期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 29, 期 5, 页码 583-590出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2002-0315OC
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资金
- NHLBI NIH HHS [HL-28737, HL-48730, HL-67100, HL-52285] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL067100, R37HL028737, R01HL052285, R01HL048730, R29HL048730, R37HL048730, R01HL028737] Funding Source: NIH RePORTER
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-incluced 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 SRFDelta5, a less myogenic SRF isoform. Before myofibroblast differentiation, SRF/SRFDelta5 was immunolocalized mostly in the cytoplasm of scattered fibroblasts at lesion sites. With the development of myofibroblasts, however, SRF/SRFDelta5 was found in myofibroblast nuclei. cDNA array analysis showed that SRFDelta5 and SRF induced expression of transforming growth factor-beta1, 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 SRFDelta5 expression and SRF/SRFDelta5 cytoplasmic accumulation, whereas addition of transforming growth factor-beta1 caused SRF/SRFDelta5 nuclear translocation followed by SM alpha-actin synthesis. Interieukin-4, another cytokine involved in myofibroblast differentiation, did not affect SRF or induce SRFDelta5 expression. Our studies therefore suggested a new mechanism whereby SRF and SRFDelta5 contribute to the emergence of myofibroblasts in lung injury and fibrosis.
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