title: Role of metallothionein in coagulatory disturbance and systemic inflammation induced by lipopolysaccharide in mice.
abstract: Although metallothionein (MT) can be induced by inflammatory mediators, its roles in coagulatory disturbance during inflammation are poorly defined. We determined whether MT protects against coagulatory and fibrinolytic disturbance and systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) in MT-I/II null (-/-) and wild-type (WT) mice. As compared with WT mice, MT (-/-) mice revealed significant prolongation of prothrombin and activated partial thromboplastin time, a significant increase in the levels of fibrinogen and fibrinogen/fibrin degradation products, and a significant decrease in activated protein C, after LPS treatment. LPS induced inflammatory organ damages in the lung, kidney, and liver in both genotypes of mice. The damages, including neutrophil infiltration, were more prominent in MT (-/-) mice than in WT mice after LPS treatment. In both genotypes of mice, LPS enhanced protein expression of interleukin (IL)-1beta, IL-6, granulocyte/macrophage-colony-stimulating factor, macrophage inflammatory protein (MIP)-1alpha, MIP-2, macrophage chemoattractant protein-1, and keratinocyte chemoattractant in the lung, kidney, and liver and circulatory levels of IL-1beta, IL-6, MIP-2, and KC. In overall trends, however, the levels of these proinflammatory proteins were greater in MT (-/-) mice than in WT mice after LPS challenge. Our results suggest that MT protects against coagulatory and fibrinolytic disturbance and multiple organ damages induced by LPS, at least partly, via the inhibition of the expression of proinflammatory proteins.
authors.affiliation: Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Inoue
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Takano
authors.forename: Akinori
authors.initials: A
authors.lastname: Shimada
authors.forename: Emiko
authors.initials: E
authors.lastname: Wada
authors.forename: Rie
authors.initials: R
authors.lastname: Yanagisawa
authors.forename: Miho
authors.initials: M
authors.lastname: Sakurai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Satoh
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000503:physiopathology; D009504:Neutrophils / Q000473:pathology; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D019851:Thrombophilia / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; C491054:Mt2 protein, mouse; C482199:lipopolysaccharide, E coli O55-B5; C407523:metallothionein isoform 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008668:Metallothionein