Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by peripheral lung fibrosis and increased interstitial extracellular matrix (ECM) deposition. In IPF, tumor growth factor (TGF)-β1 which is the major stimulus of ECM deposition, and platelet derived growth factor (PDGF)-BB is a potent stimulus of fibrosis. Thus, the effect of Treprostinil on TGF-ß1 and PDGF-induced fibroblast proliferation and ECM deposition was investigated. Human peripheral lung fibroblasts of seven IPF patients and five lung donors were stimulated by PDGF, or TGF-β1, or the combination. Cells were pre-incubated (30 min) with either Treprostinil, forskolin, di-deoxyadenosine (DDA), or vehicle. Treprostinil time dependently activated cAMP thereby preventing PDGF-BB induced proliferation and TGF-β1 secretion. Cell counts indicated proliferation; α-smooth muscle actin (α-SMA) indicted differentiation, and collagen type-1 or fibronectin deposition remodeling. Myo-fibroblast indicating α-SMA expression was significantly reduced and its formation was altered by Treprostinil. Collagen type-I and fibronectin deposition were also reduced by Treprostinil. The effect of Treprostinil on collagen type-I deposition was cAMP sensitive as it was counteracted by DDA, while the effect on fibronectin was not cAMP mediated. Treprostinil antagonized the pro-fibrotic effects of both PDGF-BB and TGF-β1 in primary human lung fibroblasts. The data presented propose a therapeutic relevant anti-fibrotic effect of Treprostinil in IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and devastating interstitial lung disease resulting in a high mortality rate with limited treatment options[1,2]
In order to understand the interactions of tumor growth factor (TGF)-β1 and platelet derived growth factor (PDGF)-BB, we investigated the effect of PDGF-BB on the secretion of active TGF-β1 and of total connective tissue growth factor (CTGF), by the two fibroblast types
DDA treatment counteracted the inhibitory effect of Treprostinil on PDGF-BB induced TGF-β1 activation and CTGF secretion suggesting a role of cyclic AMP (cAMP) in its signaling action (Fig. 1c,d)
Summary
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and devastating interstitial lung disease resulting in a high mortality rate with limited treatment options[1,2]. The tyrosine kinase inhibitor nintedanib targeting the PDGF, VEGF and FGF signaling cascades induced an anti-fibrotic effect and counteracted TGF-ß induced ECM secretion in IPF8. Two new anti-fibrotic compounds, pirfenidone and nintedanib, were licensed for IPF treatment Both drugs have a clinically documented efficacy on disease progression and target specific receptor linked protein kinases[9,10,11]. In smooth muscle cells which expressed the prostaglandin EP-2 receptor, Treprostinil elevated cyclic AMP (cAMP), but had low activity on the other receptor types. These effects of Treprostinil were different from another prostaglandin analogue Iloprost[19]. The effect of Treprostinil on fibroblast remodeling and differentiation parameters, collagen type-I, fibronectin and α-SMA was assessed
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