Transforming Growth Factor-β and Nuclear Factor E2-related Factor 2 Regulate Antioxidant Responses in Airway Smooth Muscle Cells Role in Asthma
Transforming Growth Factor-β and Nuclear Factor E2-related Factor 2 Regulate Antioxidant Responses in Airway Smooth Muscle Cells Role in Asthma
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DOI：
10.1164/rccm.201011-1780oc
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发表时间：
2011-10-15
影响因子：
24.7
通讯作者：
Chung, Kian Fan
中科院分区：
文献类型：
--
作者：
Michaeloudes, Charalambos;Chang, Po-Jui;Chung, Kian Fan
理论基础：哮喘的特点是气道平滑肌细胞(ASMC)功能异常和转化生长因子(TGF)-β的过度表达，后者调节ASMC的增殖和炎症功能，并诱导氧化剂释放。目的：探讨核因子E2相关因子2(Nrf2)在ASMCs中的作用及转化生长因子-β(TGF-β)对Nrf2的调节作用，并比较重症和非重症哮喘患者和健康人ASMCs中Nrf2的活性。我们研究了Nrf2激活对抗氧化基因表达和增殖的影响，转化生长因子-β对Nrf2转录活性的影响，以及Nrf2激活对转化生长因子-β介导的增殖和IL-6释放的影响。方法和主要结果：Nrf2激活导致抗氧化剂基因HO-1、NAD(P)H：苯醌氧化还原酶和锰超氧化物歧化酶表达上调，并抑制细胞增殖。转化生长因子-β通过诱导转录因子-3的激活而降低Nrf2介导的抗氧化剂基因转录。NRF2的激活减弱了转化生长因子-β对HO-1、ASMC增殖和IL-6释放的抑制作用。与非重症哮喘患者和正常人相比，重度哮喘患者ASMCs中NRF2-抗氧化反应元件结合减少。结论：Nrf2可调节ASMCs的抗氧化反应和增殖，并可被转化生长因子β失活。NRF2的减少可能是哮喘患者抗氧化保护受损和ASM功能异常的原因。
Rationale: Aberrant airway smooth muscle cell (ASMC) function and overexpression of transforming growth factor (TGF)-beta, which modulates ASMC proliferative and inflammatory function and induces oxidant release, are features of asthma. Nuclear factor E2-related factor 2 (Nrf2) activates antioxidant genes conferring protection against oxidative stress.Objectives: To determine the role of Nrf2 in ASMCs and its modulation by TGF-beta, and compare Nrf2 activity in ASMCs from subjects with severe and nonsevere asthma and healthy subjects.Methods: ASMCs were cultured from airways of subjects without asthma, and from airway biopsies from patients with severe and nonsevere asthma. We studied Nrf2 activation on antioxidant gene expression and proliferation, the effect of TGF-beta on Nrf2 transcriptional activity, and the impact of Nrf2 activation on TGF-beta-mediated proliferation and IL-6 release. Nrf2-antioxidant response elements binding and Nrf2-dependent antioxidant gene expression was determined in asthmatic ASMCs.Measurements and Main Results: Activation of Nrf2 led to up-regulation of the antioxidant genes heme oxygenase (HO)-1, NAD (P) H: quinone oxidoreductase, and manganese superoxide dismutase, and a reduction in proliferation. TGF-beta reduced Nrf2-mediated antioxidant gene transcription through induction of activating transcription factor-3 expression. Nrf2 activation attenuated TGF-beta-mediated reduction in HO-1, ASMC proliferation, and IL-6 release. Nrf2-antioxidant response elements binding was reduced in ASMCs from patients with severe asthma compared with ASMCs from patients with nonsevere asthma and normal subjects. HO-1 expression was reduced in ASMCs from patients with both nonsevere and severe asthma compared with healthy subjects.Conclusions: Nrf2 regulates antioxidant responses and proliferation in ASMCs and is inactivated by TGF-beta. Nrf2 reduction may underlie compromised antioxidant protection and aberrant ASM function in asthma.