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Am J Respir Crit Care Med. 2005 Dec 1;172(11):1399-411. Epub 2005 Aug 11.

Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.

Author information

1
Department of Environmental Health, P.O. Box 670056, University of Cincinnati, Cincinnati, OH 45267-0056, USA. george.leikauf@uc.edu

Abstract

RATIONALE:

Acute lung injury can occur 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 after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-beta1 protein in bronchoalveolar lavage 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 after 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 after nickel exposure, and TGF-beta1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-beta attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-beta1 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.

PMID:
16100012
PMCID:
PMC2718437
DOI:
10.1164/rccm.200502-286OC
[Indexed for MEDLINE]
Free PMC Article

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