metallothionein and Multiple-Organ-Failure

We explored the hypothesis that marked decline in plasma zinc concentrations among critically ill children is related to shifts in metallothionein expression and inflammation.. Prospective pilot study.. Intensive care unit of tertiary care children's hospital.. All children (<18 yrs) with unadjusted Pediatric Risk of Mortality III score >5 or at least one organ failure admitted to the pediatric intensive care unit from March through August 2006 were eligible for enrollment.. After consent, blood samples were collected on days 1 and 3 of illness and analyzed for serum chemistries, plasma zinc and copper levels, metallothionein isoform expression, and cytokine levels.. Twenty patients were enrolled, with median age of 2.9 yrs (interquartile range, 0.7-10.1). Male to female ratio was 1.2:1. All patients had low zinc levels (mean, 0.43; range, 0.26-0.66 mug/dL) on day 1 of pediatric intensive care unit admission, and remained low (mean, 0.51; range, 0.26-0.81 mug/dL) on day 3, even when corrected for hypoalbuminemia. In comparison, serum copper levels were normal. On day 1, there was a positive correlation between zinc levels and expression of MT-1A (p < 0.01), MT-1G (p = 0.02), and MT-1H (p = 0.03). Plasma zinc levels correlated inversely with C-reactive protein levels (r = -.75, p = 0.01) and interleukin-6 levels (r = -.53, p = 0.04) on day 3. On day 3, patients with two or more organ failures had significantly lower plasma zinc concentrations compared with patients with

Topics: Albumins; Blood Chemical Analysis; Child; Child, Preschool; Copper; Critical Illness; Female; Homeostasis; Humans; Infant; Inflammation Mediators; Intensive Care Units, Pediatric; Interleukin-6; Linear Models; Male; Metallothionein; Multiple Organ Failure; Pilot Projects; Probability; Prospective Studies; Sensitivity and Specificity; Survival Rate; Zinc

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.

Topics: Animals; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL2; Chemotactic Factors; Cytokines; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Inflammation; Interleukin-1; Interleukin-6; Kidney; Lipopolysaccharides; Liver; Lung; Macrophage Inflammatory Proteins; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Monokines; Multiple Organ Failure; Neutrophils; Systemic Inflammatory Response Syndrome; Thrombophilia