Evaluation of the Effects of Caffeic Acid Phenethyl Ester on Prostaglandin E2 and Two Key Cytokines Involved in Bleomycin-induced Pulmonary Fibrosis

Document Type: Original Article

Authors

1 Department of Pharmacology and Toxicology, School of Pharmacy and Physiology Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Immunology, School of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Statistics, School of Mathematics and Computer Sciences, Shahid Chamran University, Ahvaz, Iran

4 Department of Pathobiology, School of Veterinary Medicine, Shahid Chamran University, Ahvaz, Iran

Abstract

 




Objective(s): Pulmonary fibrosis (PF) is the most common outcome of a collection of diverse lung disorders known as interstitial lung diseases. It is proposed that alterations in the levels of fibrogenic mediators and the profibrotic/antifibrotic imbalance play a substantial role in the progression of PF in animal models and possibly in humans. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has numerous biological effects. In the present study, the main objective was to investigate the effects of CAPE on some key mediators including TGF-β1, TNF-α and prostaglandin E2 (PGE2
) involved in profibrotic/antifibrotic balance and pathogenesis of idiopathic pulmonary fibrosis (IPF).
 
Materials and Methods:
In this study, forty male Sprague–Dawley rats were divided into 5 groups (n=8). (1) “Bleomycin (BLM)-treated (Model) group”: BLM (5 mg/kg, single intratracheal dose), (2) “Saline-treated group”: the rats were given only saline, (3) “Treatment-1 group”: BLM + CAPE (5 μmol/kg/day, 28 days, IP), (4) “Treatment-2 group”: BLM + CAPE (10 μmol/kg/day, 28 days, IP) and (5) “Vehicle + CAPE group”: CAPE (10 μmol/kg/day, 28 days, IP).
Results:
BLM could significantly increase the levels of TNF-α and TGF-β1 and decrease the PGE2 concentration compared to the saline control group. CAPE could considerably improve these values almost close to normal levels.
Conclusion:
Briefly, CAPE can be suggested as a novel, attractive and effective agent for prevention and treatment of pulmonary fibrosis.

Keywords


cytokines in the balance. Eur Respir J. 1998;11:1218-1221. 2. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824.

3. American Thoracic S. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646-664.

4. Dai XM. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165:277-304.

5. Scadding JG, Hinson KF. Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosis. Thorax. 1967;22:291-304.

6. Nagaya H, Sieker HO. Pathogenetic mechanisms of interstitial pulmonary fibrosis in patients with serum antinuclear factor. A histologic and clinical correlation. Am J Med. 1972;52:51-62.

7. Chapman JR, Charles PJ, Venables PJ, Thompson PJ, Haslam PL, Maini RN, et al. Definition and clinical relevance of antibodies to nuclear ribonucleoprotein and other nuclear antigens in patients with cryptogenic fibrosing alveolitis. Am Rev Respir Dis. 1984;130:439-443. 8. Bergeron A, Soler P, Kambouchner M, Loiseau P, Milleron B, Valeyre D, et al. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF‐β and IL-10. European Respiratory Journal. 2003;22:69-76.

9. Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH. TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. The Journal of Immunology. 1997;158:954-959.

10. Cao B, Guo Z, Zhu Y, Xu W. The potential role of PDGF, IGF-1, TGF-beta expression in idiopathic pulmonary fibrosis. Chinese medical journal-beijing-english edition-. 2000;113:776-782.

11. Hocher B, Schwarz A, Fagan KA, Thone-Reineke C, El-Hag K, Kusserow H, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. American journal of respiratory cell and molecular biology. 2000;23:19-26.

12. Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, et al. IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. Journal of Clinical Investigation. 2002;109:931-938.

13. Keane M, Arenberg D, Lynch JPr, Whyte R, Iannettoni M, Burdick M, et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. The Journal of Immunology. 1997;159:1437-1443.

14. Keane MP, Belperio JA, Burdick MD, Strieter RM. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2001;281:92-97.

15. Selman M, King TE, Pardo A, American Thoracic S, European Respiratory S, American College of Chest P. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136-151.

16. Ozer MK, Parlakpinar H, Vardi N, Cigremis Y, Ucar M, Acet A. Myocardial ischemia/reperfusion-induced oxidative renal damage in rats: protection by caffeic acid phenethyl ester (CAPE). Shock. 2005;24:97-100.

17. Fesen MR, Pommier Y, Leteurtre F, Hiroguchi S, Yung J, Kohn KW. Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochem Pharmacol. 1994;48:595-608.

18. Kuo HC, Kuo WH, Lee YJ, Lin WL, Chou FP, Tseng TH. Inhibitory effect of caffeic acid phenethyl ester on the growth of C6 glioma cells in vitro and in vivo. Cancer Lett. 2006;234:199-208.

19. Chung TW, Moon SK, Chang YC, Ko JH, Lee YC, Cho G, et- al. Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEB J. 2004;18:1670-1681.

20. Mirzoeva OK, Calder PC. The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids. 1996;55:441-449.

21. Montpied P, De Bock F, Rondouin G, Niel G, Briant L, Courseau AS, et al. Caffeic acid phenethyl ester (CAPE) prevents inflammatory stress in organotypic hippocampal slice cultures. Molecular brain research. 2003;115:111-120.

Effects of CAPE on Pulmonary Fibrosis Hemmati et al

Iran J Basic Med Sci, Vol. 16, No. 7, Jul 2013

 

857

22. Schraufnagel DE, Mehta D, Harshbarger R, Treviranus K, Wang NS. Capillary remodeling in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1986;125:97-106. 23. Zaeemzadeha N, Hemmatia A, Arzia A, Jalalib M, Rashidic I. Protective Effect of Caffeic Acid Phenethyl Ester (CAPE) on Amiodarone-Induced Pulmonary Fibrosis in Rat. Iranian Journal of Pharmaceutical Research. 2011;10:321-328.

24. Sazegar G, Seyed Reza AH, Behravan E. The effects of supplemental zinc and honey on wound healing in rats. Iran J Basic Med Sci. 2011;14:391-398.

25. Lopez-De Leon A, Rojkind M. A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections. J Histochem Cytochem. 1985;33:737-743.

26. Hubner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, et al. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008;44:507-511, 514-507.

27. Arribillaga L, Dotor J, Basagoiti M, Riezu-Boj JI, Borras-Cuesta F, Lasarte JJ, et al. Therapeutic effect of a peptide inhibitor of TGF-beta on pulmonary fibrosis. Cytokine. 2011;53:327-333.

28. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J. 2004;18:816-827.

29. Kelly M, Kolb M, Bonniaud P, Gauldie J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des. 2003;9:39-49.

30. Gao J, Huang Y, Li P, Xu D, Li J, Liu Y, et al. Antifibrosis effects of total glucosides of Danggui-Buxue-Tang in a rat model of bleomycin-induced pulmonary fibrosis. J Ethnopharmacol. 2011;136:21-26.

31. Baowen Q, Yulin Z, Xin W, Wenjing X, Hao Z, Zhizhi C, et al. A further investigation concerning correlation between anti-fibrotic effect of liposomal quercetin and inflammatory cytokines in pulmonary fibrosis. Eur J Pharmacol. 2010;642:134-139.

32. Khalil N, Greenberg AH. The role of TGF-beta in pulmonary fibrosis. Ciba Found Symp. 1991;157:194-207.

33. Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989;170:655-663.

34. Chen K, Wei Y, Sharp GC, Braley-Mullen H. Decreasing TNF-α results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis. J Leukoc Biol. 2007;81:306-314.

35. Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest. 1999;104:1001-1006.

36. Kenyon NJ, Ward RW, McGrew G, Last JA. TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice. Thorax. 2003;58:772-777.

37. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739-746.

38. Keerthisingam CB, Jenkins RG, Harrison NK, Hernandez-Rodriguez NA, Booth H, Laurent GJ, et al. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am J Pathol. 2001;158:1411-1422.

39. Xaubet A, Roca-Ferrer J, Pujols L, Ramirez J, Mullol J, Marin-Arguedas A, et al. Cyclooxygenase-2 is up-regulated in lung parenchyma of chronic obstructive pulmonary disease and down-regulated in idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21:35-42.

40. Vancheri C, Mastruzzo C, Sortino MA, Crimi N. The lung as a privileged site for the beneficial actions of PGE2. Trends Immunol. 2004;25:40-46.

41. Fine A, Poliks CF, Donahue LP, Smith BD, Goldstein RH. The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts. J Biol Chem. 1989;264:16988-16991.

42. Kohyama T, Ertl RF, Valenti V, Spurzem J, Kawamoto M, Nakamura Y, et al. Prostaglandin E(2) inhibits fibroblast chemotaxis. Am J Physiol Lung Cell Mol Physiol. 2001;281:1257-1263.

43. Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med. 1997;155:1665-1669.

44. Lama V, Moore BB, Christensen P, Toews GB, Peters-Golden M. Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am J Respir Cell Mol Biol. 2002;27:752-758.

45. Orsolic N, Terzic S, Mihaljevic Z, Sver L, Basic I. Effects of local administration of propolis and its polyphenolic compounds on tumor formation and growth. Biol Pharm Bull. 2005;28:1928-1933.

46. Natarajan K, Singh S, Burke TR, Grunberger D, Aggarwal BB. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proceedings of the National Academy of Sciences. 1996;93:9090-9095.

47. Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH. TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. J Immunol. 1997;158:954-959.

48. Bonner JC, Rice AB, Ingram JL, Moomaw CR, Nyska A, Bradbury A, et al. Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis. Am J Pathol. 2002;161:459-470.

49. Hodges RJ, Jenkins RG, Wheeler-Jones CP, Copeman DM, Bottoms SE, Bellingan GJ, et al. Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production. Am J Pathol. 2004;165:1663-1676.

50. Raghunath M, Unsold C, Kubitscheck U, Bruckner-Tuderman L, Peters R, Meuli M. The cutaneous microfibrillar apparatus contains latent transforming growth factor-beta binding protein-1 (LTBP-1) and is a repository for latent TGF-beta1. J Invest Dermatol. 1998;111:559-564.

51. Fishman RH. Kosher chickens, rabbits' ears, and a scar-free future. The Lancet. 1997;350:570-581.

52. Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, et al. Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res. 1999;59:2347-2352.

Hemmati et al Effects of CAPE on Pulmonary Fibrosis

Iran J Basic Med Sci, Vol. 16, No. 7, Jul 2013

 

858

53. Molina-Molina M, Serrano-Mollar A, Bulbena O, Fernandez-Zabalegui L, Closa D, Marin-Arguedas A, et al. Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis. Thorax. 2006;61:604-610.