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Identification of Transforming Growth Factor β1–Driven Genetic Programs of Acute Lung Fibrosis

¹ Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada; ² Merck Research Laboratories, Rahway, New Jersey; ³ Rosetta Inpharmatics, Seattle, Washington; ⁴ Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut

Correspondence and requests for reprints should be addressed to Camil E. Sayegh, PhD, 16711 TransCanada Highway, Kirkland, PQ, H9H 3L1 Canada. E-mail: camil_sayegh{at}merck.com

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–β (TGF-β), a central growth factor implicated in most fibroproliferative diseases. Recently, enforced expression of bioactive human TGF-β1 (hTGF-β1) 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-β1 in this system provided a unique opportunity to characterize TGF-β–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-β1. We observe significant TGF-β1–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.

Key Words: TGF-β • lung fibrosis • gene expression profiling • alternatively activated macrophages • arginase

CLINICAL RELEVANCE To our knowledge, this is the most extensive analysis of TGF-β–mediated events in the lung. We identified several key genetic programs that precede or occur during the fibrotic response. We extended our findings to published mouse and human studies.