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Am J Physiol Lung Cell Mol Physiol (June 5, 2002). doi:10.1152/ajplung.00061.2002
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Articles in PresS, published online ahead of print June 5, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00061.2002
Submitted on February 15, 2002
Accepted on May 16, 2002

Proteoglycan expression in bleomycin lung fibroblasts: Role of transforming growth factor-ß1 and interferon-{gamma}

Narayanan Venkatesan1, Roughley J. Peter2, and Ludwig S. Mara1*

1 Medicine/Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada
2 Genetics Unit, Shriners Hospital for Crippled Children, McGill University, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: mara.ludwig{at}mcgill.ca.

Bleomycin (BM)-induced pulmonary fibrosis results in excess production of proteoglycans (PGs). Because transforming growth factor-ß1 (TGF-ß1) promotes fibrosis, and interferon-{gamma} (IFN-{gamma}) inhibits it, we hypothesized that TGF-ß1 treatment would upregulate PG production in fibrotic lung fibroblasts, and IFN-{gamma} would abrogate this effect. Primary lung fibroblasts cultures were established from rats 14 days after saline (CON) or BM (1.5 U) injection. PGs were extracted and subject to Western blot analysis. Bleomycin-exposed lung fibroblasts (BLF) exhibited increased production of versican (VS), heparan sulfate proteoglycan (HSPG) and biglycan (BG) as compared to normal lung fibroblasts (NLF). Compared to NLF, BLF released significantly increased amounts of TGF-ß1. TGF-ß1 (5 ng/ml x 48 hr) upregulated PG expression in both BLF and NLF. Incubation of BLF with anti-TGF-ß antibody (1, 5, 10 µg/ml) inhibited PG expression in a dose-dependent manner. Treatment of BLF with IFN-{gamma} (500 U/ml/48 h) reduced VS, HSPG and BG expression. Furthermore, IFN-{gamma} inhibited TGF-ß1-induced increases in PG expression by these fibroblasts. Activation of fibroblasts by TGF-ß1 promotes abnormal deposition of PGs in fibrotic lungs; downregulation of TGF-ß1 by IFN-{gamma} may have potential therapeutic benefits in this disease.




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