Theophylline attenuates bleomycin-induced oxidative stress in rats
The role of IL-6, NF-κB, and antioxidant enzymes
DOI:
https://doi.org/10.1590/s2175-97902022e20827Palavras-chave:
Theophylline, Bleomycin, IL-6, NF-κB, Antioxidant enzymesResumo
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
Referências
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
Publicado
Edição
Seção
Licença
Direitos autorais (c) 2022 Brazilian Journal of Pharmaceutical Sciences

Este trabalho está licenciado sob uma licença 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.