Heightened Endoplasmic Reticulum Stress in the Lungs of Patients with Chronic Obstructive Pulmonary Disease The Role of Nrf2-Regulated Proteasomal Activity (Retracted article. See vol. 193, pg. 344, 2016)
Heightened Endoplasmic Reticulum Stress in the Lungs of Patients with Chronic Obstructive Pulmonary Disease The Role of Nrf2-Regulated Proteasomal Activity (Retracted article. See vol. 193, pg. 344, 2016)
复制标题
DOI：
10.1164/rccm.200903-0324oc
复制
发表时间：
2009-12-15
影响因子：
24.7
通讯作者：
Biswal, Shyam
中科院分区：
文献类型：
--
作者：
Malhotra, Deepti;Thimmulappa, Rajesh;Biswal, Shyam
核因子红细胞2相关因子2 （Nrf2）是肺抗氧化防御的重要调节因子，在慢性阻塞性肺疾病（COPD）中下降。然而，Nrf2也调节蛋白酶体系统，降解受损和错误折叠的蛋白质。由于内质网（ER）中错误折叠蛋白的积累导致内质网应激和内质网应激诱导的细胞凋亡，Nrf2可能潜在地阻止内质网应激介导的COPD细胞凋亡。目的：确定nrf2调节的蛋白酶体功能是否影响内质网应激介导的COPD细胞凋亡。方法：我们评估了Nrf2、Nrf2依赖的蛋白酶体亚基、蛋白酶体活性、内质网应激标志物和凋亡在暴露于香烟烟雾（CS）的小鼠肺气肿肺以及正常对照者和COPD患者的外周肺组织中的表达。测量和主要结果：与野生型小鼠相比，cs暴露的nrf2缺陷小鼠肺气肿肺蛋白酶体活性明显降低，内质网应激和凋亡标志物升高。此外，与正常对照组相比，轻度和晚期COPD患者肺部nrf2调节的蛋白酶体亚基表达和总蛋白酶体活性均明显降低。然而，它们与更高水平的内质网应激和细胞凋亡标志物有关。体外研究表明，通过萝卜硫素（一种Nrf2的激活剂）或Nrf2调节的蛋白酶体亚基PSMB6的过表达，增强Beas2B细胞的蛋白酶体活性，可显著抑制香烟烟雾冷凝物（CSC）诱导的内质网应激和细胞死亡。结论：Nrf2信号受损导致COPD患者和cs暴露小鼠肺部蛋白酶体活性显著下降，内质网应激反应增强。因此，增强Nrf2活性的药理学方法可能通过上调抗氧化防御和缓解内质网应激来预防COPD进展。
Rationale Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD.Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD.Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD.Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosis markers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells either by sulforaphane, an activator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death.Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.