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Interferon-? enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation.

ABSTRACT: BACKGROUND:Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple pathways, and combined antifibrotic therapy is needed for future IPF therapy. Inhaled interferon-? (IFN-?) was recently shown to be safe and without systemic effects in patients with IPF. AIM:To examine the in vitro effects of individual and combined treatment with IFN-? and pirfenidone (PFD) on normal and IPF fibroblast activation and extracellular matrix remodeling after TGF-?1 and PDGF-BB stimulation. METHODS:IPF and normal human lung fibroblasts (NHLF) were treated with IFN-?, PFD or a combination of both drugs in the presence of either TGF-?1 or PDGF-BB. The effects of TGF-?1 and PDGF-BB treatment on cell viability, proliferation, differentiation and migration were examined. The expression of collagen 1, matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) was analyzed using qPCR, Western blotting and gelatin zymography. Total collagen content in conditioned media was also measured using a Sircol assay. RESULTS:Compared to that of PFD, the effect of IFN-? in downregulating normal and IPF lung fibroblast differentiation to myofibroblasts in response to TGF-?1 was more potent. Importantly, the combination of IFN-? and PFD had a possibly synergistic/additive effect in inhibiting the TGF-?1- and PDGF-BB-induced proliferation, migration and differentiation of normal and IPF lung fibroblasts. Furthermore, both drugs reversed TGF-?1-induced effects on MMP-1, -?2, -?3, -?7, and?-?9, while only PFD promoted TIMP-1 and-2 expression and release. CONCLUSIONS:Our findings demonstrate that the antifibrotic effects of IFN-? and PFD on normal and IPF lung fibroblasts are different and complementary. Combination therapy with inhaled IFN-? and PFD in IPF is promising and should be further explored in IPF clinical trials.

SUBMITTER: Vu TN

PROVIDER: S-EPMC6737625 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Interferon-γ enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation.

Vu Tuong N TN Chen Xuesong X Foda Hussein D HD Smaldone Gerald C GC Hasaneen Nadia A NA

Respiratory research 20190911 1

<h4>Background</h4>Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple pathways, and combined antifibrotic therapy is needed for future IPF therapy. Inhaled interferon-γ (IFN-γ) was recently shown to be safe and without systemic effects in patients with IPF.<h4>Aim</h4>To examine the in vitro effects of individual and combined treatment with IFN-γ and pirfenidone (PFD) on normal and IPF fibroblast activation and extracellular matrix remodeling after TGF-β1 and PDGF-BB stimulation. ...[more]

PMID: 31511015

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared the effects of pirfenidone with the pan-HDAC-inhibitor panobinostat/LBH589, a FDA-approved drug for the treatment of multiple myeloma, head-to-head on survival, fibrotic activity and proliferation of primary IPF-fibroblasts in vitro.MethodsPrimary fibroblasts from six IPF-patients were incubated for 24h with vehicle (0.25% DMSO), panobinostat (LBH589, 85 nM) or pirfenidone (2.7 mM), followed by assessment of proliferation and expression analyses for profibrotic and anti-apoptosis genes, as well as for ER stress and apoptosis-markers. In addition, the expression status of all HDAC enzymes was examined.ResultsTreatment of IPF-fibroblasts with panobinostat or pirfenidone resulted in a downregulated expression of various extracellular matrix (ECM)-associated genes, as compared to vehicle-treated cells. In agreement, both drugs decreased protein level of phosphorylated (p)-STAT3, a transcription factor mediating profibrotic responses, in treated IPF-fibroblasts. Further, an increase in histone acetylation was observed in response to both treatments, but was much more pronounced and excessive in panobinostat-treated IPF-fibroblasts. Panobinostat, but not pirfenidone, led to a significant suppression of proliferation in IPF-fibroblasts, as indicated by WST1- and BrdU assay and markedly diminished levels of cyclin-D1 and p-histone H3. Furthermore, panobinostat-treatment enhanced ?-tubulin-acetylation, decreased the expression of survival-related genes Bcl-XL and BIRC5/survivin, and was associated with induction of ER stress and apoptosis in IPF-fibroblasts. In contrast, pirfenidone-treatment maintained Bcl-XL expression, and was neither associated with ER stress-induction nor any apoptotic signaling. Pirfenidone also led to increased expression of HDAC6 and sirtuin-2, and enhanced ?-tubulin-deacetylation. But in line with its ability to increase histone acetylation, pirfenidone reduced the expression of HDAC enzymes HDAC1, -2 and -9.ConclusionsWe conclude that, beside other antifibrotic mechanisms, pirfenidone reduces profibrotic signaling also through STAT3 inactivation and weak epigenetic alterations in IPF-fibroblasts, and permits survival of (altered) fibroblasts. The pan-HDAC-inhibitor panobinostat reduces profibrotic phenotypes while inducing cell cycle arrest and apoptosis in IPF-fibroblasts, thus indicating more efficiency than pirfenidone in inactivating IPF-fibroblasts. We therefore believe that HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF.

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Interferon-? enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation.

Publications

Interferon-γ enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation.

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