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Published ahead of print on September 15, 2005, doi:10.1165/rcmb.2005-0248OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 1, January 2006, 73-82

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Submitted on July 6, 2005
Revised on September 6, 2005

The Role of Metallothionein in the Pathogenesis of Acute Lung Injury

Scott C Wesselkamper1, Susan A McDowell2, Mario Medvedovic1, Timothy P Dalton1, Hitesh S Deshmukh1, Maureen A Sartor1, Lisa M Case1, Lisa N Henning1, Michael T Borchers3, Craig R Tomlinson1, Daniel R Prows4, and George D Leikauf3*

1 Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH, USA, 2 Department of Biology, Ball State University, Muncie, IN, USA, 3 Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH, USA; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA, 4 Department of Pediatrics, Division of Human Genetics, Children's Hospital Medcial Center, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: george.leikauf{at}uc.edu.

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 metallothionein (MT) is one of the greatest increases 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 nickelinduced inflammation, surfactant associated protein B (SFTPB) 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 to 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 to 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 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 and fibrinolysis, and disruption of surfactant homeostasis.




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