title: Genomic profile of matrix and vasculature remodeling in TGF-alpha induced pulmonary fibrosis.
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.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio 45229, USA. william.hardie@cchmc.org
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Adrienne
authors.initials: A
authors.lastname: Prestridge
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: Cynthia
authors.initials: C
authors.lastname: Davidson
authors.forename: Maggie
authors.initials: M
authors.lastname: Dietsch
authors.forename: William
authors.initials: W
authors.lastname: Nichols
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004318:Doxycycline / Q000494:pharmacology; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015656:Respiratory Mechanics; D016211:Transforming Growth Factor alpha / Q000235:genetics* / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004318:Doxycycline