Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung
Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung
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DOI：
10.1152/ajplung.1998.275.6.l1192
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发表时间：
1998-12-01
影响因子：
4.9
通讯作者：
Selman, M
中科院分区：
文献类型：
--
作者：
Uhal, BD;Joshi, I;Selman, M
本实验室早期的工作表明，从纤维化的人肺组织分离出的异常成纤维细胞表型产生因子(S)，能够在体外诱导肺泡上皮细胞凋亡和坏死[B.D.Uhal，I.Joshi，A.True，S.Mundle，A.Raza，A.Pardo和M.Selman]。上午好。J.Physiol.269(肺细胞。梅尔。物理。13)：L819-L828,1995]。为了确定上皮细胞死亡是否与体内异常成纤维细胞的接近有关，在先前用于成纤维细胞分离的同一组织标本中，检测了上皮细胞丢失、DNA片段化和肌成纤维细胞的空间分布。采用原位末端标记(ISEL)和α-平滑肌肌动蛋白(α-SMA)免疫标记技术，对正常和纤维化人肺组织石蜡切片进行原位末端标记，复制标本进行电子显微镜观察和印迹红法检测胶原蛋白。正常人肺中除支气管和血管周围的平滑肌呈α-SMA免疫反应阳性外，其余仅有极少量标记。相比之下，纤维化的人肺表现为中到重度的间质细胞、立方上皮细胞和游离肺泡细胞。肺泡上皮的ISEL分布不均匀，但在靠近α-SMA阳性的成纤维细胞样间质细胞的基底灶附近最为密集。电子显微镜和印天狼红均证实成纤维细胞样细胞周围胶原堆积灶附近的上皮细胞凋亡、坏死和细胞丢失。这些结果表明，纤维化肺的立方上皮既含有死亡细胞，也含有增殖细胞，支持肺泡上皮细胞死亡是由异常的肺成纤维细胞在体内和体外诱导的假说。
Earlier work from this laboratory showed that abnormal fibroblast phenotypes isolated from fibrotic human lung produce factor(s) capable of inducing apoptosis and necrosis of alveolar epithelial cells in vitro [B. D. Uhal, I. Joshi, A. True, S. Mundle, A. Raza, A. Pardo, and M. Selman. Am. J. Physiol. 269 (Lung Cell. Mel. Physiol. 13): L819-L828, 1995]. To determine whether epithelial cell death is associated with proximity to abnormal fibroblasts in vivo, the spatial distribution of epithelial cell loss, DNA fragmentation, and myofibroblasts was examined in the same tissue specimens used previously for fibroblast isolation. Paraffin sections of normal and fibrotic human lung were subjected to in situ end labeling (ISEL) of fragmented DNA and simultaneous immunolabeling of alpha-smooth muscle actin (alpha-SMA); replicate samples were subjected to electron microscopy and detection of collagens by the picrosirius red technique. Normal human lung exhibited very little labeling except for positive alpha-SMA immunoreactivity of smooth muscle surrounding bronchi and vessels. In contrast, fibrotic human lung exhibited moderate to heavy ISEL of interstitial, cuboidal epithelial, and free alveolar cells. ISEL of the alveolar epithelium was not distributed uniformly but was most intense immediately adjacent to underlying foci of alpha-SMA-positive fibroblast-like interstitial cells. Both electron microscopy and picrosirius red confirmed epithelial cell apoptosis, necrosis, and cell loss adjacent to foci of collagen accumulation surrounding fibroblast-like cells. These results demonstrate that the cuboidal epithelium of the fibrotic lung contains dying as well as proliferating cells and support the hypothesis that alveolar epithelial cell death is induced by abnormal lung fibroblasts in vivo as it is in vitro.