The role of PPARs in lung fibrosis

Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
PPAR Research (Impact Factor: 1.64). 02/2007; 2007:71323. DOI: 10.1155/2007/71323
Source: PubMed


Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARα agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARα agonist significantly inhibited the fibrotic response, while PPARα knockout mice developed more serious fibrosis. PPARβ/δ appears to play a critical role in regulating the transition from inflammation to
wound healing. PPARβ/δ agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγ agonists. PPARγ ligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis.
PPARγ ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARα and PPARγ agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

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Available from: Thomas H Thatcher, Dec 12, 2013
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    • "Endogenous ligands include 15-deoxy−Δ12,14-pros- taglandin J2 (15d-PGJ2), lysophosphatidic acid, and nitrolinoleic acid. PPAR can also be activated by synthetic ligands including the thiazolidinediones (TZD) as well as oleanic acid derivatives known as triterpenoids (2-cyano-3,12-dioxool- ean-1,9-dien-28-oic-acid (CDDO)) [14]. The TZDs are highly potent PPAR agonists. "
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    ABSTRACT: Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPAR ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPAR function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPAR as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.
    Full-text · Article · May 2015 · PPAR Research
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    • "Idiopathic pulmonary fibrosis (IPF) is a specific kind of chronic, progressive fibrosing interstitial pneumonia of unknown origin and there is no sufficient evidence to support the use of any specific pharmacologic therapy (1, 2). To date, animal trials on therapeutic drugs for the treatment of IPF suggest a possible benefit, but most of these studies relied on the pathologic examination to establish the results (3, 4, 5, 6). Recently, micro-CT has become a useful imaging tool for the investigation of lung diseases in rats and mice, and it has been reported that findings of lung fibrosis on imaging correlated to pathologic findings (7, 8, 9, 10, 11). "
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    ABSTRACT: Objective The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. Materials and Methods We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. Results One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n = 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. Conclusion A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.
    Full-text · Article · Jul 2014 · Korean journal of radiology: official journal of the Korean Radiological Society
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    • "Evidence continues to accumulate indicating that natural and synthetic PPARγ ligands exert beneficial effects in experimental models of IPF [14], [15]. Mechanisms by which PPAR ligands exert their antifibrogenic effects are poorly understood but potentially involve numerous complementary pathways, including antagonism of TGF-β signaling, upregulation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and increased hepatocyte growth factor activity [29]. Specifically, PPARγ ligands have been shown to attenuate TGF-β1-driven differentiation of both pulmonary- and hepatic-derived fibroblasts to myofibroblasts [9]. "
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    ABSTRACT: Peroxisome proliferator activated receptor γ (PPARγ) agonists are effective antifibrotic agents in a number of tissues. Effects of these agents on epithelial-mesenchymal transition (EMT) of primary alveolar epithelial cells (AEC) and potential mechanisms underlying effects on EMT have not been well delineated. We examined effects of troglitazone, a synthetic PPARγ agonist, on transforming growth factor (TGF)-β1-induced EMT in primary rat AEC and an alveolar epithelial type II (AT2) cell line (RLE-6TN). TGF-β1 (2.5 ng/mL) induced EMT in both cell types, as evidenced by acquisition of spindle-like morphology, increased expression of the mesenchymal marker α-smooth muscle actin (α-SMA) and downregulation of the tight junctional protein zonula occludens-1 (ZO-1). Concurrent treatment with troglitazone (or rosiglitazone), ameliorated effects of TGF-β1. Furthermore, following stimulation with TGF-β1 for 6 days, troglitazone reversed EMT-related morphological changes and restored both epithelial and mesenchymal markers to control levels. Treatment with GW9662 (an irreversible PPARγ antagonist), or overexpression of a PPARγ dominant negative construct, failed to inhibit these effects of troglitazone in AEC. Troglitazone not only attenuated TGF-β1-induced phosphorylation of Akt and glycogen synthase kinase (GSK)-3β, but also inhibited nuclear translocation of β-catenin, phosphorylation of Smad2 and Smad3 and upregulation of the EMT-associated transcription factor SNAI1. These results demonstrate inhibitory actions of troglitazone on TGF-β1-induced EMT in AEC via a PPARγ-independent mechanism likely through inhibition of β-catenin-dependent signaling downstream of TGF-β1, supporting a role for interactions between TGF-β and Wnt/β-catenin signaling pathways in EMT.
    Full-text · Article · Jun 2012 · PLoS ONE
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