年龄依赖变应性哮喘的发展与胱硫醚γ-裂解酶缺陷
2017/10/23
摘要
目的：变应性哮喘儿童较成人高发的发病机制目前尚不清楚。胱硫醚γ-裂解酶（CSE）是促进硫化氢（H2S）表达的关键酶，表达有年龄依赖性，本研究旨在研究年龄依赖变应性哮喘是否与CSE表达有关。
结果：变应性哮喘模型为卵蛋白刺激诱导的低龄及高龄的野生型和CSE敲除的小鼠。低龄野生型小鼠免疫细胞中CSE表达与H2S含量较高龄野生型小鼠低。与此一致，较高龄野生型小鼠，低龄野生型小鼠中严重哮喘症状更多，2型免疫反应更强。H2S增补后哮喘症状被逆转。与成人外周血单核细胞相比，人脐血单核细胞中CSE表达水平较低。CSE敲除小鼠中哮喘年龄依赖性消失，但哮喘严重程度较野生型小鼠更重。在低龄野生型小鼠和各年龄段CSE敲除小鼠中更多的淋巴细胞分化为2型细胞因子生成细胞。增加H2S抑制了这种分化倾向。GATA3被H2S修饰后，GATA3转移到细胞核中，淋巴细胞2型免疫反应被抑制。
创新与结论:本实验首次描述了CSE的低达降及H2S产物增强了2型免疫反应，表明在低龄时期变应性哮喘发病较高。同样的，H2S表达水平可能是哮喘发展的一个生物标志物，H2S的干预可作为预防、治疗哮喘的手段。
Age-Dependent Allergic Asthma Development and Cystathionine Gamma-Lyase Deficiency
Wang P, Wu L, Ju Y, Fu M, Shuang T, Qian Z, Wang R.
Abstract
Aims:The pathogenic mechanisms for the higher prevalence of allergic asthma in children than in adults have not been settled. The aim of the present study is to examine whether the age-dependent development of allergic asthma is caused by age-dependent expression of cystathionine gamma-lyase (CSE), a key enzyme that catalyzes the production of hydrogen sulfide (H2S).
Results:Allergic asthma was induced with ovalbumin in wild-type (WT) and CSE knock-out (KO) mice at young and old ages. CSE expression and H2S production were lower in immune cells of young WT mice than in those of old WT mice. Coincidentally, more severe asthmatic symptoms with a greater type-2 immunoreaction were found in young WT mice than old WT mice. H2S supplementation reversed the asthmatic symptoms. Lower expression levels of CSE proteins were also found in human umbilical cord blood mononuclear cells in comparison with that of peripheral blood mononuclear cells from adult people. The age-dependent asthma propensity vanished in CSE-KO mice, but these mice developed more severe asthma than WT mice. More splenocytes were differentiated to type-2 cytokine-generating cells in young WT mice and in CSE-KO mice at all ages. This differentiation was inhibited by H2S donors. GATA3 translocation to the nucleus and type-2 immunoreaction of splenocytes were inhibited after GATA3 was S-sulfhydrated by H2S.
Innovation and Conclusion:For the first time, this study demonstrated that lower abundance of CSE expression and H2S production enhances type-2 immunoreaction and renders a higher incidence of allergic asthma at a young age. As such, H2S level may be a biomarker for asthma development and a H2S-based strategy can be perceived for asthma prevention and treatment.
目的：变应性哮喘儿童较成人高发的发病机制目前尚不清楚。胱硫醚γ-裂解酶（CSE）是促进硫化氢（H2S）表达的关键酶，表达有年龄依赖性，本研究旨在研究年龄依赖变应性哮喘是否与CSE表达有关。
结果：变应性哮喘模型为卵蛋白刺激诱导的低龄及高龄的野生型和CSE敲除的小鼠。低龄野生型小鼠免疫细胞中CSE表达与H2S含量较高龄野生型小鼠低。与此一致，较高龄野生型小鼠，低龄野生型小鼠中严重哮喘症状更多，2型免疫反应更强。H2S增补后哮喘症状被逆转。与成人外周血单核细胞相比，人脐血单核细胞中CSE表达水平较低。CSE敲除小鼠中哮喘年龄依赖性消失，但哮喘严重程度较野生型小鼠更重。在低龄野生型小鼠和各年龄段CSE敲除小鼠中更多的淋巴细胞分化为2型细胞因子生成细胞。增加H2S抑制了这种分化倾向。GATA3被H2S修饰后，GATA3转移到细胞核中，淋巴细胞2型免疫反应被抑制。
创新与结论:本实验首次描述了CSE的低达降及H2S产物增强了2型免疫反应，表明在低龄时期变应性哮喘发病较高。同样的，H2S表达水平可能是哮喘发展的一个生物标志物，H2S的干预可作为预防、治疗哮喘的手段。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Antioxid Redox Signal. 2017 Nov 1;27(13):931-944. doi: 10.1089/ars.2016.6875. Epub 2017 Apr 4.)
(Antioxid Redox Signal. 2017 Nov 1;27(13):931-944. doi: 10.1089/ars.2016.6875. Epub 2017 Apr 4.)
Age-Dependent Allergic Asthma Development and Cystathionine Gamma-Lyase Deficiency
Wang P, Wu L, Ju Y, Fu M, Shuang T, Qian Z, Wang R.
Abstract
Aims:The pathogenic mechanisms for the higher prevalence of allergic asthma in children than in adults have not been settled. The aim of the present study is to examine whether the age-dependent development of allergic asthma is caused by age-dependent expression of cystathionine gamma-lyase (CSE), a key enzyme that catalyzes the production of hydrogen sulfide (H2S).
Results:Allergic asthma was induced with ovalbumin in wild-type (WT) and CSE knock-out (KO) mice at young and old ages. CSE expression and H2S production were lower in immune cells of young WT mice than in those of old WT mice. Coincidentally, more severe asthmatic symptoms with a greater type-2 immunoreaction were found in young WT mice than old WT mice. H2S supplementation reversed the asthmatic symptoms. Lower expression levels of CSE proteins were also found in human umbilical cord blood mononuclear cells in comparison with that of peripheral blood mononuclear cells from adult people. The age-dependent asthma propensity vanished in CSE-KO mice, but these mice developed more severe asthma than WT mice. More splenocytes were differentiated to type-2 cytokine-generating cells in young WT mice and in CSE-KO mice at all ages. This differentiation was inhibited by H2S donors. GATA3 translocation to the nucleus and type-2 immunoreaction of splenocytes were inhibited after GATA3 was S-sulfhydrated by H2S.
Innovation and Conclusion:For the first time, this study demonstrated that lower abundance of CSE expression and H2S production enhances type-2 immunoreaction and renders a higher incidence of allergic asthma at a young age. As such, H2S level may be a biomarker for asthma development and a H2S-based strategy can be perceived for asthma prevention and treatment.
