Theophylline attenuates bleomycin-induced oxidative stress in rats
The role of IL-6, NF-κB, and antioxidant enzymes
DOI:
https://doi.org/10.1590/s2175-97902022e20827Keywords:
Theophylline, Bleomycin, IL-6, NF-κB, Antioxidant enzymesAbstract
The purpose of this study was to evaluate the antifibrotic and antioxidant roles of theophylline (Theo), a bioactive compound, in bleomycin (BLM)-induced pulmonary fibrosis in Wistar albino rats. Assigned into 4 groups were 32 Wistar albino rats, comprising the control group (administered 0.9% isotonic saline), BLM group (treated with BLM at a dose of 2.5 mg/kg), BLM+Theo group (treated with Theo at a dose of 75 mg/kg + BLM at a dose of 2.5 mg/kg), and Theo group (treated with Theo at a dose of 75 mg/kg). In the BLM group, a significant decrease was observed in the catalase and glutathione peroxidase enzyme activities, and reduced glutathione (GSH) (p < 0.05, p< 0.05, p< 0.001, respectively), while the malondialdehyde (MDA) levels (p< 0.001) were significantly elevated when compared to the control group. However, the MDA levels in the BLM+Theo group were also significantly higher than in the control group (p< 0.01). Similarly, the GSH levels were significantly higher in the BLM+Theo group than in the BLM group (p< 0.05). The results indicated that Theo reduced the BLM-induced activation of nuclear factor-kappaB (NF-κB) and decreased interleukin-6 (IL-6) levels, together with significant amelioration of the immunohistochemical and histopathological architecture in the lung tissues. It was concluded that the administration of Theo had a positive effect on the GSH level, and activation of NF-κB and IL-6 expression, which were significant proinflammatory markers in the BLM-treated rats.
Downloads
References
Aebi H. Catalase in vitro. In: Methods in Enzymol. 1984;105:121-126.
Altintas N, Erboga M, Aktas C, Bilir B, Aydin M, Sengul A, et al. Protective effect of infliximab, a tumor necrosis factor-alfa inhibitor, on bleomycin-induced lung fibrosis in rats. Inflammation. 2016;39(1):65-78.
Ayaub EA, Kolb PS, Mohammed Ali Z, Tat V, Murphy J, Bellaye PS, et al. GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis. J Pathol. 2016;239(4):411-425.
Bartella L, Di Donna L, Napoli A, Siciliano C, Sindona G, Mazzotti F. A rapid method for the assay of methylxanthines alkaloids: Theobromine, theophylline and caffeine, in cocoa products and drugs by paper spray tandem mass spectrometry. Food Chem. 2019;278:261-266.
Chang YL, Hsu YJ, Chen Y, Wang YW, Huang SM. Theophylline exhibits anti-cancer activity via suppressing SRSF3 in cervical and breast cancer cell lines. Oncotarget. 2017;8(60):101461-101474.
Cordella M, Tabolacci C, Senatore C, Rossi S, Mueller S, Lintas C, et al. Theophylline induces differentiation and modulates cytoskeleton dynamics and cytokines secretion in human melanoma-initiating cells. Life Sci. 2019;230:121-131.
Cuzzocrea S, Genovese T, Failla M, Vecchio G, Fruciano M, Mazzon E, et al. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2007;292(5):L1095-L1104.
Dong Z, Tai W, Yang Y, Zhang T, Li Y, Chai Y, et al. The role of all-trans retinoic acid in bleomycin-induced pulmonary fibrosis in mice. Exp Lung Res. 2012;38(2):82-89.
Gallelli L, Falcone D, Cannataro R, Perri M, Serra R, Pelaia G, et al. Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach. Drug Des Devel Ther. 2017;11:265.
He H, Tang H, Gao L, Wu Y, Feng Z, Lin H, Wu T. Tanshinone IIA attenuates bleomycin-induced pulmonary fibrosis in rats. Mol Med Rep. 2015;11(6):4190-4196.
Iyer SS, Ramirez AM, Ritzenthaler JD, Torres-Gonzalez E, Roser-Page S, Mora AL, et al. Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol . 2009;296(1):L37-L45.
Jain SK, McVie R, Duett J, Herbst JJ. Erythrocyte membrane lipid peroxidation and glycosylated hemoglobin in diabetes. Diabetes. 1989;38(12):1539-1543.
Kabel AM, Omar MS, Elmaaboud MAA. Amelioration of bleomycin-induced lung fibrosis in rats by valproic acid and butyrate: role of nuclear factor kappa-B, proinflammatory cytokines and oxidative stress. Int Immunopharmacol. 2016;39:335-342.
Kalayarasan S, Sriram N, Sudhandiran, G. Diallyl sulfide attenuates bleomycin-induced pulmonary fibrosis: Critical role of iNOS, NF-κB, TNF-α and IL-1β. Life Sci . 2008;82(23-24):1142-1153.
Liu L, Lu W, Ma Z, Li, Z. Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/ Smad signaling pathway. Int J Mol Med. 2012;29(5):815-822.
Lucattelli M, Fineschi S, Selvi E, Gonzalez EG, Bartalesi B, De Cunto G, et al. Ajulemic acid exerts potent anti-fibrotic effect during the fibrogenic phase of bleomycin lung. Respir Res. 2016;17(1):49.
Min F, Gao F, Li Q, Liu Z. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol Med Rep . 2015;11(4):2387-2396.
Nikbakht J, Hemmati AA, Arzi A, Mansouri MT, Rezaie A, Ghafourian M. Protective effect of gallic acid against bleomycin-induced pulmonary fibrosis in rats. Pharmacol Rep. 2015;67(6):1061-1067.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158-169.
Rao F, Chen Z, Zhou D, Kang Y, Guo L, Xue Y. DFT investigation on the metabolic mechanisms of theophylline by cytochrome P450 monooxygenase. J Mol Graph Model. 2018;84:109-117.
Rizzi R, Caroli A, Bolla P, Acciaioli A, Pagnacc G. Variability of reduced glutathione levels in Massese ewes and its effect on daily milk production. J Dairy Res. 1988;55(3):345-353.
Ruan H, Lv Z, Liu S, Zhang L, Huang K, Gao S, et al. Anlotinib attenuated bleomycin-induced pulmonary fibrosis via the TGF-β1 signalling pathway. J Pharm Pharmacol. 2020;72(1):44-55.
Serrano-Mollar A, Closa D, Prats N, Blesa S, Martinez Losa M, Cortijo J, et al. In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol. 2003;138(6):1037-1048.
Shih YN, Chen YT, Chu H, Shih CJ, Ou SM, Hsu YT, et al. Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. Respir Med. 2017;125:33-38.
Sun YI, Oberley LW, Li YA. Simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34(3):497-500.
Zhang K, Si XP, Huang J, Han J, Liang X, Xu XB, et al. Preventive effects of Rhodiola rosea L. on bleomycin-induced pulmonary fibrosis in rats. Int J Mol Sci. 2016;17(6):879.
Downloads
Published
Issue
Section
License
Copyright (c) 2022 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on line journal has open and free access.
