This Article Full Text Full Text (PDF) All Versions of this Article: 200502-286OCv1 172/11/1399    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wesselkamper, S. C. Articles by Leikauf, G. D. Search for Related Content PubMed PubMed Citation Articles by Wesselkamper, S. C. Articles by Leikauf, G. D.

Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor

Department of Environmental Health, Center for Environmental Genetics, and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Cincinnati Medical Center, University of Cincinnati, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to George D. Leikauf, Ph.D., Department of Environmental Health, P.O. Box 670056, University of Cincinnati, Cincinnati, OH 45267-0056. E-mail: george.leikauf{at}uc.edu

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 (TGF-) 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-1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-, was assessed in nickel-exposed mice. The effect of TGF- 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- signaling. MAPPFinder analysis further established TGF- signaling to be significantly altered. TGF-–inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF- attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-–responsive region in the Sftpb promoter was identified.

Conclusions: These data suggest that TGF- acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.

Key Words: microarray • surfactant • fibrinolysis • extracellular matrix

This article has been cited by other articles:

				M. T. Borchers, S. C. Wesselkamper, B. L. Eppert, G. T. Motz, M. A. Sartor, C. R. Tomlinson, M. Medvedovic, and J. W. Tichelaar Nonredundant Functions of {alpha}{beta} and {gamma}{delta} T Cells in Acrolein-Induced Pulmonary Pathology Toxicol. Sci., September 1, 2008; 105(1): 188 - 199. [Abstract] [Full Text] [PDF]

				C. C. Lewis, J. Y. H. Yang, X. Huang, S. K. Banerjee, M. R. Blackburn, P. Baluk, D. M. McDonald, T. S. Blackwell, V. Nagabhushanam, W. Peters, et al. Disease-Specific Gene Expression Profiling in Multiple Models of Lung Disease Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 376 - 387. [Abstract] [Full Text] [PDF]

				K. Ganguly, T. Stoeger, S. C. Wesselkamper, C. Reinhard, M. A. Sartor, M. Medvedovic, C. R. Tomlinson, I. Bolle, J. M. Mason, G. D. Leikauf, et al. Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure Physiol Genomics, November 14, 2007; 31(3): 410 - 421. [Abstract] [Full Text] [PDF]

				J. K. Dunnick, K. A. Thayer, and G. S. Travlos Inclusion of Biomarkers for Detecting Perturbations in the Heart and Lung and Lipid/Carbohydrate Metabolism in National Toxicology Program Studies Toxicol. Sci., November 1, 2007; 100(1): 29 - 35. [Abstract] [Full Text] [PDF]

				D. M. Guidot, H. G. Folkesson, L. Jain, J. I. Sznajder, J.-F. Pittet, and M. A. Matthay Integrating acute lung injury and regulation of alveolar fluid clearance Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L301 - L306. [Abstract] [Full Text] [PDF]

				E. B. Milbrandt, A. Ishizaka, and D. C. Angus Update in critical care 2005. Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 833 - 841. [Full Text] [PDF]