Genomic profile of matrix and vasculature remodeling in TGF-α-induced pulmonary fibrosis

William D. Hardie*, Thomas R. Korfhagen, Maureen A. Sartor, Adrienne Prestridge, Mario Medvedovic, Timothy D. Le Cras, Machiko Ikegami, Scott C. Wesselkamper, Cynthia Davidson, Maggie Dietsch, William Nichols, Jeffrey A. Whitsett, George D. Leikauf

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Expression of transforming growth factor α (TGF-α) 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 after TGF-α expression and revealed changes consistent with a role for TGF-α 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 TCF-α 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 TCF-α were similar to those altered in the lungs of patients with idiopathic pulmonary fibrosis. These studies support a role for epithelial cell-derived TCF-α in the regulation of processes that alter the airway and vascular architecture and function.

Original languageEnglish (US)
Pages (from-to)309-321
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume37
Issue number3
DOIs
StatePublished - Sep 2007

Keywords

  • Angiogenesis
  • Epidermal growth factor receptor
  • Idiopathic pulmonary fibrosis
  • Interstitial lung disease
  • Vasculogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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