Abstract
BackgroundIdiopathic 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.AimTo 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.MethodsIPF and normal human lung fibroblasts (NHLF) were treated with IFN-γ, PFD or a combination of both drugs in the presence of either TGF-β1 or PDGF-BB. The effects of TGF-β1 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.ResultsCompared to that of PFD, the effect of IFN-γ in downregulating normal and IPF lung fibroblast differentiation to myofibroblasts in response to TGF-β1 was more potent. Importantly, the combination of IFN-γ and PFD had a possibly synergistic/additive effect in inhibiting the TGF-β1- and PDGF-BB-induced proliferation, migration and differentiation of normal and IPF lung fibroblasts. Furthermore, both drugs reversed TGF-β1-induced effects on MMP-1, − 2, − 3, − 7, and − 9, while only PFD promoted TIMP-1 and-2 expression and release.ConclusionsOur findings demonstrate that the antifibrotic effects of IFN-γ and PFD on normal and IPF lung fibroblasts are different and complementary. Combination therapy with inhaled IFN-γ and PFD in IPF is promising and should be further explored in IPF clinical trials.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and patients with IPF exhibit poor survival and have limited therapeutic options [1, 2]
Our findings demonstrate that the antifibrotic effects of IFN-γ and PFD on normal and IPF lung fibroblasts are different and complementary
IFN-γ and PFD attenuate the proliferation of normal human lung fibroblasts (NHLF) and IPF fibroblasts in response to Transforming Growth Factor-β1 (TGF-β1) and Platelet Derived Growth Factor-BB (PDGF-BB) For in vitro experiments, we selected a range of IFN-γ (10–40 ng/mL) and PFD (100–500 μg/mL) concentrations similar to those used in published studies [38,39,40,41,42]
Summary
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and patients with IPF exhibit poor survival and have limited therapeutic options [1, 2]. Dysregulated wound healing is thought to cause the development of fibrosis through excess fibroblast proliferation, migration, and differentiation to myofibroblasts and extracellular matrix (ECM) deposition [3]. In the IPF lung, aggregates of proliferating fibroblasts and myofibroblasts, termed “fibroblast foci”, are a key histopathological finding that indicates ongoing fibrosis [4]. Targeting the inhibition of key fibroblast activities may lead to novel therapeutic approaches for IPF [5,6,7]. MMPs degrade all the components of the extracellular matrix, but they are able to release, cleave and activate a wide. Inhaled interferon-γ (IFN-γ) was recently shown to be safe and without systemic effects in patients with IPF
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