Morissette Mathieu C, Vachon-Beaudoin Guillaume, Parent Julie, Chakir Jamila, Milot Julie
Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Quebec City, Canada.
Am J Respir Crit Care Med. 2008 Aug 1;178(3):240-7. doi: 10.1164/rccm.200710-1486OC. Epub 2008 May 29.
Emphysema is mainly known for the complex inflammatory processes associated with its development. In addition to lung inflammation, it is now accepted that increased alveolar cell apoptosis is also part of emphysema pathophysiology. However, little is known about the mechanisms involved in alveolar apoptosis. We postulate that oxidative stress and proinflammatory cytokines could lead to p53 accumulation, Bax/Bcl-x(L) ratio elevation, and higher tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor levels in the emphysematous lung.
To evaluate the expression of p53, Bax, Bcl-x(L), TRAIL, and TRAIL receptors in lung parenchyma from nonemphysematous nonsmokers and smokers and emphysematous smokers and ex-smokers and to determine whether H2O2 and/or TNF can modulate the expression of these apoptotic proteins.
p53, Bax, Bcl-x(L), and TRAIL receptor protein levels in lung parenchyma were measured by Western blot, and TRAIL mRNA levels were measured by real-time polymerase chain reaction. Changes in TRAIL receptor, Bax, Bcl-x(L), and p53 protein levels after in vitro H2O2 and/or TNF stimulation of A549 cells were also assessed by Western blot.
The p53 protein levels, the Bax/Bcl-x(L) ratio, and TRAIL receptors 1, 2, and 3 protein levels were significantly higher in subjects with emphysema. Moreover, they were also increased after H2O2 and TNF treatments of A549 cells.
These findings suggest that oxidative stress and proinflammatory cytokines may be involved in the elevation of p53 levels, the Bax/Bcl-x(L) ratio, and TRAIL receptor levels, new mechanisms that may be implicated in the increased alveolar cell apoptosis that occurs in emphysema.
肺气肿主要因其发展过程中相关的复杂炎症过程而为人所知。除了肺部炎症外，现在人们还认为肺泡细胞凋亡增加也是肺气肿病理生理学的一部分。然而，关于肺泡凋亡所涉及的机制知之甚少。我们推测氧化应激和促炎细胞因子可能导致肺气肿肺组织中p53积累、Bax/Bcl-x(L)比值升高以及肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）受体水平升高。
评估非肺气肿非吸烟者、吸烟者以及肺气肿吸烟者和戒烟者肺实质中p53、Bax、Bcl-x(L)、TRAIL和TRAIL受体的表达，并确定H2O2和/或TNF是否能调节这些凋亡蛋白的表达。
通过蛋白质印迹法测量肺实质中p53、Bax、Bcl-x(L)和TRAIL受体蛋白水平，通过实时聚合酶链反应测量TRAIL mRNA水平。还通过蛋白质印迹法评估体外H2O2和/或TNF刺激A549细胞后TRAIL受体、Bax、Bcl-x(L)和p53蛋白水平的变化。
肺气肿患者的p53蛋白水平、Bax/Bcl-x(L)比值以及TRAIL受体1、2和3蛋白水平显著更高。此外，H2O2和TNF处理A549细胞后这些指标也有所增加。
这些发现表明氧化应激和促炎细胞因子可能参与了p53水平、Bax/Bcl-x(L)比值和TRAIL受体水平的升高，这些新机制可能与肺气肿中肺泡细胞凋亡增加有关。
