Rayees Sheikh, Mabalirajan Ulaganathan, Bhat Wajid Waheed, Rasool Shafaq, Rather Rafiq Ahmad, Panda Lipsa, Satti Naresh Kumar, Lattoo Surrinder Kumar, Ghosh Balaram, Singh Gurdarshan
PK-PD Toxicology Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India; School of Biotechnology, Shri Mata Vaishno Devi University, Katra Jammu, India.
Molecular Immunogenetics Laboratory, Institute of genomics and Integrative Biology-CSIR, Delhi, India.
Int Immunopharmacol. 2015 May;26(1):246-56. doi: 10.1016/j.intimp.2015.03.035. Epub 2015 Apr 8.
This is a follow-up study of our previous work in which we screened a series of Vasicine analogues for their anti-inflammatory activity in a preventive OVA induced murine model of asthma. The study demonstrated that R8, one of the analogues, significantly suppressed the Th2 cytokine production and eosinophil recruitment to the airways. In the present study, we have been using two standard experimental murine models of asthma, where the mice were treated with R8 either during (preventive use) or after (therapeutic use) the development of asthma features. In the preventive model, R8 reduced inflammatory cell infiltration to the airways, OVA specific IgE and Th2 cytokine production. Also, the R8 treatment in the therapeutic model decreased methacholine induced AHR, Th2 cytokine release, serum IgE levels, infiltration of inflammatory cells into the airways, phosphorylation of STAT6 and expression of GATA3. Moreover, R8 not only reduced goblet cell metaplasia in asthmatic mice but also reduced IL-4 induced Muc5AC gene expression in human alveolar basal epithelial cells. Further, R8 attenuated IL-4 induced differentiation of murine splenocytes into Th2 cells in vitro. So, we may deduce that R8 treatment profoundly reduced asthma features by attenuating the differentiation of T cells into Th2 cells by interfering with the binding of IL-4 to its receptor in turn decreasing the phosphorylation of STAT6 and expression of GATA3 in murine model of asthma. These preclinical findings suggest a possible therapeutic role of R8 in allergic asthma.
这是我们之前工作的一项后续研究，在该研究中，我们筛选了一系列鸭嘴花碱类似物在卵清蛋白诱导的哮喘小鼠预防模型中的抗炎活性。该研究表明，其中一种类似物R8能显著抑制Th2细胞因子的产生以及嗜酸性粒细胞向气道的募集。在本研究中，我们使用了两种标准的哮喘实验小鼠模型，在哮喘特征出现期间（预防性使用）或之后（治疗性使用）用R8处理小鼠。在预防模型中，R8减少了炎症细胞向气道的浸润、卵清蛋白特异性IgE和Th2细胞因子的产生。此外，在治疗模型中，R8治疗降低了乙酰甲胆碱诱导的气道高反应性、Th2细胞因子释放、血清IgE水平、炎症细胞向气道的浸润、STAT6的磷酸化以及GATA3的表达。此外，R8不仅减少了哮喘小鼠的杯状细胞化生，还降低了白细胞介素-4诱导的人肺泡基底上皮细胞中Muc5AC基因的表达。此外，R8在体外减弱了白细胞介素-4诱导的小鼠脾细胞向Th2细胞的分化。因此，我们可以推断，在哮喘小鼠模型中，R8治疗通过干扰白细胞介素-4与其受体的结合，进而减少STAT6的磷酸化和GATA3的表达，从而减弱T细胞向Th2细胞的分化，显著减轻了哮喘特征。这些临床前研究结果表明R8在过敏性哮喘中可能具有治疗作用。
