Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI:10.1002/prp2.70018
Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

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色甘酸钠和马西替尼复方制剂可抑制成纤维细胞-肌成纤维细胞转化,并对博莱霉素诱导的体外纤维化模型产生细胞保护和抗氧化作用。
特发性肺纤维化(IPF)是一种进行性致命肺纤维化疾病。虽然最近的研究表明酪氨酸激酶抑制剂在治疗 IPF 方面具有潜在疗效,但马西替尼作为一种临床常用的酪氨酸激酶抑制剂,其在肺纤维化疾病中的疗效尚未得到研究。在之前的一项体外神经退行性模型研究中,我们证实了马西替尼与美国食品及药物管理局(FDA)批准的肥大细胞稳定剂色甘宁钠(cromolyn sodium)联用具有协同解毒和抗氧化作用。本研究旨在体外肺纤维化模型中研究马西替尼与色甘酸钠联合用药的抗纤维化和抗氧化作用。用博莱霉素和/或过氧化氢(H2O2)处理成纤维细胞培养物后,再用马西替尼和/或色甘酸钠处理成纤维细胞培养物,然后评估细胞活力、形态学和细胞凋亡核变化、三重免疫荧光标记、总氧化剂/抗氧化剂能力,以及作为细胞凋亡指标的 Bax 和 Bcl-2 mRNA 表达比值。马西替尼与色甘酸钠联合治疗可有效阻止纤维化的标志--成纤维细胞向肌成纤维细胞转化,并显著减少博莱霉素/H2O2诱导的细胞凋亡和氧化应激。本研究首次在体外纤维化模型中证明了马西替尼-色甘酸钠联合疗法具有抗纤维化、细胞保护和抗氧化的叠加效应,表明它有可能成为治疗肺纤维化的一种创新疗法。联合疗法的优势在于两种药物的用药剂量较低,副作用较小,同时还能提供多种作用机制。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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