Chronic obstructive pulmonary disease (COPD) is a devastating, non-reversible, global health disease affecting millions of people worldwide. Although significant understanding of the COPD pathomechanisms and identification of new valid candidates for potential therapeutic approaches are increased during last years, the clinical studies showed disappointing results, amongst others based on elevated comorbidities and systemic inflammation in extra pulmonary organs. Thus, there is still a need for alternative therapeutic possibilities.
Peroxisome proliferators activated receptor γ (PPARγ) is an emerging anti-inflammatory and anti-oxidative gene and its role in the pathomechanisms of COPD is not well understood. The expression and activity of PPARγ is pulmonary cell type-dependent. This interactive discussion describes the multiple roles of PPARγ in different lung cell types and a possible treatment of COPD with PPARγ agonists. Although the recent literature implicates the potential role of PPARγ in the pathomechanisms of COPD, the research in this direction requires future studies to enlighten the hidden molecular pathways. This interactive discussion aims to challenge scientists and other persons who are interested in this field to express their views about the potential of PPARγ-associated treatments of COPD.
Chronic obstructive pulmonary disease (COPD) is a chronic condition of airflow limitation characterized by abnormal inflammation and impairs respiratory gas exchange that is not fully reversible and is progressive in nature1 . The main risk factors that are associated with COPD are tobacco smoke. However, other factors such as air pollution, occupational hazards and infections are also important2,3. Although COPD is primarily a lung disease, this disease exerts systemic manifestation and comorbidities in extra pulmonary organs and tissues such as heart, bone, pancreas and skeletal muscle dysfunction4,5. The worldwide prevalence of COPD is estimated to be approximately 10% of individuals older than 40 years of age6 . Further, due to the lack of effective treatments, COPD is the seventh-leading cause of disability and fourth-leading cause of death internationally according to the world health organization7 . At present, the accepted treatment for most inflammatory diseases is glucocorticoid therapy. However, this treatment is beneficial only to acute exacerbations of COPD patients8-10, and unfortunately produce unwanted side effects whilst exhibiting limited efficacy. Additionally, some COPD patients develop a resistance to corticosteroid treatment, further underscoring the need for an alternative therapeutic approach11,12.
Peroxisome proliferator activated receptors (PPAR-α, -β, -γ) are members of the ligand-activated nuclear hormone receptor super family. PPARγ agonists exerts strong anti-atherogenic, anti-inflammatory13-16 and anti-oxidant effects by inhibiting several inflammatory mediators such as TNFα, IL-1, IL-6, iNOS and transcription factors such as nuclear factor-κB (NF-κB), Nrf2, FOXO, Egr-1, AP-1 and other pro-inflammatory transcription factors via multiple mechanisms17-20.
In recent years, several hundreds of publications on the PPARγ receptor were published suggesting its importance in controlling the complex cellular mechanisms by regulating the transcription of genes (transactivation) that are involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. PPARγ can also inhibit gene transcription, through transrepression mechanisms that involve interactions with other transcription factors and their coactivators to prevent effective DNA binding21. In addition, various preclinical studies have already shown that PPARγ ligands have pleiotropic effects preventing cardiovascular complications. PPARγ is also used as therapeutic drug target for chronic inflammatory diseases such as atherosclerosis. This has led to increased interest of this receptor and to its therapeutic role in a variety of diseases including type 2 diabetes, atherosclerosis, inflammatory bowel disease, asthma, arthritis, myocarditis, cancer, fibrosis and endotoxin shock22.
PPARγ exerts its function depending on the cell type. Thus, Figure 1 summarizes the functional roles of PPARγ protein in a variety of pulmonary cell types such as the airway epithelium23,24, bronchial smooth muscle cells23,25, endothelial cells26,27, macrophages28,29, fibroblasts13, T-lymphocytes30-32, eosinophils33, alveolar epithelial cells type II (AECII)34 and dendritic cells35. Though PPARγ ligands exhibit cell type dependent functions, the most common anti-inflammatory effects were observed in various animal models of airway diseases such as asthma and COPD28,30.
Although PPARγ has been known for more than 25 years36, the mechanism that triggers the anti-inflammatory potentials of PPARγ protein in cigarette smoke exposure and COPD have not been elucidated. Further, the functional role of PPARγ in the pathomechanisms of smoke-induced COPD is still poorly understood.
Recently, Lakshmi et al. showed that the PPARγ protein and DNA binding activity was reduced in human bronchiolar epithelial cells of COPD patients. In addition, downregulation of GRα and HDAC2 was observed, whereas pro-inflammatory NF-κB was upregulated. Interestingly, treatment with a PPARγ agonist (rosiglitazone) reversed cigarette smoke extract (CSE)-mediated effects by strong upregulation of PPARγ expression and activity, suppressed cytokines and reversed the activation of NF-κB by promoting direct inhibitory binding of PPARγ to NF-κB. Thus, the authors claimed that downregulation of epithelial cell PPARγ expression and activity plays an important role in cigarette smoke-induced inflammation and the pathophysiology of COPD37. Since Lea et al. showed that PPARγ levels were not altered in alveolar macrophages (AM) of COPD patients28, lung epithelial cells were suggested to be a key locus for the pathogenesis of COPD. However, Malur et al. showed that alveolar macrophages and lung myloid dendritic cells (mDC) are important antigen presenting abundant inflammatory cells of the lungs of smokers that are strongly associated with emphysema38. Macrophage-specific PPARγ deficient mice showed spontaneous lung inflammation and increased Th1 polarization38. Interestingly, a recent publication from Shan et al. showed a reduced expression of PPARγ in human mDCs in smokers with emphysema. Moreover, smoke-exposed mice showed a reduced PPARγ expression in lung alveolar macrophages suggesting that PPARγ deficiency in antigen presenting cells leads to spontaneous development of emphysema. These authors showed that mice treated with a PPARγ agonist (ciglitazone) in an early emphysema model or CD11c-specific deletion of PPARγ or ablation of the Spp1 gene reversed emphysema, which suggests targeting the Osteopontin/PPARγ axis as a new therapeutic option39. However, it is not clear whether this treatment could reverse the effects by a late stage or end stage smoking emphysema.
Summary and the question for interactive discussion
The current literature and knowledge suggests an active role of PPARγ in the pathogenesis of COPD in bronchiolar epithelial cells and mDCs. Since bronchiolar epithelium is continuously exposed to smoke-induced oxidants, it is unclear whether PPARγ downregulation or inhibition directly reflects inflammatory signaling which can cause oxidative stress. PPARγ can regulate many anti-oxidative enzymes and acts as an anti-oxidant gene19. Thus, future studies are required to explore and assess the diagnostic and therapeutic methods in smoking-related diseases. Based on existing literature and heterogeneous regulation of PPARγ in different pulmonary cell types, we would like to postulate the following question to the scientific community worldwide:
Is a PPARγ-mediated regulation in individual cell types sufficient to reverse the emphysema or COPD?
We would like to invite all experts and other persons interested in this field to reply and express their views on this topic, in the next volume of PVRI Chronicle.
1. Barnes PJ. Corticosteroids: the drugs to beat. European journal of pharmacology. 2006;533(1-3):2-14.
2. Mannino DM, and Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765-73.
3. Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, and Busquets X. Systemic effects of chronic obstructive pulmonary disease. The European respiratory journal. 2003;21(2):347-60.
4. Roca M, and Mihaescu T. [Peripheral muscle dysfunction in chronic obstructive pulmonary disease]. Pneumologia. 2012;61(3):178-82.
5. Cazzola M, Matera MG, Rogliani P, and Page C. Treating systemic effects of COPD. Trends in pharmacological sciences. 2007;28(10):544-50.
6. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, and Mannino DM. Global burden of COPD: systematic review and meta-analysis. The European respiratory journal. 2006;28(3):523-32.
7. Mathers CD, Iburg KM, Salomon JA, Tandon A, Chatterji S, Ustun B, and Murray CJ. Global patterns of healthy life expectancy in the year 2002. BMC public health. 2004;4(66.
8. Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, Duerring U, Henzen C, Leibbrandt Y, Maier S, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA : the journal of the American Medical Association. 2013;309(21):2223-31.
9. Schuetz P, Leuppi JD, Tamm M, Briel M, Bingisser R, Durring U, Muller B, Schindler C, Viatte S, and Rutishauser J. Short versus conventional term glucocorticoid therapy in acute exacerbation of chronic obstructive pulmonary disease - the “REDUCE” trial. Swiss medical weekly. 2010;140(w13109.
10. Sethi S, and Nag N. A 5-day course of systemic corticosteroids is adequate to treat acute exacerbations of chronic obstructive pulmonary disease. Evidence-based medicine. 2014;19(2):57.
11. Hakim A, Adcock IM, and Usmani OS. Corticosteroid resistance and novel anti-inflammatory therapies in chronic obstructive pulmonary disease: current evidence and future direction. Drugs. 2012;72(10):1299-312.
12. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. The Journal of allergy and clinical immunology. 2013;131(3):636-45.
13. Huang TH, Razmovski-Naumovski V, Kota BP, Lin DS, and Roufogalis BD. The pathophysiological function of peroxisome proliferator-activated receptor-gamma in lung-related diseases. Respir Res. 2005;6(102.
14. Huang W, and Glass CK. Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arteriosclerosis, thrombosis, and vascular biology. 2010;30(8):1542-9.
15. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, and Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437(7059):759-63.
16. Wahli W, and Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends in endocrinology and metabolism: TEM. 2012;23(7):351-63.
17. Barish GD, Narkar VA, and Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. The Journal of clinical investigation. 2006;116(3):590-7.
18. Cabrero A, Laguna JC, and Vazquez M. Peroxisome proliferator-activated receptors and the control of inflammation. Current drug targets Inflammation and allergy. 2002;1(3):243-8.
19. Polvani S, Tarocchi M, and Galli A. PPARgamma and Oxidative Stress: Con(beta) Catenating NRF2 and FOXO. PPAR research. 2012;2012(641087.
20. Staels B, and Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54(8):2460-70.
21. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, and Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998;395(6698):137-43.
22. Spears M, McSharry C, and Thomson NC. Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2006;36(12):1494-504.
23. Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret MC, Mechighel P, Megret J, Leseche G, Aubier M, and Pretolani M. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1487-94.
24. Wang AC, Dai X, Luu B, and Conrad DJ. Peroxisome proliferator-activated receptor-gamma regulates airway epithelial cell activation. Am J Respir Cell Mol Biol. 2001;24(6):688-93.
25. Patel HJ, Belvisi MG, Bishop-Bailey D, Yacoub MH, and Mitchell JA. Activation of peroxisome proliferator-activated receptors in human airway smooth muscle cells has a superior anti-inflammatory profile to corticosteroids: relevance for chronic obstructive pulmonary disease therapy. J Immunol. 2003;170(5):2663-9.
26. Calnek DS, Mazzella L, Roser S, Roman J, and Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arteriosclerosis, thrombosis, and vascular biology. 2003;23(1):52-7.
27. Reddy AT, Lakshmi SP, Kleinhenz JM, Sutliff RL, Hart CM, and Reddy RC. Endothelial cell peroxisome proliferator-activated receptor gamma reduces endotoxemic pulmonary inflammation and injury. J Immunol. 2012;189(11):5411-20.
28. Lea S, Plumb J, Metcalfe H, Spicer D, Woodman P, Fox JC, and Singh D. The effect of peroxisome proliferator-activated receptor-gamma ligands on in vitro and in vivo models of COPD. The European respiratory journal. 2014;43(2):409-20.
29. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, and Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998;273(40):25573-80.
30. Belvisi MG, and Hele DJ. Peroxisome proliferator-activated receptors as novel targets in lung disease. Chest. 2008;134(1):152-7.
31. Hammad H, de Heer HJ, Soullie T, Angeli V, Trottein F, Hoogsteden HC, and Lambrecht BN. Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. The American journal of pathology. 2004;164(1):263-71.
32. Trifilieff A, Bench A, Hanley M, Bayley D, Campbell E, and Whittaker P. PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect. British journal of pharmacology. 2003;139(1):163-71.
33. Woerly G, Honda K, Loyens M, Papin JP, Auwerx J, Staels B, Capron M, and Dombrowicz D. Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation. J Exp Med. 2003;198(3):411-21.
34. Michael LF, Lazar MA, and Mendelson CR. Peroxi some proliferator-activated receptor gamma1 expression is induced during cyclic adenosine monophosphate-stimulated differentiation of alveolar type II pneumonocytes. Endocrinology. 1997;138(9):3695-703.
35. Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, Tonnel AB, and Trottein F. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur J Immunol. 2001;31(10):2857-65.
36. Issemann I, and Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645-50.
37. Lakshmi SP, Reddy AT, Zhang Y, Sciurba FC, Mallampalli RK, Duncan SR, and Reddy RC. Down-regulated Peroxisome Proliferator-activated Receptor gamma (PPARgamma) in Lung Epithelial Cells Promotes a PPARgamma Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD). J Biol Chem. 2014;289(10):6383-93.
38. Malur A, McCoy AJ, Arce S, Barna BP, Kavuru MS, Malur AG, and Thomassen MJ. Deletion of PPAR gamma in alveolar macrophages is associated with a Th-1 pulmonary inflammatory response. J Immunol. 2009;182(9):5816-22.
39. Shan M, You R, Yuan X, Frazier MV, Porter P, Seryshev A, Hong JS, Song LZ, Zhang Y, Hilsenbeck S, et al. Agonis