metallothionein and Respiratory-Distress-Syndrome

Among putative small molecules that affect sensitivity to acute lung injury, zinc and nitric oxide are potentially unique by virtue of their interdependence and dual capacities to be cytoprotective or injurious. Nitric oxide and zinc appear to be linked via an intracellular signaling pathway involving S-nitrosation of metallothoinein--itself a small protein known to be an important inducible gene product that may modify lung injury. In the present article, we summarize recent efforts using genetic and fluorescence optical imaging techniques to: (1) demonstrate that S-nitrosation of metallothionein affects intracellular zinc homeostasis in intact pulmonary endothelial cells; and (2) reveal a protective role for this pathway in hyperoxic and LPS-induced injury.

Topics: Animals; Apoptosis; Homeostasis; Humans; Lung; Metallothionein; Nitric Oxide; Respiratory Distress Syndrome; Signal Transduction; Zinc

Often fatal, acute lung injury has a complicated etiology. Previous studies from our laboratory in mice have demonstrated that survival during acute lung injury is a complex trait governed by multiple loci. We also found that the increase in metallothionein (MT) is one of the greatest noted in transcriptome-wide analyses of gene expression. To assess the role of MT in nickel-induced acute lung injury, the survival of Mt-transgenic, Mt1/2(+/+), and Mt1/2(-/-) mice was compared. Pulmonary inflammation and global gene expression were compared in Mt1/2(+/+) and Mt1/2(-/-) mice. Gene-targeted Mt1/2(-/-) mice were more susceptible than Mt1/2(+/+) mice to nickel-induced inflammation, surfactant-associated protein B transcript loss, and lethality. Similarly, Mt-transgenic mice exhibited increased survival. MAPPFinder analyses also noted significant decreases in genes involved in protein processing (e.g., ubiquitination, folding), which were greater in Mt1/2(-/-) mice as compared with Mt1/2(+/+) mice early in the progression of acute lung injury, possibly due to a zinc-mediated transcript destabilization. In contrast, transcript levels of genes associated with the inflammatory response, extracellular matrix regulation, and coagulation/fibrinolysis were increased more in Mt1/2(-/-) mice as compared with Mt1/2(+/+) mice late in the development of acute lung injury. Thus, MT ultimately improves survival in the progression of acute lung injury in mice. Transcriptome-wide analysis suggests that this survival may be mediated through changes in the destabilization of transcripts associated with protein processing, the subsequent augmentation of transcripts controlling inflammation, extracellular matrix regulation, coagulation/fibrinolysis, and disruption of surfactant homeostasis.

Topics: Animals; Disease Progression; Gene Expression Profiling; Gene Expression Regulation; Humans; Metallothionein; Mice; Mice, Inbred Strains; Mice, Knockout; Nickel; Oligonucleotide Array Sequence Analysis; Respiratory Distress Syndrome; Survival Rate

To monitor the systemic gene expression profile in a murine model of lipopolysaccharide-induced acute lung injury.. Acute lung injury was induced by intratracheal injection of lipopolysaccharide in 3 mice. Another 3 normal mice receiving same volume of normal saline were taken as the controls. The comprehensive gene expression profile was monitored by the recently modified long serial analysis of gene expression.. A total of 24,670 tags representing 12,168 transcripts in the control mice and 26,378 tags representing 13,397 transcripts in the mice with lung injury were identified respectively. There were 11 transcripts increasing and 7 transcripts decreasing more than 10 folds in the lipopolysaccharide-treated mice. The most overexpressed genes in the mice with lung injury included serum amyloid A3, metallothionein 2, lipocalin 2, cyclin-dependent kinase inhibitor 1A, lactate dehydrogenase 1, melatonin receptor, S100 calcium-binding protein A9, natriuretic peptide precursor, etc. Mitogen activated protein kinase 3, serum albumin, complement component 1 inhibitor, and ATP synthase were underexpressed in the lung injury mice.. Serial analysis of gene expression provides a molecular characteristic of acute lung injury.

Topics: Animals; Cyclin-Dependent Kinases; Disease Models, Animal; DNA-Binding Proteins; Gene Expression; Gene Expression Profiling; Lipopolysaccharides; Male; Metallothionein; Mice; Mice, Inbred C57BL; Neoplasm Proteins; Nuclear Proteins; Nucleophosmin; Protein Folding; Reference Values; Respiratory Distress Syndrome; S100 Proteins; Serum Amyloid A Protein