metallothionein and Hyperoxia

Superoxide formation in pulmonary tissue is modulated by cytokines, PO2, shear force, and disease states, and can be stimulated by drugs. Superoxide has diverse actions on pulmonary cells, including smooth muscle contraction, interaction with redox enzymes, cell proliferation, and gene transcription. In the lungs, there is an impressive array of specific defence mechanisms that destroy superoxide, especially superoxide dismutase (SOD) and metallothionein. Superoxide formation is increased in hyperoxia (e.g., oxygen therapy); however, superoxide-forming enzymes also can be up-regulated in hypoxia. Superoxide has been implicated in acute respiratory distress syndrome, lung ischaemia-reperfusion injury, and lung transplantation. Novel approaches to therapy have been explored, including SOD gene therapy and SOD targeting to the lung. In the future, new drugs interacting with superoxide may provide significant advances in the treatment of lung diseases.

Topics: Animals; Cell Division; Cell Membrane Permeability; Genetic Therapy; Humans; Hyperoxia; Hypoxia; Lung Diseases; Metallothionein; Pulmonary Artery; Reperfusion Injury; Superoxide Dismutase; Superoxides; Transcription, Genetic

Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ~4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury.

Topics: Acute Lung Injury; Animals; Female; Hyperoxia; Inflammation; Liver; Lung; Metallothionein; Mice; Mice, Knockout; Microtubule-Associated Proteins; Respiratory Mucosa; Superoxide Dismutase; Zinc

We investigate the aging effects of the hyperoxia-mediated induction of two antioxidants and three antioxidant enzymes in the rat brain. All of these genes responded to hyperoxia in young but not aged brains. Despite the partial inactivation of CuZn SOD and glutathione peroxidase by hyperoxia in aged rat brains, lipid peroxidation did not increase. The higher growth inhibitory factor (GIF) content in aged rat brains may be utilized as an antioxidant during hyperoxia.

Topics: Age Factors; Aging; Animals; Brain; Brain Chemistry; Female; Glutathione Peroxidase; Hyperoxia; Metallothionein; Metallothionein 3; Nerve Tissue Proteins; Oxygen; Rats; RNA, Messenger; Superoxide Dismutase; Time Factors

Ceruloplasmin, metallothionein, and ferritin are metal-binding proteins with potential antioxidant activity. Despite evidence that they are upregulated in pulmonary tissue after oxidative stress, little is known regarding their influence on trace metal homeostasis. In this study, we have used copper- and zinc-containing superoxide dismutase (Cu/Zn SOD) transgenic-overexpressing and gene knockout mice and hyperoxia to investigate the effects of chronic and acute oxidative stress on the expression of these metalloproteins and to identify their influence on copper, zinc, and iron homeostasis. We found that the oxidative stress-mediated induction of ceruloplasmin and metallothionein in the lung had no effect on tissue levels of copper, iron, or zinc. However, Cu/Zn SOD expression had a marked influence on hepatic copper and iron as well as circulating copper homeostasis. These results suggest that ceruloplasmin and metallothionein may function as antioxidants independent of their role in trace metal homeostasis and that Cu/Zn SOD functions in copper homeostasis via mechanisms distinct from its superoxide scavenging properties.

Topics: Animals; Antioxidants; Ceruloplasmin; Copper; Ferritins; Homeostasis; Hyperoxia; Iron; Liver; Lung; Male; Metalloproteins; Metallothionein; Mice; Mice, Knockout; Superoxide Dismutase; Zinc