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: 6966967
• 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/6966967
• 关键词: abdomen neoplasm; asthma; bone density; cellular pathology; diphosphonate; disease /disorder prevention /control; epidemiology; estrogens; female; gene expression; histopathology; hormone therapy; human subject; human therapy evaluation; longitudinal human study; lymphangioleiomyomatosis; melanoma; osteoporosis; pathologic process; patient oriented research; progesterone; respiratory function; smooth muscle; tuberous sclerosis; women' s health

Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (lymphangiomyomas and angiomyolipomas). The disease, which presents in middle-aged women, is characterized by the proliferation of abnormal smooth muscle containing premelanosomal structures similar to those found in melanoma cells. 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 an inherited disorder, tuberous sclerosis complex. Gene expression and cell regulatory pathways have been examined in tissue samples. We have found that lung diffusion (DLCO) and/or forced expiratory volume in the first second (FEV1) are decreased, but, frequently, not in parallel with each other. Cardiopulmonary exercise testing (CPET) uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements. LAM appears to be exacerbated by estrogens. Hence, hormonal therapy with progesterone is frequently employed; however, efficacy has not been demonstrated. Our aim was to determine whether progesterone administration slowed the decline in lung function in LAM. The study population comprised 348 patients with LAM participating in our longitudinal research protocol. Declines in DLCO and FEV1 were measured in 275 patients followed for approximately four years. The declines in DLCO and FEV1 of patients treated with progesterone, orally (n=67) or intramuscularly (n=72), were compared with those of untreated patients (n=136). Overall yearly rates of decline in DLCO and FEV1 were, respectively, 2.4?0.4 (0.69?0.07 ml/min/mmHg) and 1.7?0.4 (75?9 ml) percent- predicted. The most significant predictors of functional decline were initial lung function and age. After adjusting for initial FEV1, age, and duration of disease, patients treated with intramuscular progesterone tended to have lower rates of decline in FEV1 than patients treated orally (1.9?0.6 versus 3.2?0.8 percent-predicted, respectively, p=0.081). However, there was no significant difference in rates of decline in FEV1 between patients treated with intramuscular progesterone and untreated patients (1.9?0.6 versus 0.8?0.5 percent-predicted, respectively, p=0.520), and patients treated with oral progesterone and untreated patients (3.2?0.8 versus 0.8?0.5 percent-predicted, respectively, p=0.064). After adjusting for initial DLCO, rates of decline in DLCO were significantly higher in patients treated with oral (3.6?0.7 percent-predicted, p=0.002) and intramuscular (2.8?0.5 percent-predicted, p=0.022) progesterone, than in untreated patients (1.6?0.6 percent-predicted). Within the limitations of a retrospective study, our data suggest that progesterone therapy does not slow the decline in lung function in LAM. Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM) is frequently treated with anti-estrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether anti-estrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD, found in 70% of the patients, was correlated with severity of lung disease and age. Greater severity of lung disease, menopause and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, similar rates of BMD decline were found in progesterone-treated (n=122) and untreated patients (n=89). After similar adjustments we found that bisphosphonate-treated patients (n=98) had lower rates of decline in lumbar spine BMD (---00...004?0.003 vs. -0.015?0.003 gm/cm 2, p=0.036) and T-scores (-0.050?0.041 vs. -0.191? 0.041, p<0.001), than untreated patients (n=113). Thus, abnormal BMD was frequent in LAM. Progesterone therapy was not associated with changes in BMD; bisphosphonate therapy was associated with lower rates of bone loss. Based on these observations we recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.

淋巴管平滑肌瘤病 (LAM) 是一种多系统疾病，以囊性肺病和腹部肿瘤（淋巴管肌瘤和血管平滑肌脂肪瘤）为特征。这种疾病出现在中年女性中，其特征是异常平滑肌的增殖，其中含有与黑色素瘤细胞中发现的类似的前黑素体结构。临床方案使该分部能够聚集一大批 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遗传性疾病、结节性硬化症的关系。已经在组织样本中检查了基因表达和细胞调控途径。我们发现肺弥散量 (DLCO) 和/或第一秒用力呼气量 (FEV1) 减少，但常常彼此不平行。心肺运动测试（CPET）可发现运动引起的低氧血症的存在，并有助于对疾病的严重程度进行分级并确定补充氧气的需求。 雌激素似乎会加剧 LAM。因此，经常采用黄体酮激素治疗。然而，其功效尚未得到证实。我们的目的是确定黄体酮给药是否可以减缓 LAM 肺功能的下降。研究人群包括参与我们纵向研究方案的 348 名 LAM 患者。对 275 名患者进行了为期大约四年的随访，测量了 DLCO 和 FEV1 的下降情况。将口服黄体酮 (n=67) 或肌肉注射 (n=72) 治疗的患者的 DLCO 和 FEV1 下降与未经治疗的患者 (n=136) 进行比较。 DLCO 和 FEV1 的总体年下降率预计分别为 2.4±0.4 (0.69±0.07 ml/min/mmHg) 和 1.7±0.4 (75±9 ml)%。功能下降最重要的预测因素是初始肺功能和年龄。在调整初始 FEV1、年龄和病程后，肌内黄体酮治疗的患者 FEV1 下降率往往低于口服治疗的患者（预测分别为 1.9±0.6% 和 3.2±0.8%，p=0.081）。然而，肌注黄体酮治疗的患者和未治疗的患者之间、以及口服黄体酮治疗的患者和未治疗的患者之间，FEV1 下降率没有显着差异（预测分别为 1.9±0.6% 与 0.8±0.5%，p=0.520）。 （预测百分比分别为 3.2±0.8 与 0.8±0.5，p=0.064）。调整初始 DLCO 后，口服黄体酮（预测为 3.6±0.7%，p=0.002）和肌肉注射（预测为 2.8±0.5%，p=0.022）黄体酮治疗的患者的 DLCO 下降率显着高于未治疗的患者患者（1.6%？0.6% 预测）。在回顾性研究的局限性内，我们的数据表明黄体酮治疗并不能减缓 LAM 肺功能的下降。 雌激素缺乏和肺部疾病与骨矿物质密度（BMD）损失有关。淋巴管平滑肌瘤病 (LAM) 经常采用抗雌激素治疗，即黄体酮和/或卵巢切除术来治疗。因此，我们每年评估 211 名 LAM 患者的 BMD，以确定 BMD 异常的发生率、抗雌激素治疗是否会降低 BMD，以及双磷酸盐治疗是否可以预防骨质流失。 70% 的患者发现 BMD 异常，与肺部疾病的严重程度和年龄相关。肺部疾病、更年期和卵巢切除术的严重程度与 BMD 下降幅度更大相关。调整初始肺功能和 BMD 的差异后，在接受黄体酮治疗的患者 (n=122) 和未经治疗的患者 (n=89) 中发现 BMD 下降率相似。经过类似的调整，我们发现双膦酸盐治疗的患者 (n=98) 腰椎 BMD 下降率较低 (---00...004?0.003 vs. -0.015?0.003 gm/cm 2, p=0.036)和 T 分数（-0.050?0.041 与 -0.191?0.041， p<0.001)，高于未治疗的患者 (n=113)。因此，LAM 中 BMD 异常很常见。黄体酮治疗与 BMD 变化无关；双膦酸盐治疗与较低的骨丢失率相关。基于这些观察结果，我们建议对 LAM 患者进行 BMD 系统评估和早期双磷酸盐治疗。