Mechanisms of autoimmune emphysema.
Mechanisms of autoimmune emphysema.
复制标题
DOI：
10.1513/pats.200603-063ms
复制
发表时间：
2006-08
期刊：
影响因子：
--
通讯作者：
L. Taraseviciene‐Stewart;N. Burns;Donatas Kraskauskas;M. Nicolls;R. Tuder;N. Voelkel
中科院分区：
文献类型：
--
作者：
L. Taraseviciene‐Stewart;N. Burns;Donatas Kraskauskas;M. Nicolls;R. Tuder;N. Voelkel
尽管吸烟与肺气肿的发病机制有关，但慢性进行性肺泡间隔破坏的确切机制尚不清楚。在这里，我们在一种新的动物模型中证明，具有免疫能力但无胸腺的裸鼠腹腔注射异种内皮细胞会产生针对内皮细胞的抗体并发展为肺气肿。抗内皮细胞抗体在体外引起内皮细胞凋亡。 TUNEL 测定和激活的 caspase-3 蛋白质印迹和免疫染色显示，与对照大鼠肺相比，免疫动物肺中发生细胞死亡的细胞更多。与对照大鼠肺相比，免疫动物肺中基质金属蛋白酶 (MMP) MMP-9 和 MMP-2 显着上调。抗内皮细胞抗体可识别多种内皮细胞表位，包括血管内皮生长因子受体 (VEGFR)-2 和血管紧张素转换酶 (ACE)。注射抗内皮细胞血清的小鼠也会出现肺气肿。注射抗内皮细胞抗体的小鼠的肺形态测量显示，与注射正常大鼠血清的对照组相比，5周内肺泡空腔扩大了20%。免疫还会导致 CD4+ T 细胞在肺部积聚。将来自脾脏的致病性 CD4+ 细胞群过继转移到免疫能力正常的幼稚动物体内也会导致肺气肿。此外，将CD4+脾细胞过继转移到继代同系大鼠中会导致肺气肿，即使这些继代大鼠没有接受人脐静脉内皮细胞（HUVEC）免疫。在这项研究中，我们首次证明体液和 CD4+ 细胞依赖性机制足以引发肺气肿的发展。我们的数据表明，致病性 CD4+ T 淋巴细胞对于破坏免疫功能正常大鼠的调节耐受性并引起肺气肿是必要且充分的，这表明自身免疫机制参与了肺泡间隔细胞的破坏。
Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. Here we show in a novel animal model (1) that immune competent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells produce antibodies against endothelial cells and develop emphysema. Anti–endothelial cell antibodies cause endothelial cell apoptosis in vitro. TUNEL assay and activated caspase-3 Western blot and immunostaining showed more cells undergoing cell death in immunized animal lungs than in control rat lungs. There is a significant up-regulation of matrix metalloproteases (MMPs) MMP-9 and MMP-2 in the lungs of immunized animals when compared with control rat lungs. Anti–endothelial cell antibodies recognize several endothelial cell epitopes, including vascular endothelial growth factor receptor (VEGFR)-2 and angiotensin-converting enzyme (ACE). Mice injected with anti–endothelial cell serum also develop emphysema. Lung morphometry of mice injected with anti–endothelial cell antibody showed 20% enlargement of alveolar airspaces over a 5-wk period as compared with normal rat serum–injected controls. Immunization also causes accumulation of CD4+ T cells in the lung. Adoptive transfer of a pathogenic, spleen-derived CD4+ cell population into naive immune-competent animals also results in emphysema. Moreover, adoptive transfer of CD4+ spleen cells into secondary syngeneic rats resulted in emphysema, even though these secondary rats had not been immunized with human umbilical vein endothelial cells (HUVEC). In this study, we show for the first time that humoral and CD4+ cell–dependent mechanisms are sufficient to trigger the development of emphysema. Our data demonstrate that pathogenic CD4+ T lymphocytes are necessary and sufficient in breaking a regulatory tolerance and causing emphysema in naive immune-competent rats, suggesting the involvement of autoimmune mechanisms in alveolar septal cell destruction.