Identification of transforming growth factor beta1-driven genetic programs of acute lung fibrosis.
Lung fibrosis is characterized by excessive accumulation of extracellular matrix components leading to progressive airflow limitation. Distinct profibrotic pathways converge on the activation of transforming growth factor-beta (TGF-beta), a central growth factor implicated in most fibroproliferative diseases. Recently, enforced expression of bioactive human TGF-beta1 (hTGF-beta1) in lungs of transgenic mice was shown to recapitulate several key pathophysiologies observed in fibrotic disorders of the lung, including cellular inflammation, tissue fibrosis, and myofibroblast hyperplasia. Inducible expression of hTGF-beta1 in this system provided a unique opportunity to characterize TGF-beta-driven mechanisms that precede and/or follow the onset of inflammation and fibrosis. Using gene expression profiling in lungs, we demonstrate temporal activation of key genetic programs regulating cell movement and invasiveness, inflammation, organ remodeling, and fibrosis. Consistent with our gene expression data, multiple soluble mediators associated with inflammation and tissue remodeling were markedly elevated in the bronchoalveolar lavage fluid of mice expressing hTGF-beta1. We observe significant TGF-beta1-driven infiltration of F4/80+ mononuclear cells producing bioactive arginase, a marker of alternatively activated macrophages. Finally, we identified a common "fibrosis" gene signature when comparing our findings with published data derived from preclinical and clinical studies.
Pulichino
Anne-Marie
AM
Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.
Wang
I-Ming
IM
Caron
Alexandre
A
Mortimer
James
J
Auger
Anick
A
Boie
Yves
Y
Elias
Jack A
JA
Kartono
Aileen
A
Xu
Lijing
L
Menetski
Joseph
J
Sayegh
Camil E
CE
D000208:Acute Disease; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000235:genetics*; D002634:Chemotaxis, Leukocyte; D004318:Doxycycline / Q000008:administration & dosage; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008168:Lung / Q000378:metabolism; D008262:Macrophage Activation; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*
D018925:Chemokines; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D004318:Doxycycline