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

Am J Respir Cell Mol Biol. 2007 Sep;37(3):309-21. doi: 10.1165/rcmb.2006-0455OC. Epub 2007 May 11.

Abstract

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 after 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Pressure
  • Doxycycline / pharmacology
  • Extracellular Matrix / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertrophy, Right Ventricular / genetics
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / physiopathology
  • Lung / blood supply
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / pathology
  • Pulmonary Fibrosis / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Respiratory Mechanics
  • Transforming Growth Factor alpha / genetics*
  • Transforming Growth Factor alpha / physiology

Substances

  • RNA, Messenger
  • Transforming Growth Factor alpha
  • Doxycycline