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Published ahead of print on August 11, 2005, doi:10.1164/rccm.200502-286OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 11, December 2005, 1399-1411

A more recent version of this article appeared on December 1, 2005
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Submitted on February 22, 2005
Accepted on August 9, 2005

Gene Expression Changes During the Development of Acute Lung Injury: Role of TGF-{beta}

Scott C Wesselkamper1, Lisa M Case1, Lisa N Henning1, Michael T Borchers2, Jay W Tichelaar1, John M Mason1, Nadine Dragin1, Mario Medvedovic1, Maureen A Sartor1, Craig R Tomlinson1, and George D Leikauf2*

1 Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA, 2 Department of Environmental Health, Center for Environmental Genetics, 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

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

Rationale: Acute lung injury occurs from multiple causes resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain. Objectives: To integrate molecular pathways and investigate the role of transforming growth factor-beta (TGF-{beta}) in acute lung injury in mice. Methods: cDNA microarray analyses were used to identify lung gene expression changes following nickel exposure. MAPPFinder analysis of the microarray data was utilized to determine significantly altered molecular pathways. TGF-{beta}1 protein in bronchoalveolar lavage (BAL) fluid, as well as the effect of inhibition of TGF-{beta}, was assessed in nickel-exposed mice. The effect of TGF-{beta} on surfactant associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells. Measurements and Main Results: Genes that decreased the most following nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-{beta} signaling. MAPPFinder analysis further established TGF-{beta} signaling to be significantly altered. TGF-{beta}-inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased following nickel exposure, and TGF-{beta}1 protein was also increased in the lavage fluid. Pharmacological inhibition of TGF-{beta} attenuated nickel-induced protein in BAL. Additionally, treatment with TGF-{beta}1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-{beta} responsive region in the Sftpb promoter was identified. Conclusions: These data suggest that TGF-{beta} acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.
Key words: acute lung injury, transforming growth factor-beta, microarray, fibrinolysis, surfactant protein B




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