) displays anti-inflammatory and cytoprotective activities in sepsis. Here, we investigated the effects of HO-1 on thrombus formation and the protein C system in a septic C57BL/6 mouse model induced by cecal ligation and perforation (CLP). Septic mice were either preinjected with the vehicle, pretreated with hemin (an HO-1 inducer) or zinc protoporphyrin IX (ZnPP, an HO-1 inhibitor), or given a combination of hemin + ZnPP. CLP increased significantly the hepatic expression of HO-1; increased thrombosis in livers, kidneys, and lungs; shortened the prothrombin time (PT) and activated partial thromboplastin time (APTT); elevated the levels of tumor necrosis factor-1α (TNF-1α), interleukin-6 (IL-6), and thrombomodulin (TM); reduced the levels of protein C (PC) and activated protein C (aPC); and downregulated hepatic expression of PC and TM. The preadministration of hemin to septic mice increased the expression and activity of HO-1; inhibited thrombosis in the preceding 3 organs; prolonged PT and APTT; inhibited the production of TNF-α and IL-6; upregulated the expression of PC and TM in livers; elevated the plasma levels of PC and aPC; and reduced the plasma levels of TM. In contrast, ZnPP showed opposite effects to hemin and reversed the effects of hemin by inhibiting the activity of HO-1. The administration of tricarbonyl dichloro ruthenium (II) dimer (CORM-2), which is a CO-releasing molecule, had a similar effect to hemin on thrombosis and the protein C system. The data indicate that the enhanced induction of HO-1 inhibits thrombus formation and affects the protein C system in sepsis.
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fei
authors.forename: Xianglin
authors.initials: X
authors.lastname: Meng
authors.forename: Mingran
authors.initials: M
authors.lastname: Zhao
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.forename: Gang
authors.initials: G
authors.lastname: Tan
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Luo
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Chuanchuan
authors.initials: C
authors.lastname: Nan
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhao
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006427:Hemin / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000008:administration & dosage; D011486:Protein C / Q000032:analysis / Q000378:metabolism*; D011524:Protoporphyrins / Q000008:administration & dosage; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism; D018180:Thrombomodulin / Q000097:blood; D013927:Thrombosis / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015850:Interleukin-6; D009942:Organometallic Compounds; D011486:Protein C; D011524:Protoporphyrins; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; C017803:zinc protoporphyrin; D006427:Hemin; D051547:Heme Oxygenase-1