CHARACTERIZATION OF THE PATHOGENESIS OF LYMPHANGIOLEIOMYOMATOSIS (LAM)

淋巴管平滑肌瘤病 (LAM) 发病机制的特征

• 批准号: 2441409
• 负责人: J MOSS
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2441409
• 关键词: antigen antibody reaction; ascites; cellular pathology; clinical research; dyspneas; glycoproteins; histopathology; human subject; immunocytochemistry; immunoelectron microscopy; leiomyoma; lung; monoclonal antibody; northern blottings; oncoproteins; pneumothorax disorder; respiratory reflex; smooth muscle

Pulmonary lymphangioleiomyomatosis (LAM) is an uncommon disorder that occurs almost exclusively in women of childbearing age. The clinical presentation of LAM is quite distinctive and includes recurrent spontaneous pneumothorax, chylothorax, hemoptysis, chylous ascites and slowly progressive dyspnea. The cardinal histopathologic finding is a remarkable proliferation of immature-appearing, disorganized smooth muscle cells in the lung and along axial lymphatics in the thorax and abdomen. It is likely that most clinical symptoms and signs of LAM are due to abnormal smooth cell proliferation. The abnormal smooth muscle cells in LAM are shorter, plumper, and have a higher ratio of nucleus to cytoplasm than normal smooth muscle cells. Interestingly, these abnormal smooth muscle cells, unlike their normal counterparts in airways or blood vessels, react with monoclonal antibody HMB45, which reacts with a 100- kDa glycoprotein (termed gp100) found in human melanoma cells. To characterize the antigens recognized by HMB45, normal human lung tissue, lung specimens from four patients with LAM, and cells from three melanoma cell lines (Malme-3M, A2058, and CHL-1) were subjected to Northern analysis, immunohistochemical and electron microscopic studies as well as Northern analysis using a full-length gp100 cDNA probe generated by reverse transcription-polymerase chain reaction from total RNA isolated from Malme-3M cells. Levels of gp100 mRNA were highest in Malme-3M cells, followed by A2058 cells, and then lung tissue of individuals with LAM; it was not detected in normal lung or CHL-1 cells. Immunohistochemical staining for HMB45 was intense in Malme-3M cells, and less in A2058 cells and lung tissue of individuals with LAM. HMBYS reactivity; it was not detected in normal lung or CHL-1 cells. Electron-dense small granules with a fine lamellar structure in the cytoplasm of abnormal smooth muscle cells in LAM lung were detected by electron microscopy. These granules resembled immature melanosomes in Malme-3M cells. Further, these electron-dense granules contained HMB45-binding sites as demonstrated by immunoelectron microscopy.

肺淋巴管平滑肌瘤病 (LAM) 是一种罕见的疾病， 几乎只发生在育龄妇女身上。临床上 LAM 的呈现非常独特，并且包括反复出现的 自发性气胸、乳糜胸、咯血、乳糜腹水等 缓慢进行性呼吸困难。主要的组织病理学发现是 表面上不成熟、杂乱无章的光滑细胞的显着增殖 肺部的肌肉细胞和胸部的轴向淋巴管 腹部。 LAM 的大多数临床症状和体征可能是 由于平滑细胞异常增殖。异常平滑肌 LAM 中的细胞更短、更丰满，并且细胞核与细胞核的比例更高。 细胞质高于正常平滑肌细胞。有趣的是，这些异常 平滑肌细胞，与气道或血液中的正常对应物不同 血管，与单克隆抗体 HMB45 反应，该抗体与 100- 在人类黑色素瘤细胞中发现的 kDa 糖蛋白（称为 gp100）。 到 表征 HMB45、正常人肺组织识别的抗原， 四名 LAM 患者的肺标本和三名黑色素瘤的细胞 细胞系（Malme-3M、A2058 和 CHL-1）经过 Northern 分析、免疫组织化学和电子显微镜研究 使用由以下方法生成的全长 gp100 cDNA 探针进行 Northern 分析 从总 RNA 中分离的逆转录聚合酶链反应 来自 Malme-3M 细胞。 Malme-3M 细胞中 gp100 mRNA 的水平最高， 其次是 A2058 细胞，然后是 LAM 个体的肺组织； 在正常肺或 CHL-1 细胞中未检测到它。 免疫组织化学 Malme-3M 细胞中 HMB45 的染色较强烈，而 A2058 细胞中的染色较弱 和 LAM 患者的肺组织。 HMBYS 反应性；不是 在正常肺或 CHL-1 细胞中检测到。电子致密小颗粒 异常平滑肌的细胞质中具有精细的层状结构 通过电子显微镜检测LAM肺中的细胞。 这些颗粒 类似于 Malme-3M 细胞中未成熟的黑素体。此外，这些 电子致密颗粒含有 HMB45 结合位点，如下所示 免疫电子显微镜。