Targeting PPARγ in Lung fibroblasts: Prospects of therapeutic treatment for IPF

PVRI Member Authors: Michael Seimetz, Eveline Baumgart-Vogt, Srikanth Karnati

Eistine Boateng1,Natalia El-Merhie1, Omelyan Trompak2, Srinu Tumpara1, Michael Seimetz2,  Adrian Pilatz3, Eveline Baumgart-Vogt1, Srikanth Karnati1

1) Institute for Anatomy and Cell Biology II, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, D-35385 Giessen, Germany

2) Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany

3) Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Giessen, Germany



Idiopathic pulmonary fibrosis (IPF) is a devastating disease and the most common form of idiopathic interstitial pneumonias1. Former assumptions described IPF as a chronic inflammatory disease resulting from a response to an unknown stimulus which later progresses to lung injury and fibrosis2, 3. Median survival of patients diagnosed with IPF is reported to be from 2.5 to 3.5 years1, 4 and most available treatment compounds have not proved effective 5, including the antioxidant Nacetylcysteine which is only known to slow the decline in lung functions though has no impact on mortality 6. Another approach to therapeutically target IPF was by using agonists of peroxisome proliferator-activated receptor γ (PPARγ), as they were reported to possess anti-inflammatory and anti-fibrotic potentials 7, 8, 9, 10. However, first trials of PPARγ agonists in pulmonary fibrosis did not yield conclusive results, possibly due to vastly diverse experimental approaches used to assess the efficacy of the treatment. Thus, the role of PPARγ in the pathomechanisms of IPF remains elusive. This interactive discussion therefore summarizes the therapeutic role of PPARγ in IPF model systems and proposes new experimental strategies for treatment of IPF with PPARγ agonists. Our aim is also to challenge all researchers interested in this field to express their opinions on the potential of using PPARγ-associated treatment for IPF patients.

IPF is a progressive disease that can result in respiratory failure11. IPF is characterized by scarring of lung tissues due to uncontrolled deposition of extracellular matrix (ECM) proteins and further disruption of the lung architecture and normal function12. Clinical staging of IPF has been well delineated to inform management practices and clinical trials26. Clinical development of IPF starts with a slow progression over time followed by acute exacerbation of symptoms, loss of lung function and early death11, 27, 28.  Devastating effects of IPF and high mortality rates therefore demand biological studies to experimentally model the disease, find the underlying molecular mechanisms, and target the pathways involved in IPF progression as means of potential treatment. Despite the clear clinical staging of the disease, pathogenesis of IPF has not yet been fully elucidated. Current hypothesis suggests that an initial lung injury disrupts the alveolar-capillary basement membrane leading to a deterioration of re-epithelialisation and re-endothelialisation and a further cytokine-mediated fibroblast proliferation13. One of the major cytokines involved is the transforming growth factor β1 (TGFβ1)14. TGFβ1 is a ubiquitously expressed cytokine that functions in numerous biological pathways and was shown to be both important for normal physiology, and implicated in playing a role in diverse diseases15, 16. This cytokine is specifically known to mediate the recruitment and activation of fibroblasts during injury17, stimulate the regeneration of connective tissue, and inhibit its degradation18. Additionally, TGFβ1 stimulation leads to transdifferentiation of fibroblasts into aggressive myofibroblasts which are responsible for the production and secretion of components of the ECM19, 20, 21, 22. Interestingly, interfering with the pathways that lead to myofibroblast expansion have been proposed as potential means of treatment for IPF patients 23 since regimens targeting inflammation have been ineffective 24, 25.

Anti-fibrotic potential of PPARγ agonists in IPF

In previous studies PPARs were shown to control multiple physiological activities29 and disease conditions.  PPARs are part of a superfamily of nuclear receptors activated by lipid-derived substrates30 and regulate gene expression by binding to specific nucleotide sequences called PPAR response elements (PPREs) within promoters31 together with their heterodimeric partners, retinoid X receptors (RXRs)32. Three isotypes of PPARs characterized in lower vertebrates and mammals are PPARα, PPARβ and PPARγ33 of which the latter is subdivided into γ1, γ234, γ335, and γ436 isoforms. PPARs are ubiquitously and specifically expressed in various tissues and cell types37.

Recently, natural and synthetic activators of PPARγ were reported to elicit anti-fibrotic properties and inhibit myofibroblast differentiation and collagen secretion in cultured human lung fibroblasts10, 38, 39, 40.Burgess et al. (2005) suggested that endogenous and synthetic activators of PPARγ can control TGFβ1-mediated profibrotic effects, reverse primary human pulmonary myofibroblast differentiation and collagen production10. In this study, primary human fibroblasts were treated with different PPARγ agonists concomitant with recombinant human TGFβ1. We suggest that the therapeutic effect of PPARγ ligands on myofibroblast after exogenous addition of TGFβ1 to fibroblasts in culture would possibly model the pathogenic mechanism in patients though this may not be the focus of the authors. Furthermore, in this study, PPARγ antagonist could not reverse the inhibition of differentiation of fibroblasts into myofibroblasts by PPARγ agonists, indicating the existence of a possible PPARγ-independent mechanism by the agonists.  

Another study by Milam and colleagues (2008) demonstrated that treatment of lung fibroblasts in culture with PPARγ agonists, Troglitazone and ciglitazone, and in vivo administration of Troglitazone to bleomycin-treated lung mice inhibited TGFβ1-induced myofibroblast differentiation and collagen secretion, showing the potentials of PPARγagonists as novel therapeutic agents for the treatment of fibrotic lung diseases38. Noteworthy is the fact that the mechanism of the inhibition of profibrotic phenotype caused by TGFβ1 is addressed in this study. In the models used, PPARγagonists were administered in a pre-treatment setting: before TGFβ1 stimulation in vitro, and before induction of lung injury in vivo. Despite the important findings of the study, a drawback in the in vivo model used has to be mentioned: It is known that inflammation caused by lung injury may lead to many disease outcomes and not IPF alone41. In addition, pre-treatment with PPARγ ligands may interfere with the inflammatory process before a possible lung remodeling could occur. Thus, the experimental approach could only confirm the anti-inflammatory potential of PPARγ agonists which was reported earlier29, 42. In attempts to assess the effectiveness of agonist treatment in an established IPF model, troglitazone was given to another group of mice on day 11 following bleomycin instillation. However, authors provided no evidence of the extent of tissue remodeling and fibrosis on day 11 after bleomycin instillation alone. In all, the authors investigated only the preventive role of PPARγ agonists and not the proposed therapeutic effects on IPF. This experimental model however presents further questions regarding the therapeutic potential of PPARγ ligands.

Ferguson et al. (2009) also reported that PPARγ ligands and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) block critical TGFβ1-mediated profibrogenic activities through pathways independent of PPARγafter co-treating human lung fibroblasts with TGFβ1 and PPARγ ligands39. The study did not investigate the exogenously secreted collagens in the ECM. Moreover, it is well known that IPF progression is characterized by aberrant cellular release of collagens, proteoglycans, tenascin, laminin, and fibronectininto the ECM43. The study also proposed possible roles of PPARγagonists and CDDO in the inhibition of myofibroblast differentiation in IPF, though it would be interesting to know the regulation of fibrosis markers by PPARγ agonists after TGFβ1 stimulation.

Lin et al. (2010) defined the role of rosiglitazone, a PPARγ agonist, in suppressing myofibroblast transdifferentiation40. The study suggested a potential preventive role of PPARγ agonist in pulmonary fibrosis since human fetal lung fibroblasts were co-treated with TGFβ1 and rosiglitazone. Rosiglitazone downregulated αSMA, however IPF markers specifically the abundance of ECM proteins such as collagen was not investigated.

Question for interactive discussion

Translation of in vitro and in vivo studies to clinical applications may be very challenging from the viewpoint of predicting the efficacy of the developed experimental approaches in alleviating clinical symptoms of patients. Though much progress has been made towards the understanding of the pathogenesis of IPF with regards to the PPARγpathway, studies are often limited to focusing on the inhibition of fibroblast to myofibroblast conversion using PPARγ agonists (figure 1A). Cells accumulated at the fibroblastic foci of IPF patients present a mixed population of fibroblasts and myofibroblasts44. We therefore query the molecular effect of PPARγ agonists on the already existing myofibroblasts or TGF-β1 stimulated fibroblasts. Additionally, we propose that experimental models should be developed to investigate the role of PPARγ ligands on ECM deposition and reversal of the progressive fibrotic phenotype after TGFβ1 stimulation in vitro (figure 1B) and in vivo using alternate lung fibrosis mouse models. Studies in this direction might complement the already existing knowledge about the anti-fibrotic potential of PPARγ agonists.

Chronicle image 3.png.jpg

Fig. 1 Models for studying anti-fibrotic action of PPARγ agonists. (A) Experimental models previously described: co-treatment of fibroblast with TGFβ1 and PPARγ agonist (I) and treatment of PPARγ agonist followed by TGFβ1 stimulation (II). TGFβ1 stimulates fibroblast conversion to myofibroblast and PPARγagonist inhibits the process. (B) Proposed model for future studies: TGFβ1 transdifferentiation of fibroblast to myofibroblast followed by PPARγ agonist treatment. Are PPARγ agonists capable of reversing myofibroblasts to fibroblasts or could they prevent/promote synthesis of excess collagen and ECM deposition by myofibroblasts?


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