Pentoxifylline and its active metabolite lisofylline attenuate transforming growth factor β1-induced asthmatic bronchial fibroblast-to-myofibroblast transition

• Authors: Katarzyna Wójcik-Pszczoła , Kinga Hińcza , Dawid Wnuk , Dominika Kądziołka , Paulina Koczurkiewicz , Marek Sanak , Zbigniew Madeja , Elżbieta Pękala , Marta Michalik
• Languages of publication: EN

Abstracts

EN

Bronchial asthma is characterized by persistent airway inflammation and airway wall remodeling. Among many different cells and growth factors triggering changes in bronchi structure, transforming growth factor β1-induced fibroblast to myofibroblast transition is believed to be very important. The aim of this study was to evaluate whether theophylline (used in asthma therapy) and two other methylxanthines (pentoxifylline and its active metabolite lisofylline), may affect transforming growth factor β1-induced fibroblast to myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. We show here for the first time that selected methylxanthines effectively reduce transforming growth factor β1-induced myofibroblast formation in asthmatic bronchial fibroblast populations. PTX was found to be the most effective methylxanthine. The number of differentiated myofibroblasts after PTX, LSF and THEO administration was reduced at least twofold. Studies on the use of methylxanthines opens a new perspective in the development of novel strategies in asthma therapy through their two-pronged, anti-inflammatory and anti-fibrotic action. In the future they can be considered as promising anti-fibrotic drugs.

Keywords

EN

theophylline; pentoxifylline; lisofylline; transforming growth factor type β; fibroblast-to-myofibroblast transition; asthma

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2016
• Volume: 63
• Issue: 3
• Pages: 437-442

Dates

published

2016

received

2016-04-01

revised

2016-05-09

accepted

2016-06-01

(unknown)

2016-07-30

Contributors

author

Katarzyna Wójcik-Pszczoła

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Polan
• Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

author

Kinga Hińcza

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

author

Dawid Wnuk

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

author

Dominika Kądziołka

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

author

Paulina Koczurkiewicz

• Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

author

Marek Sanak

• Department of Molecular Biology and Clinical Genetics, Jagiellonian University Medical College, Kraków, Poland

author

Zbigniew Madeja

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

author

Elżbieta Pękala

• Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

author

Marta Michalik

• Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

References

• Al-Muhsen S, Johnson JR, Hamid Q (2011) Remodeling in asthma. J Allergy Clin Immunol 128: 451-462. doi: 10.1016/j.jaci.2011.04.047.
• Baldwin L, Roche WR (2002) Does remodelling of the airway wall precede asthma? Paediatr Respir Rev 3: 315-320.
• Batra V, Musani AI, Hastie AT, Khurana S, Carpenter KA, Zangrilli JG, Peters SP (2004) Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 34: 437-444.
• Beckett PA, Howarth PH (2003) Pharmacotherapy and airway remodelling in asthma? Thorax 58: 163-174. doi: 10.1136/thorax.58.2.163.
• Berair R, Brightling CE (2014) Asthma therapy and its effect on airway remodelling. Drugs 74: 1345-1369. doi: 10.1007/s40265-014-0250-4.
• Bergeron C, Tulic MK, Hamid Q (2010) Airway remodelling in asthma: from benchside to clinical practice. Can Respir J 17: e85-e93.
• Bolick DT, Hatley ME, Srinivasan S, Hedrick CC, Nadler JL (2003) Lisofylline, a novel antiinflammatory compound, protects mesangial cells from hyperglycemia- and angiotensin II-mediated extracellular matrix deposition. Endocrinology 144: 5227-5231. doi: 10.1210/en.2003-0739.
• Chiou YL, Shieh JJ, Lin CY (2006) Blocking of Akt/NF-kappaB signaling by pentoxifylline inhibits platelet-derived growth factor-stimulated proliferation in Brown Norway rat airway smooth muscle cells. Pediatr Res 60: 657-662. doi: 10.1203/01.pdr.0000246105.56278.98.
• Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29: 265-273. doi: 10.1016/j.tibs.2004.03.008.
• Entzian P, Bitter-Suermann S, Burdon D, Ernst M, Schlaak M, Zabel P (1998) Differences in the anti-inflammatory effects of theophylline and pentoxifylline: important for the development of asthma therapy? Allergy 53: 749-754. doi: 10.1111/j.1398-9995.1998.tb03970.x.
• Fredholm BB (1985) On the mechanism of action of theophylline and caffeine. Acta Med Scand 217: 149-153. doi: 10.1111/j.0954-6820.1985.tb01650.x.
• GINA (2015) Global Initiative for Asthma (GINA), Global Strategy for Asthma Management and Prevention, 2015.
• Gu Y, Lambert JD (2013) Modulation of metabolic syndrome-related inflammation by cocoa. Mol Nutr Food Res 57: 948-961. doi: 10.1002/mnfr.201200837.
• Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 99: 8921-8926. doi: 10.1073/pnas.132556899.
• Kasahara K, Shiba K, Ozawa T, Okuda K, Adachi M (2002) Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma. Thorax 57: 242-246. doi: 10.1136/thorax.57.3.242.
• Khalifa EA, Nemenqani DM (2014) Efficacy of pentoxifylline as an antifibrotic drug in experimental murine schistosomal hepatic fibrosis. J Egypt Soc Parasitol 44: 475-488.
• Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005) Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol 16: 2702-2713. doi: 10.1681/ASN.2005040435.
• Makinde T, Murphy RF, Agrawal DK (2007) The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol 85: 348-356. doi: 10.1038/sj.icb.7100044.
• Margay SM, Farhat S, Kaur S, Teli HA (2015) To Study the Efficacy and Safety of Doxophylline and Theophylline in Bronchial Asthma. J Clin Diagn Res 9: FC05-FC08. doi: 10.7860/JCDR/2015/12438.5743.
• Mauad T, Bel EH, Sterk PJ (2007) Asthma therapy and airway remodeling. J Allergy Clin Immunol 120: 997-1009. doi: 10.1016/j.jaci.2007.06.03.
• Michalik M, Pierzchalska M, Legutko A, Ura M, Ostaszewska A, Soja J, Sanak M (2009) Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture. Med Sci Monit 15: BR194-BR201.
• Michalik M, Pierzchalska M, Włodarczyk A, Wójcik KA, Czyż J, Sanak M, Madeja Z (2011) Transition of asthmatic bronchial fibroblasts to myofibroblasts is inhibited by cell - cell contacts. Respir Med 105: 1467-1475. doi: 10.1016/j.rmed.2011.04.009.
• Michalik M, Wójcik KA, Jakieła B, Szpak K, Pierzchalska M, Sanak M, Madeja Z, Czyż J (2012) Lithium attenuates TGF-β(1)-induced fibroblasts to myofibroblasts transition in bronchial fibroblasts derived from asthmatic patients. J Allergy (Cairo) doi: 10.1155/2012/206109.
• Michalik M, Soczek E, Kosińska M, Rak M, Wójcik KA, Lasota S, Pierzchalska M, Czyż J, Madeja Z (2013) Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. Eur J Pharmacol 704: 23-32. doi: 10.1016/j.ejphar.2013.02.023.
• Ohta A, Sitkovsky M (2011) Methylxanthines, inflammation, and cancer: fundamental mechanisms. Handb Exp Pharmacol 200: 469-481. doi: 10.1007/978-3-642-13443-2_19.
• Oñatibia-Astibia A, Martínez-Pinilla E, Franco R (2016) The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respir Med 112: 1-9. doi: 10.1016/j.rmed.2016.01.022.
• Pękala E, Godawska-Matysik A, Żelaszczyk D (2007) Enantioselective reduction of pentoxifylline to lisofylline using whole-cell Lactobacillus kefiri biotransformation. Biotechnol J 2: 492-496. doi: 10.1002/biot.200600236.
• Persson CG (1985) On the medical history of xanthines and other remedies for asthma: a tribute to HH Salter. Thorax 40: 881-886.
• Phan SH (2008) Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5: 334-337. doi: 10.1513/pats.200708-146DR.
• Pierzchalska M, Szabó Z, Sanak M, Soja J, Szczeklik A (2003) Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J Allergy Clin Immunol 111: 1041-1048. doi: 10.1067/mai.2003.1491.
• Prabhu N, Rao SS, Kotrashetti SM, Baliga SD, Hallikerimath SR, Angadi PV, Issrani R (2015) Pentoxifylline in patients with oral submucous fibrosis-a randomized clinical trial. J Maxillofac Oral Surg 14: 81-89. doi: 10.1007/s12663-013-0580-x.
• Saglani S, Lloyd CM (2015) Novel concepts in airway inflammation and remodelling in asthma. Eur Respir J 46: 1796-1804. doi: 10.1183/13993003.01196-2014.
• Sang YH, Cy-Hyun K, Yoon ML, Dae HK, Kum-Hyun H, Dae RC (2015) Pentoxifylline inhibits angiotensin II-induced proliferation in rat vascular smooth muscle cells. Biomedical Research 26: 744-749. doi: 10.1006/jmcc.1998.0910.
• Sarna M, Wojcik KA, Hermanowicz P, Wnuk D, Burda K, Sanak M, Czyż J, Michalik M (2015) Undifferentiated bronchial fibroblasts derived from asthmatic patients display higher elastic modulus than their non-asthmatic counterparts. PLoS One doi: 10.1371/journal.pone.0116840.
• Shifren A, Witt C, Christie C, Castro M (2012) Mechanisms of remodeling in asthmatic airways. J Allergy (Cairo) doi: 10.1155/2012/316049.
• Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 343: 1006-1008. doi: 10.1016/S0140-6736(94)90127-9.
• Tilley SL (2011) Methylxanthines in asthma. Handb Exp Pharmacol 200: 439-456. doi: 10.1007/978-3-642-13443-2_17.
• Wang Y, Lin K, Wang C, Liao X (2011) Addition of theophylline or increasing the dose of inhaled corticosteroid in symptomatic asthma: a meta-analysis of randomized controlled trials. Yonsei Med J 52: 268-275. doi: 10.3349/ymj.2011.52.2.268.
• Ward C, Pais M, Bish R, Reid D, Feltis B, Johns D, Walters EH (2002) Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 57: 309-316. doi: 10.1136/thorax.57.4.309.
• Wójcik K, Koczurkiewicz P, Michalik M, Sanak M (2012) Transforming growth factor-β₁-induced expression of connective tissue growth factor is enhanced in bronchial fibroblasts derived from asthmatic patients. Pol Arch Med Wewn 122: 326-332.
• Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, Takimoto T, Hirata H, Kijima T, Kumagai T, Osaki T, Tachibana I, Kawase I (2006) Anti-fibrotic effects of theophylline on lung fibroblasts. Biochem Biophys Res Commun 341: 684-690. doi: 10.1016/j.bbrc.2006.01.018.
• Zhang X, Meng F, Song J, Zhang L, Wang J, Li D, Li L, Dong P, Yang B, Chen Y (2016) Pentoxifylline Ameliorates Cardiac Fibrosis, Pathological Hypertrophy, and Cardiac Dysfunction in Angiotensin II-induced Hypertensive Rats. J Cardiovasc Pharmacol 67: 76-85. doi: 10.1097/FJC.0000000000000316.

Identifiers

DOI

10.18388/abp.2016_1357