Valencia Julio C, Pacheco-Rodriguez Gustavo, Carmona Adriana K, Xavier Janina, Bruneval Patrick, Riemenschneider William K, Ikeda Yoshihiko, Yu Zu-Xi, Ferrans Victor J, Moss Joel
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Respir Cell Mol Biol. 2006 Jul;35(1):40-7. doi: 10.1165/rcmb.2005-0387OC. Epub 2006 Feb 10.
Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas, lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin, affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play a role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser-captured microdissection from LAM nodules. Angiotensin I-converting enzyme and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II type 1 and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing alpha-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacologic target.
淋巴管平滑肌瘤病（LAM）是一种在中年女性中发现的多系统疾病，其特征为肺囊性破坏和腹部肿瘤（如血管平滑肌脂肪瘤、淋巴管肌瘤），由外观异常的平滑肌样细胞（LAM细胞）增殖所致。LAM细胞与其他细胞共同在肺间质和囊肿壁内形成结节状结构。LAM细胞在结节性硬化复合物TSC1和/或TSC2基因中存在突变，这导致雷帕霉素哺乳动物靶点失调，影响细胞生长和增殖。血管平滑肌细胞的增殖和迁移以及血管生成因子的产生部分受血管紧张素II调节。为了确定LAM特异性肾素 - 血管紧张素系统是否可能在LAM发病机制中起作用，我们研究了该系统的基因和基因产物在LAM结节中的表达。通过激光捕获显微切割从LAM结节分离的RNA中存在血管紧张素原的mRNA。LAM结节内存在血管紧张素I转换酶和产生糜酶的肥大细胞。通过mRNA的存在和免疫组织化学测定，我们在LAM细胞中检测到了肾素。通过免疫组织化学和显微切割的LAM结节的免疫印迹在LAM细胞中鉴定出血管紧张素II 1型和II型受体。血管紧张素II定位于含有α平滑肌肌动蛋白的细胞（LAM细胞）中。一种LAM特异性肾素 - 血管紧张素系统似乎在LAM结节内作为自分泌系统发挥作用，可促进LAM细胞增殖和迁移，并且可能代表一个药理学靶点。
