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Published ahead of print on May 11, 2007, doi:10.1165/rcmb.2006-0455OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 3, September 2007, 309-321

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Submitted on December 8, 2006
Revised on May 9, 2007

Genomic Profile of Matrix and Vasculature Remodeling in TGF {alpha}-induced Pulmonary Fibrosis

William D Hardie1*, Thomas R Korfhagen2, Maureen A Sartor3, Adrienne Prestridge4, Mario Medvedovic3, Timothy D Le Cras5, Machiko Ikegami5, Scott C Wesselkamper3, Cynthia Davidson6, Maggie Dietsch7, William Nichols8, Jeffrey A Whitsett5, and George D Leikauf3

1 Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University Of Cincinnati School of Medicine, Center of Environmental Genetics, Cincinnati, OH, USA, 2 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University Of Cincinnati School of Medicine, Center of Environmental Genetics, Cincinnati, OH, USA, 3 University Of Cincinnati School of Medicine, Center of Environmental Genetics, Cincinnati, OH, USA; University of Cincinnati School of Medicine, Center of Environmental Health, Cincinnati, OH, USA, 4 Division of Pulmonary Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, 5 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 6 Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 7 University of Cincinnati School of Medicine, Center of Environmental Health, Cincinnati, OH, USA, 8 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: william.hardie{at}cchmc.org.

Expression of transforming growth factor {alpha} (TGF{alpha}) in the respiratory epithelium of transgenic mice caused pulmonary fibrosis, cachexia, pulmonary hypertension and altered lung function. To identify genes and molecular pathways mediating lung remodeling, mRNA microarray analysis was performed at multiple times following TGF{alpha} expression and revealed changes consistent with a role for TGF{alpha} in the regulation of extracellular matrix and vasculogenesis. Transcripts for extracellular matrix proteins were augmented along with transcripts for genes previously identified to have roles in pulmonary fibrosis including tenascin C, osteopontin and serine (or cysteine) peptidase inhibitor, clade F, member 1. Transcripts regulating vascular processes including endothelin receptor type B, endothelial-specific receptor tyrosine kinase and caveolin, caveolae protein 1 were decreased. When TGF{alpha} expression was no longer induced, lung remodeling partially reversed and lung function and pulmonary hypertension normalized. Transcripts increased during resolution included midkine, matrix metalloproteinase 2 and hemolytic complement. Hierarchical clustering revealed that genes regulated by TGF{alpha} were similar to those altered in the lungs of patients with idiopathic pulmonary fibrosis. These studies support a role for epithelial cell-derived TGF{alpha} in the regulation of processes that alter the airway and vascular architecture and function.




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