① 最近研究表明哮喘时气道平滑肌细胞（ASMC）表型在增生和收缩之间的变化，强调了ASMC的可塑性在哮喘病理生理学中的作用；② 小鼠每周在屋尘螨提取物中暴露5次，共试验5周；③ 给予H3K27去甲基化酶抑制剂(GSK-J4)可改善哮喘的经典特征，如气道高反应性(AHR)、气道炎症和重塑；④ GSK-J4通过Akt/JNK信号转导途径抑制PDGF诱导的ASMCs增殖和迁移；GSK-J4还通过Smad3途径抑制TGF-β诱导的ASMCs收缩蛋白的上调；⑤ 抑制H3K27me3去甲基化可减轻哮喘气道疾病的发生，体外调节ASMCs表型。
Clinical & Experimental Allergy
Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype
Background: The shift in airway smooth muscle cells (ASMCs) phenotype between proliferation and contraction during asthma has been reported recently, highlighting a role of ASMCs plasticity in the pathophysiology of asthma. As an event involved in epigenetic post-translational modification, histone H3 lysine27 (H3K27) demethylation has attracted significant attention with respect to the epigenetic changes in diverse cells; however, little is known about its contribution to the switching of ASMCs phenotype in asthma .
Methods: Mice were exposed five times a week to house dust mite (HDM) extract for 5 weeks. Lung function was measured following the final HDM challenge. Airway inflammation and remodelling were then assessed in lungs of individual mice. Human ASMCs were purchased from Sciencell Research Laboratories. Proliferation, synthesis,migration and contraction of ASMCs were analyzed, respectively.
Results: We observed demethylation at H3k27me3 sites in lungs harvested from mice exposed to house dust mite (HDM) extract. Administration of a selective inhibitor of H3K27 demethylase (GSK-J4) could ameliorate the classical hallmarks of asthma, such as airway hyperresponsiveness (AHR), airway inflammation and remodelling. We established a proliferative as well as a contractive model of human ASMCs to explore the impacts of H3K27 demethylase inhibition on ASMCs phenotype. Our results indicated that GSK-J4 decreased ASMCs proliferation and migration elicited by PDGF through the Akt/JNK signalling; GSK-J4 also prevented the upregulation of contractile proteins in ASMCs induced by TGF-β through the Smad3 pathway .
Conclusions: Inhibition of H3K27me3 demethylation alleviated the development of asthmatic airway disease in vivo and modulated ASMCs phenotype in vitro. Collectively, our findings highlight a role of H3K27me3 demethylation in experimental asthma and ASMCs phenotype switch .
Department of Respiratory & Critical Care Medicine
Qijun Yu, Xiaowei Yu, Wenxue Zhao, Manni Zhu, Zhengxia Wang, Jiaxiang Zhang,Mao Huang, Xiaoning Zeng