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Release date：2018-11-26

Clinical & Experimental Allergy

[IF:5.158]

Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype
DOI: 10.1111/cea.13244
Abstract:
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 .
First Author:
Qijun Yu
Correspondence:
Department of Respiratory & Critical Care Medicine
All Authors:
Qijun Yu, Xiaowei Yu, Wenxue Zhao, Manni Zhu, Zhengxia Wang, Jiaxiang Zhang,Mao Huang, Xiaoning Zeng

2018-11-13 Article