The Role of PPARs in Lung Fibrosis

Abstract

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. PPARalpha 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 PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma 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 PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

Figure 1

PPARγ ligands promote fibroblast differentiation to adipocytes and inhibit differentiation to myofibroblasts. Primary human fibroblasts (center panel) can be differentiated to adipocyte-like cells (left panel) by treatment with 1 μM 15d-PGJ₂ for 8 days. Lipid droplets were visualized with oil red O staining. Alternatively, incubation with 10 ng/mL TGF-β for 3 days will differentiate fibroblasts to myofibroblasts (right panel). α-SMA was detected by immunocytochemistry. Note the long bundles of contractile fibers.

Figure 2

The TGF-β signaling pathway. Binding of TGF-β to TGF-β receptor II recruits TGF-β receptor I (TGF-βR-I). The kinase domain of TGF-βR-I phosphorylates Smad2 and 3, which form a heteromeric complex with Smad4 that translocates into the nucleus where it activates transcription of target genes. Numbers indicate points in the pathway where PPARγ ligands have been demonstrated to interfere with TGF-β signaling. (1) GW7845, a PPARγ ligand, inhibited Smad3 phosphorylation in human hepatic stellate cells [88]. (2) 15d-PGJ₂ inhibited nuclear translocation of Smad2/3 in rat kidney fibroblasts [84]. (3) In human renal mesangial cells, 15d-PGJ₂ induced hepatocyte growth factor (HGF), which upregulates the Smad corepressor TG-interacting factor (TGIF) [84]. (4) In mouse L929 fibroblasts, 15d-PGJ₂ or retinoic acid upregulated the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), leading to repression of TGF-β1 transcription [89].

Figure 3

Key concepts in the regulation of fibrosis by PPARs.