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Published ahead of print on May 30, 2003, doi:10.1165/rcmb.2002-0315OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 5, November 2003, 583-590

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Submitted on December 27, 2002
Revised on May 28, 2003

Involvement of SRF Isoforms in Myofibroblast Differentiation During Bleomycin-Induced Lung Injury

Yan Yang1, Xiaoning Zhe2, Sem H Phan3, Matt Ullenbruch3, and Lucia Schuger2*

1 Pathology, Wayne State University School of Medicine, Detroit, MI, USA; Human Genome Sciences, Inc., Rockville, MD, USA, 2 Pathology, Wayne State University School of Medicine, Detroit, MI, USA, 3 Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

* To whom correspondence should be addressed. 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. Here 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. Prior to 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 TGF-{beta}1, a critical factor in myofibroblast differentiation. This was accompanied by de novo expression of several inflammatory cell-specific mRNAs. The latter was confirmed by RT-PCR. Treatment of lung fibroblasts with TNF-{alpha}, which is produced early in the bleomycin model, induced SRF{Delta}5 expression and SRF/SRF{Delta}5 cytoplasmic accumulation, whereas addition of TGF-{beta}1 caused SRF/SRF{Delta}5 nuclear translocation followed by SM {alpha}-actin synthesis. IL-4, another cytokine involved in myofibroblast differentiation did not affect SRF or induce SRF{Delta}5 expression. Our studies therefore suggested a new mechanism thereby SRF and SRF{Delta}5 contribute to the emergence of myofibroblasts in lung injury and fibrosis.




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