Yanagisawa Satoru, Baker Jonathan R, Vuppusetty Chaitanya, Fenwick Peter, Donnelly Louise E, Ito Kazuhiro, Barnes Peter J
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Am J Physiol Lung Cell Mol Physiol. 2017 Aug 1;313(2):L230-L239. doi: 10.1152/ajplung.00382.2016. Epub 2017 May 18.
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD ( < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; = 0.50; = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels ( = -0.41; = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by -acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
磷脂酰肌醇3激酶（PI3K）通路在慢性阻塞性肺疾病（COPD）中被激活，但其调节机制尚待阐明。本研究旨在确定PI3K通路的负调节因子10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）在COPD中的表达及作用。将COPD患者的肺外周组织PTEN蛋白表达与吸烟和非吸烟对照者进行比较。使用原代肺上皮细胞和细胞系（BEAS-2B），在存在或不存在L-丁硫氨酸-亚砜亚胺（BSO）以消耗细胞内谷胱甘肽的情况下，评估香烟烟雾提取物（CSE）对PTEN表达的直接影响。还研究了RNA干扰敲低PTEN对细胞因子产生的影响。在肺外周组织中，与无COPD的受试者相比，COPD患者的PTEN蛋白显著降低（<0.001），且与气流阻塞的严重程度呈正相关（1秒用力呼气容积占预计值百分比；r = 0.50；P = 0.0012）。相反，作为PI3K激活标志物的磷酸化Akt与PTEN蛋白水平呈负相关（r = -0.41；P = 0.0042）。在原代支气管上皮细胞和BEAS-2B细胞中，CSE均降低了PTEN蛋白，而N-乙酰半胱氨酸处理可使其逆转。PTEN敲低增强了Akt磷酸化，并增加了促炎细胞因子如IL-6、CXCL8、CCL2和CCL5的产生。总之，氧化应激降低了PTEN蛋白水平，这可能导致COPD中PI3K信号增加和炎症放大。
