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Published ahead of print on May 30, 2003, doi:10.1165/rcmb.2002-0315OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 583-590, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0315OC

Involvement of Serum Response Factor Isoforms in Myofibroblast Differentiation During Bleomycin-Induced Lung Injury

Yan Yang*, Xiaoning Zhe*, Sem H. Phan, Matt Ullenbruch and Lucia Schuger

Department of Pathology, Wayne State University School of Medicine, Detroit; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

Address correspondence to: Lucia Schuger, M.D., Department of Pathology, Wayne State University, 540 E. Canfield St., Rm. 9248, Detroit, MI 48201. E-mail: lschuger{at}med.wayne.edu

Serum response factor (SRF) is a transcription factor essential for smooth muscle (SM) myogenesis. Its role in myofibroblast differentiation is, however, unknown. We studied the expression and the localization of SRF in bleomycin-induced pulmonary fibrosis, where myofibroblasts are abundant. We found that SRF levels were upregulated in bleomycin-exposed mouse lungs mainly due to de novo synthesis of SRF{Delta}5, a less myogenic SRF isoform. Before myofibroblast differentiation, SRF/SRF{Delta}5 was immunolocalized mostly in the cytoplasm of scattered fibroblasts at lesion sites. With the development of myofibroblasts, however, SRF/SRF{Delta}5 was found in myofibroblast nuclei. cDNA array analysis showed that SRF{Delta}5 and SRF induced expression of transforming growth factor-ß1, a critical factor in myofibroblast differentiation. This was accompanied by de novo expression of several inflammatory cell-specific mRNAs. The latter was confirmed by reverse transcriptase–polymerase chain reaction. Treatment of lung fibroblasts with tumor necrosis factor-{alpha}, which is produced early in the bleomycin model, induced SRF{Delta}5 expression and SRF/SRF{Delta}5 cytoplasmic accumulation, whereas addition of transforming growth factor-ß1 caused SRF/SRF{Delta}5 nuclear translocation followed by SM {alpha}-actin synthesis. Interleukin-4, another cytokine involved in myofibroblast differentiation, did not affect SRF or induce SRF{Delta}5 expression. Our studies therefore suggested a new mechanism whereby SRF and SRF{Delta}5 contribute to the emergence of myofibroblasts in lung injury and fibrosis.

Abbreviations: Dulbecco's Modified Eagle Media, DMEM • extracellular matrix, ECM • fetal bovine serum, FBS • interleukin, IL • matrix metalloproteinases, MMPs • plasma-derived sera, PDS • p-selectin glycoprotein ligand-1, PSGL-1 • reverse transcriptase–polymerase chain reaction, RT-PCR • serum response factor, SRF • smooth muscle, SM • tissue inhibitor of metalloproteinases, TIMPs • transforming growth factor-ß, TGF-ß • tumor necrosis factor-{alpha}, TNF-{alpha}




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