Identification of Transforming Growth Factor β1–Driven Genetic Programs of Acute Lung Fibrosis
| Autor: | Anne-Marie Pulichino, James R. Mortimer, I-Ming Wang, Yves Boie, Jack A. Elias, Lijing Xu, Anick Auger, Alexandre Caron, Camil E. Sayegh, Aileen Kartono, Joseph Menetski |
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| Rok vydání: | 2008 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pulmonary Fibrosis medicine.medical_treatment Clinical Biochemistry Mice Transgenic Inflammation Biology Transforming Growth Factor beta1 Extracellular matrix Bleomycin Mice Fibrosis medicine Animals Humans Lung Molecular Biology Gene Expression Profiling Growth factor Cell Biology Macrophage Activation Flow Cytometry medicine.disease Gene expression profiling Chemotaxis Leukocyte Phenotype medicine.anatomical_structure Doxycycline Acute Disease Immunology Cancer research Chemokines medicine.symptom Bronchoalveolar Lavage Fluid Myofibroblast Transforming growth factor |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 39:324-336 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2007-0186oc |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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