Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 48, Issue 5, Pages 550-558Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2012-0262OC
Keywords
E prostanoid receptor; transforming growth factor-beta 1; endothelin-1; alpha-smooth muscle actin; focal adhesion kinase
Funding
- National Heart, Lung, and Blood Institute [HL094311, HL094657]
- American Thoracic Society Coalition for Pulmonary Fibrosis/Pulmonary Fibrosis Foundation Research Grant
- American Lung Association Senior Fellowship Training Award
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Differentiation of fibroblasts into alpha-smooth muscle actin (SMA)-expressing myofibroblasts represents a critical step in the pathogenesis of fibrotic disorders, and is generally regarded as irreversible. Prostaglandin E-2 (PGE(2)) has been shown to prevent multiple aspects of fibroblast activation, including the differentiation of fibroblasts to myofibroblasts. Here, we investigated its ability to reverse this differentiated phenotype. Fetal and adult lung fibroblasts were induced to differentiate into myofibroblasts by 24-hour culture with transforming growth factor (TGF)-beta 1 or endothelin-1. Cells were then treated without or with PGE2 for various intervals and assessed for alpha-SMA expression. In the absence of PGE(2) treatment, alpha-SMA expression induced by TGF-beta 1 was persistent and stable for up to 8 days. By contrast, PGE(2) treatment effected a dose-dependent decrease in alpha-SMA and collagen I expression that was observed 2 days after PGE(2) addition, peaked at 3 days, and persisted through 8 days in culture. This effect was not explained by an increase in myofibroblast apoptosis, and indeed, reintroduction of TGF-beta 1 2 days after addition of PGE(2) prompted dedifferentiated fibroblasts to re-express alpha-SMA, indicating redifferentiation to myofibroblasts. This effect of PGE(2) was associated with inhibition of focal adhesion kinase signaling, and a focal adhesion kinase inhibitor was also capable of reversing myofibroblast phenotype. These data unambiguously demonstrate reversal of established myofibroblast differentiation. Because many patients have established or even advanced fibrosis by the time they seek medical attention, this capacity of PGE(2) has the potential to be harnessed for therapy of late-stage fibrotic disorders.
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