Differential Mechanisms of the Effect of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Bleomycin-Induced Lung Fibrosis

DOI: 10.4236/ojrd.2013.32006   PDF   HTML     2,892 Downloads   5,066 Views  


Background and Objectives: Peroxisome proliferator-activated receptor-g (PPAR-g) is a nuclear receptor whose activation regulates inflammation and fibrosis in various organs. We aimed to investigate the effect of two PPAR-g ligands, telmisartan and rosiglitazone, on lung injury and fibrosis induced by intratracheal bleomycin (BLM). Methods: Lung injury and fibrosis was induced in female C57Bl/6 mice by intratracheal instillation of 1.0 mg/kg of BLM. Some of the animals received rosiglitazone intraperitoneally or telmisartan in drinking water. Bronchoalveolar lavage (BAL) was performed 2, 7, 14 or 21 days after BLM instillation for cell counting and measurement of mediators in the lung. In a separate series, the lungs were sampled for collagen assay and histopathological evaluation. Results: Treatment with rosiglitazone or telmisartan significantly attenuated the BLM-induced increases in lung collagen content, pathological score, and inflammatory cells in BAL fluid. Rosiglitazone significantly suppressed BLM-induced elevation of TGF-b1, MCP-1, and IL-6 levels in the lung. In contrast, telmisartan made no changes in these cytokines, whereas it mitigated the BLM-induced increase in prostaglandin F2a in the lung. Higher concentrations of rosiglitazone and telmisartan attenuated proliferation of lung fibroblasts in vitro. Conclusions: Two PPAR-g ligands, rosiglitazone and telmisartan, exert protective effects on BLM-induced lung fibrosis through the suppression of different profibrotic mediators.

Share and Cite:

Miyamoto, K. , Tasaka, S. , Nakano, Y. , Shinoda, H. , Kamata, H. , Yamasawa, W. , Ishii, M. , Hasegawa, N. and Betsuyaku, T. (2013) Differential Mechanisms of the Effect of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Bleomycin-Induced Lung Fibrosis. Open Journal of Respiratory Diseases, 3, 31-38. doi: 10.4236/ojrd.2013.32006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] American Thoracic Society, “Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment. International Consensus Statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS),” American Journal of Respiratory and Critical Care Medicine, Vol. 161, No. 2, 2000, pp. 646-664. doi:10.1164/ajrccm.161.2.ats3-00
[2] A. Moeller, K. Ask, D. Warburton, et al., “The Bleomycin Animal Model: A Useful Tool to Investigate Treatment Options for Idiopathic Pulmonary Fibrosis?” International Journal of Biochemistry and Cell Biology, Vol. 40, No. 3, 2008, pp. 362-382. doi:10.1016/j.biocel.2007.08.011
[3] D. H. Bowden, “Unraveling Pulmonary Fibrosis: The Bleomycin Model,” Laboratory Investigation, Vol. 50, No. 5, 1984, pp. 487-488.
[4] C. Agostini and C. Gurrieri, “Chemokine/Cytokine Cocktail in Idiopathic Pulmonary Fibrosis,” Proceedings of the American Thoracic Society, Vol. 3, No. 4, 2006, pp. 357-363. doi:10.1513/pats.200601-010TK
[5] R. L. Riha, I. A. Yang, G. C. Rabnott, et al., “Cytokine Gene Polymorphisms in Idiopathic Pulmonary Fibrosis,” Internal Medicine Journal, Vol. 34, No. 3, 2004, pp. 126-129. doi:10.1111/j.1444-0903.2004.00503.x
[6] Y. Wang, J. Santos, R. Sakurai, et al., “Peroxisome Proliferator-Activated Receptor Gamma Agonists Enhance Lung Maturation in a Neonatal Rat Model,” Pediatric Research, Vol. 65, No. 2, 2009, pp. 150-155. doi:10.1203/PDR.0b013e3181938c40
[7] T. J. Standiford, V. G. Keshamouni and R. C. Reddy, “Peroxisome Proliferator-Activated Receptor-γ as a Regulator of Lung Inflammation and Repair,” Proceedings of the American Thoracic Society, Vol. 2, No. 3, 2005, pp. 226-231. doi:10.1513/pats.200501-010AC
[8] M. Ricote, A. C. Li, T. M. Willson, et al., “The Peroxisome Proliferator-Activated Receptor-Gamma Is a Negative Regulator of Macrophage Activation,” Nature, Vol. 391, No. 6662, 1998, pp. 79-82. doi:10.1038/34178
[9] K. Asada, S. Sasaki, T. Suda, et al., “Antiinflammatory Roles of Peroxisome Proliferators-Activated Receptor Gamma in Human Alveolar Macrophages,” American Journal of Respiratory and Critical Care Medicine, Vol. 169, No. 2, 2004, pp. 195-200. doi:10.1164/rccm.200207-740OC
[10] R. A. Daynes and D. C. Jones, “Emerging Roles of PPARs in Inflammation and Immunity,” Nature Reviews Immunology, Vol. 2, No. 10, 2002, pp. 748-759. doi:10.1038/nri912
[11] J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, et al., “An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ(PPAR-γ),” Journal of Biological Chemistry, Vol. 270, No. 22, 1995, pp. 12953-12956. doi:10.1074/jbc.270.22.12953
[12] T. Genovese, S. Cuzzocrea, R. Di Paola, et al., “Effect of Rosiglitazone and 15-Deoxy-Δ12,14-Prostaglandin J2 on Bleomycin-Induced Lung Injury,” European Respiratory Journal, Vol. 25, No. 2, 2005, pp. 225-234. doi:10.1183/09031936.05.00049704
[13] T. Tagami, H. Yamamoto, K. Moriyama, et al., “A Selective Peroxisome Proliferator-Activated Receptor-Gamma Modulator, Telmisartan, Binds to the Receptor in a Different Fashion from Thiazolidinediones,” Endocrinology, Vol. 150, No. 2, 2009, pp. 862-870. doi:10.1210/en.2008-0502
[14] M. Schupp, J. Janke, R. Clasen, et al., “Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator-Activated Receptor-Gamma Activity,” Circulation, Vol. 109, No. 17, 2004, pp. 2054-2057. doi:10.1161/01.CIR.0000127955.36250.65
[15] M. Otsuka, H. Takahashi, M. Shiratori, et al., “Reduction of Bleomycin Induced Lung Fibrosis by Candesartan Cilexetil, an Angiotensin II Type 1 Receptor Antagonist,” Thorax, Vol. 59, No. 1, 2004, pp. 31-38. doi:10.1136/thx.2003.000893
[16] T. J. Broekelmann, A. H. Limper, T. V. Colby, et al., “Transforming Growth Factor β1 is Present at Sites of Extracellular Matrix Gene Expression in Human Pulmonary Fibrosis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, No. 15, 1991, pp. 6642-6646. doi:10.1073/pnas.88.15.6642
[17] R. E. Smith, R. M. Strieter, K. Zhang, et al., “A Role for C-C Chemokines in Fibrotic Lung Disease,” Journal of Leukocyte Biology, Vol. 57, No. 5, 1995, pp. 782-787.
[18] I. Shahar, E. Fireman, M. Topilsky, et al., “Effect of IL-6 on Alveolar Fibroblast Proliferation in Interstitial Lung Diseases,” Clinical Immunology and Immunopathology, Vol. 79, No. 3, 1996, pp. 244-251. doi:10.1006/clin.1996.0075
[19] F. Saito, S. Tasaka, K. Inoue, et al., “Role of Interleukin-6 in Bleomycin-Induced Lung Inflammatory Changes in Mice,” American Journal of Respiratory Cell and Molecular Biology, Vol. 38, No. 5, 2008, pp. 566-571. doi:10.1165/rcmb.2007-0299OC
[20] T. Oga, T. Matsuoka, C. Yao, et al., “Prostaglandin F Receptor Signaling Facilitates Bleomycin-Induced Pulmonary Fibrosis Independently of Transforming Growth Factor-β,” Nature Medicine, Vol. 15, No. 12, 2009, pp. 1426-1430. doi:10.1038/nm.2066
[21] T. Ashcroft, J. M. Simpson and V. Timbrell, “Simple Method of Estimating Severity of Pulmonary Fibrosis on a Numerical Scale,” Journal of Clinical Pathology, Vol. 41, No. 4, 1988, pp. 467-470. doi:10.1136/jcp.41.4.467
[22] K. Zhang, K. C. Flanders and S. H. Phan, “Cellular Localization of Transforming Growth Factor-Beta Expression in Bleomycin-Induced Pulmonary Fibrosis,” American Journal of Pathology, Vol. 147, No. 2, 1995, pp. 352-361.
[23] N. Khalil, T. V. Parekh, R. N. O’Connor, et al., “Differential Expression of Transforming Growth Factor-Beta Type I and II Receptors by Pulmonary Cells in Bleomycin-Induced Lung Injury: Correlation with Repair and Fibrosis,” Expimental Lung Research, Vol. 28, No. 3, 2002, pp. 233-250. doi:10.1080/019021402753570527
[24] X. Tan, H. Dagher, C. A. Hutton, et al., “Effects of PPAR Gamma Ligands on TGF-β1-Induced Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells,” Respiratory Research, Vol. 11, 2010, p. 21. doi:10.1186/1465-9921-11-21
[25] K. Zhang, M. Gharaee-Kermani, M. L. Jones, et al., “Lung monocyte Chemoattractant Protein-1 Gene Expression in Bleomycin-Induced Pulmonary Fibrosis,” Journal of Immunology, Vol. 153, No. 10, 1994, pp. 4733-4741.
[26] S. T. Buckley, C. Medina and C. Ehrhardt, “Differential Susceptibility to Epithelial-Mesenchymal Transition (EMT) of Alveolar, Bronchial and Intestinal Epithelial Cells in Vitro and the Effect of Angiotensin II Receptor Inhibition,” Cell and Tissue Research, Vol. 342, No. 1, 2010, pp. 39-51. doi:10.1007/s00441-010-1029-x
[27] S. C. Benson, H. A. Pershadsingh, C. I. Ho, et al., “Identification of Telmisartan as a Unique Angiotensin Ii Receptor Antagonist with Selective PPAR Gamma-Modulating Activity,” Hypertension, Vol. 43, No. 5, 2004, pp. 993-1002. doi:10.1161/01.HYP.0000123072.34629.57
[28] R. P. Marshall, P. Gohlke, R. C. Chambers, et al., “Angiotensin II and the Fibroproliferative Response to Acute Lung Injury,” American Journal of Physiology Lung Cellular and Molecular Physiology, Vol. 286, No. 1, 2004, pp. L156-L164. doi:10.1152/ajplung.00313.2002
[29] S. C. Benson, R. Iguchi, C. I. Ho, et al., “Inhibition of Cardiovascular Cell Proliferation by Angiotensin Receptor Blockers: Are All Molecules the Same?” Journal of Hypertension, Vol. 26, No. 5, 2008, pp. 973-980. doi:10.1097/HJH.0b013e3282f56ba5
[30] Q. Lin, L. P. Fang, W. W. Zhou, et al., “Rosiglitazone Inhibits Migration, Proliferation, and Phenotypic Differentiation in Cultured Human Lung Fibroblasts,” Experimental Lung Research, Vol. 36, No. 2, 2010, pp. 120-128. doi:10.3109/01902140903214659
[31] A. K. Ghosh, S. Bhattacharyya, G. Lakos, et al., “Disruption of Transforming Growth Factor β Signaling and Profibrotic Responses in Normal Skin Fibroblasts by Peroxisome Proliferator-Activated Receptor γ,” Arthritis and Rheumatism, Vol. 50, No. 4, 2004, pp. 1305-1318. doi:10.1002/art.20104
[32] D. Lu and D. A. Carson, “Repression of β-Catenin Signaling by PPAR γ Ligands,” European Journal of Pharmacology, Vol. 636, No. 1-3, 2010, pp. 198-202. doi:10.1016/j.ejphar.2010.03.010
[33] W. Xu, C. L. Chou, D. D. Israel, et al., “PGF Stimulates FP Prostanoid Receptor Mediated Crosstalk between Ras/Raf Signaling and Tcf Transcriptional Activation,” Biochemical and Biophysical Research Communication, Vol. 381, No. 4, 2009, pp. 625-629. doi:10.1016/j.bbrc.2009.02.102

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.