Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Street 13, 10-719 Olsztyn, Poland.
Molecules. 2024 Nov 9;29(22):5293. doi: 10.3390/molecules29225293.
Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma. For this purpose, we assessed the effect of administration of MMF and TFB on the development of a mouse model of allergic airway inflammation (AAI) and accompanying CD4 (cluster of differentiation 4) T-cell immune response in the lung-draining mediastinal lymph nodes (MLNs) and lungs, i.e., in the inductive and effector sites, respectively, of the immune response underlying the development of allergic asthma. The results from a histopathological scoring system demonstrated that the administration of MMF and TFB did not prevent or abolish ovalbumin-induced AAI, but strongly attenuated its severity. The pulmonary function tests revealed that the treatment with MMF and TFB significantly reduced methacholine-induced bronchoconstriction. These results indicate that the treatment with TFB and MMF attenuated the development of ovalbumin-induced AAI. The magnitude of the anti-asthmatic effect was comparable between both agents. The study revealed that the impairment of the clonal expansion of effector CD4 T cells in the MLNs is a critical event in the mechanism underlying the anti-asthmatic effect of MMF and TFB. Apart from this, the findings of the study strongly suggest that the suppression of the interleukin-33/suppression of tumorigenicity-2 signaling pathway may constitute an additional mechanism responsible for producing this effect. In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4 regulatory T cells. Clinical implication of the results: the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment.
治疗抵抗性哮喘仍然是一个未解决的临床问题，也是当前医学科学面临的挑战。因此，对于哮喘的治疗，开发新的或替代的治疗选择的需求日益增长且紧迫。本研究提出的研究问题是评估和比较霉酚酸酯（MMF），肌苷单磷酸脱氢酶抑制剂，和托法替尼（TFB），一种 Janus 激酶抑制剂，在抗哮喘特性方面的作用，进而确定这些药物是否可能成为治疗过敏性哮喘的替代选择。为此，我们评估了给予 MMF 和 TFB 对过敏性气道炎症（AAI）的小鼠模型发展的影响，以及伴随的 CD4（分化簇 4）T 细胞免疫反应在肺引流纵隔淋巴结（MLNs）和肺中的影响，即在免疫反应的诱导和效应部位，分别为过敏性哮喘发展的免疫反应。组织病理学评分系统的结果表明，给予 MMF 和 TFB 既不能预防也不能消除卵清蛋白诱导的 AAI，但能强烈减轻其严重程度。肺功能测试显示，MMF 和 TFB 治疗显著降低了乙酰甲胆碱诱导的支气管收缩。这些结果表明，MMF 和 TFB 的治疗减轻了卵清蛋白诱导的 AAI 的发展。两种药物的抗哮喘作用的幅度相当。该研究表明，MLNs 中效应性 CD4 T 细胞克隆扩增的损害是 MMF 和 TFB 抗哮喘作用的机制中的关键事件。除此之外，研究结果还强烈表明，抑制白细胞介素-33/肿瘤抑制因子-2 信号通路可能构成产生这种作用的另一个机制。反过来，研究结果表明，研究药物诱导的抗哮喘作用不是通过产生叉头框蛋白 3 表达的 CD4 调节性 T 细胞介导的。结果的临床意义：结果表明，MMF 和 TFB 可能发挥抗哮喘作用，因此它们可能被认为是治疗对常规/现有治疗有抵抗性的过敏性哮喘病例的治疗选择。
