Albertine Kurt H, Soulier Matthew F, Wang Zhengming, Ishizaka Akitoshi, Hashimoto Satoru, Zimmerman Guy A, Matthay Michael A, Ware Lorraine B
Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah, Salt Lake City 84132, USA.
Am J Pathol. 2002 Nov;161(5):1783-96. doi: 10.1016/S0002-9440(10)64455-0.
Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in human disease processes, including pulmonary disorders. However, the role of the Fas/FasL system in acute lung injury (ALI) and in the acute respiratory distress syndrome (ARDS) is poorly defined. Accordingly, we investigated both the soluble and cellular expression of the Fas/FasL system in patients with ALI or ARDS. The major findings are summarized as follows. First, the soluble expression of the Fas/FasL system was assessed in undiluted pulmonary edema fluid and simultaneous plasma. Pulmonary edema fluid obtained from patients with ALI or ARDS (n = 51) had significantly higher concentrations of both soluble Fas (27 ng/ml; median; P < 0.05) and soluble FasL (0.125 ng/ml; P < 0.05) compared to control patients with hydrostatic pulmonary edema (n = 40; soluble Fas, 12 ng/ml; soluble FasL, 0.080 ng/ml). In addition, the concentrations of both soluble Fas and soluble FasL were significantly higher in the pulmonary edema fluid of the patients with ALI or ARDS compared to simultaneous plasma samples (soluble Fas, 16 ng/ml; soluble FasL, 0.058 ng/ml; P < 0.05), indicating local release in the lung. Higher soluble Fas concentrations were associated with worse clinical outcomes. Second, cellular expression of the Fas/FasL system was assessed by semiquantitative immunofluorescence microscopy in lung tissue obtained at autopsy from a different set of patients. Both Fas and FasL were immunolocalized to a greater extent in the patients who died with ALI or ARDS (n = 10) than in the patients who died without pulmonary disease (n = 10). Both proteins were co-expressed by epithelial cells that lined the alveolar walls, as well as by inflammatory cells and sloughed epithelial cells that were located in the air spaces. Semiquantitative immunohistochemistry showed that markers of apoptosis (terminal dUTP nick-end labeling, caspase-3, Bax, and p53) were more prevalent in alveolar wall cells from the patients who died with ALI or ARDS compared to the patients who died without pulmonary disease. These findings indicate that alveolar epithelial injury in humans with ALI or ARDS is in part associated with local up-regulation of the Fas/FasL system and activation of the apoptotic cascade in the epithelial cells that line the alveolar air spaces.
由Fas/Fas配体（FasL）相互作用介导的细胞凋亡与人类疾病进程相关，包括肺部疾病。然而，Fas/FasL系统在急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）中的作用尚不清楚。因此，我们研究了ALI或ARDS患者中Fas/FasL系统的可溶性和细胞表达情况。主要研究结果总结如下。首先，在未稀释的肺水肿液和同步采集的血浆中评估Fas/FasL系统的可溶性表达。与静水压性肺水肿对照患者（n = 40；可溶性Fas，12 ng/ml；可溶性FasL，0.080 ng/ml）相比，从ALI或ARDS患者（n = 51）获得的肺水肿液中可溶性Fas（中位数27 ng/ml；P < 0.05）和可溶性FasL（0.125 ng/ml；P < 0.05）的浓度显著更高。此外，与同步采集的血浆样本（可溶性Fas，16 ng/ml；可溶性FasL，0.058 ng/ml；P < 0.05）相比，ALI或ARDS患者肺水肿液中可溶性Fas和可溶性FasL的浓度显著更高，表明在肺内局部释放。较高的可溶性Fas浓度与较差的临床结局相关。其次，通过半定量免疫荧光显微镜在另一组患者尸检获得的肺组织中评估Fas/FasL系统的细胞表达。与无肺部疾病死亡的患者（n = 10）相比，死于ALI或ARDS的患者（n = 10）中Fas和FasL的免疫定位程度更高。这两种蛋白在肺泡壁内衬的上皮细胞以及位于气腔内的炎性细胞和脱落的上皮细胞中共同表达。半定量免疫组织化学显示，与无肺部疾病死亡的患者相比，死于ALI或ARDS的患者肺泡壁细胞中凋亡标志物（末端脱氧核苷酸转移酶介导的缺口末端标记、半胱天冬酶-3、Bax和p53）更为普遍。这些发现表明，ALI或ARDS患者的肺泡上皮损伤部分与Fas/FasL系统的局部上调以及肺泡气腔内衬上皮细胞凋亡级联反应的激活有关。
