Characterization of the Pathogenesis of Lymphangioleiomy

淋巴管平滑肌切除术发病机制的表征

• 批准号: 7321600
• 负责人: Joel 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/7321600
• 关键词: Characterization; Pathogenesis; Lymphangioleiomy

Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (e.g., lymphangioleiomyomas, angiomyolipomas). The disease, which often presents in middle-aged women, is characterized by the proliferation of abnormal-appearing smooth muscle-like cells, LAM cells, which contain mutations in one of two tuberous sclerosis complex genes (TSC), TSC1 or TSC2. LAM occurs more frequently in women with TSC, an autosomal dominant disorder. A clinical protocol has enabled the Branch to assemble a large cohort of patients with LAM and to document the natural history of the disease, the histopathological findings, the radiographic appearance, characteristic pulmonary function abnormalities, and the association with tuberous sclerosis complex. Patients with LAM frequently develop pneumothoraces, which may be treated by pleuredesis. We examined the spectrum and frequency of pleural abnormalities on high resolution computed tomography (CT) in patients with lymphangioleiomyomatosis (LAM) and the pleural findings associated with different types of pleurodesis (talc, mechanical, and chemical) performed to treat the complications of pleural disease in these patients. Two hundred fifty-eight patients with LAM underwent CT of the chest. Pleural abnormalities assessed included pleural thickening, presence of a pleural mass, areas of high attenuation, effusion, and pneumothorax. In patients who had had pleurodesis, the CT findings were correlated with the type of procedure performed. One hundred thirty-three (52%) of 258 patients had pleurodesis (unilateral, 68/133; bilateral, 65/133). Pleural abnormalities were more common in patients who had pleurodesis (101/133, 76%) than in those who had not had the procedure (47/125, 38%); further, the abnormalities were more prevalent on the operated side than on the unoperated side of those 68 patients who had unilateral pleurodesis. The frequencies of findings for the group without pleurodesis versus the group with pleurodesis were pleural thickening (26% vs 65%), effusion (10% vs 13%), loculated effusion (2.4% vs 11%), pneumothorax (1.6% vs 10%), areas of high attenuation (1.6% vs 23%), and mass (0.8% vs 14%), respectively. Areas of high attenuation in the pleura were present in all types of pleurodesis (mechanical, 8%; chemical, 13%; talc, 40%) and in two patients who had had repeated thoracentesis or pleurectomy. Pleural masses were present in patients who had had all types of pleurodesis (mechanical, 10%; chemical, 9%; talc, 24%) and in one patient who had had thoracentesis and thoracostomy; of importance in the differential diagnosis, the masses commonly enhanced and did not change in size over time. From this study, we conclude that abnormalities are common in patients with LAM as complications of the disease itself and as sequelae of pleurodesis and other pleura manipulations. Pneumothorax and pleural effusion result from the underlying pathophysiology of LAM, whereas areas of high attenuation and masses develop after all types of pleurodesis and other manipulations of the pleura (i.e., thoracentesis, thoracostomy). The P-CCMB continued to support the NHLBI lymphangioleiomyomatosis Registry; we were responsible for ~84-86% of the sporadic LAM and LAM/TSC patients enrolled in the study. An objective of the LAM Registry was to provide a patient database for this rare disease. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients. The initial report, published this year, described the baseline clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms. From 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded from thhe current analysis. All 230 of the remaining subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Recruitment of LAM patients with TSC was based on referral for symptoms to the lung or referral for high resolution CT to determine whether cysts characteristic of LAM were present, given a prior diagnosis of TSC. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form. The analysis of the TSC cohort with LAM was affected by the ascertainment bias in patient recruitment. Based on these data, we conclude that the age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry. The cystic lung destruction in LAM is believed to result from the proliferation of LAM cells in the lung parenchyma. 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 LAM 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) 是一种多系统疾病，以囊性肺疾病和腹部肿瘤（例如淋巴管平滑肌瘤、血管平滑肌脂肪瘤）为特征。这种疾病常见于中年女性，其特征是外观异常的平滑肌样细胞（LAM 细胞）的增殖，这些细胞含有两个结节性硬化症基因 (TSC)（TSC1 或 TSC2）之一的突变。 LAM 在患有 TSC（一种常染色体显性遗传疾病）的女性中更常见。临床方案使该部门能够收集大量 LAM 患者，并记录该疾病的自然史、组织病理学发现、放射学外观、特征性肺功能异常以及与结节性硬化症的关联。 LAM 患者经常发生气胸，可以通过胸膜固定术治疗。 我们检查了淋巴管平滑肌瘤病 (LAM) 患者的高分辨率计算机断层扫描 (CT) 胸膜异常的范围和频率，以及与不同类型胸膜固定术（滑石粉、机械和化学）治疗胸膜疾病并发症相关的胸膜表现在这些患者中。 258 名 LAM 患者接受了胸部 CT 检查。评估的胸膜异常包括胸膜增厚、存在胸膜肿块、高衰减区域、积液和气胸。在接受过胸膜固定术的患者中，CT 结果与所进行的手术类型相关。 258 名患者中有 133 名 (52%) 接受了胸膜固定术（单侧，68/133；双侧，65/133）。接受胸膜固定术的患者（101/133，76%）比未接受胸膜固定术的患者（47/125，38%）更常见胸膜异常；此外，在 68 名接受单侧胸膜固定术的患者中，手术侧的异常现象比未手术侧更为普遍。未胸膜固定术组与胸膜固定术组的发现频率为胸膜增厚（26% vs 65%）、胸腔积液（10% vs 13%）、局限性积液（2.4% vs 11%）、气胸（1.6% vs 10） %）、高衰减区域（1.6% vs 23%）和质量（0.8% vs 14%），分别。胸膜高衰减区域存在于所有类型的胸膜固定术中（机械，8%；化学，13%；滑石粉，40%）以及两名重复胸腔穿刺术或胸膜切除术的患者。接受过所有类型胸膜固定术的患者（机械，10%；化学，9%；滑石粉，24%）以及一名接受过胸腔穿刺术和胸廓造口术的患者均出现胸膜肿块；在鉴别诊断中很重要的是，肿块通常会增大，并且大小不会随着时间的推移而改变。从这项研究中，我们得出结论，作为疾病本身的并发症以及胸膜固定术和其他胸膜操作的后遗症，异常在 LAM 患者中很常见。气胸和胸腔积液是由 LAM 的潜在病理生理学引起的，而高衰减区域和肿块是在所有类型的胸膜固定术和其他胸膜操作（即胸腔穿刺术、胸廓造口术）后形成的。 P-CCMB 继续支持 NHLBI 淋巴管平滑肌瘤病登记处；参与该研究的散发性 LAM 和 LAM/TSC 患者中约有 84-86% 是由我们负责的。 LAM 登记处的目标是为这种罕见疾病提供患者数据库。先前对淋巴管平滑肌瘤病受试者临床特征的描述是基于有限数量的患者。今年发表的初步报告描述了肺淋巴管肌瘤病（散发性和结节性硬化症相关形式）受试者的基线临床特征。从1998年到2001年，243名患有肺淋巴管肌瘤病的受试者被纳入国家登记册； 13 名已接受肺移植的受试者被排除在当前分析之外。其余 230 名受试者均为女性，年龄在 18 岁至 76 岁之间（平均值 +/- SE，44.5 +/- 0.65 岁）。症状出现时的平均年龄为 38.9 +/- 0.73 岁，诊断时的平均年龄为 41.0 +/- 0.65 岁。 14.8% 的受试者存在结节性硬化症。患有 TSC 的 LAM 患者的招募是基于转诊肺部症状或转诊进行高分辨率 CT 以确定是否存在 LAM 特征的囊肿（在先前诊断为 TSC 的情况下）。 86.5% 的病例中，肺部表现（最常见的是自发性气胸）是导致诊断的主要事件。近 55% 的受试者正在接受黄体酮衍生物治疗。 57.3% 的受试者观察到肺功能测试出现阻塞模式，而 33.9% 的受试者肺量测定结果正常。与散发性淋巴管肌瘤病患者相比，患有结节性硬化症相关淋巴管平滑肌瘤病的女性更年轻，肺功能受损也更轻。 TSC 队列与 LAM 的分析受到患者招募中确定偏差的影响。根据这些数据，我们得出结论，患有肺淋巴管平滑肌瘤病的女性的年龄范围比以前认识的更广泛，并且肺功能程度可能差异很大，三分之一的受试者在登记时肺量测定正常。 LAM 中的囊性肺破坏被认为是由于肺实质中 LAM 细胞的增殖所致。 LAM 细胞与其他细胞结合，在肺间质内和囊肿壁中形成结节结构。 LAM 细胞的结节性硬化症 TSC1 和/或 TSC2 基因发生突变，导致哺乳动物雷帕霉素靶点失调，影响 LAM 细胞的生长和增殖。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到血管紧张素II的调节。为了确定 LAM 特异性肾素-血管紧张素系统是否在 LAM 的发病机制中发挥作用，我们研究了该系统在 LAM 结节中的基因和基因产物的表达。通过激光捕获显微切割从 LAM 结节中分离出的 RNA 中存在血管紧张素原的 mRNA。 LAM 结节内存在血管紧张素 I 转换酶和产生食糜酶的肥大细胞。我们通过 mRNA 的存在和免疫组织化学检测了 LAM 细胞中的肾素。通过免疫组织化学和免疫印迹显微解剖 LAM 结节，鉴定了 LAM 细胞中的血管紧张素 II 1 型和 II 型受体。血管紧张素 II 位于含有 α-平滑肌肌动蛋白的细胞（LAM 细胞）中。 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，可以促进 LAM 细胞增殖和迁移，并且可以代表药理学靶点。