淋巴管肌瘤病导致肺损伤的机制研究

Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease almost exclusively affecting young women, especially during children-bearing years. LAM is characterized by smooth muscle cell infiltration and emphysema-like lung destruction, leading to lung collapse and respiratory failure and mortality. The pathogenesis of LAM is very unusual: LAM cells are histologically benign smooth muscle cells carrying TSC1 or TSC2 gene mutations that are believed to metastasize to the lungs where they cause cystic lung degeneration and respiratory obstruction. It is an urgent unmet need to understand the molecular mechanisms underlying lung remodeling and translate the research findings to clinical interventions. Our preliminary studies demonstrated that estrogen stimulated matrix metalloproteinase-2 (MMP2) expression and activity and reduced the accumulation of extracellular matrix protein Type IV collagen in LAM-associated cell-based and preclinical models. Moreover, we found that TSC2-deficient cells exhibited aberrant activation of toll-like receptor signaling pathway, elevated production and secretion of pro-inflammatory cytokines, and inflammation in LAM lungs. These preliminary results formulate the rationale for this proposal. Our ultimate goal is to develop novel cell culture models and mouse models to investigate the mechanisms responsible for lung remodeling in LAM. The advancement of LAM research has been limited by the lack of in vivo models that closely recapitulate LAM lung destruction. We have successfully established a chronic lung injury model I which TSC2-deficient cells have been repeatedly inoculated intravenously to promote the formation of lung lesions, resulting in cystic lung parenchymal destruction. The significance of this project is that it will reveal for the first time how estrogen contributes to lung destruction and functional decline. This study will have high impact because LAM leads progresses much more rapidly in women with an intact estrogen axis and results in respiratory failure and death. There remains a critical need for more effective therapeutic options for women with LAM and other estrogen dependent neoplasms.

淋巴管肌瘤病（LAM）是一种罕见病，几乎都发生于孕龄期妇女。LAM以不典型淋巴管平滑肌细胞过度增生为特征，随疾病进展出现进行加重的呼吸困难，最终常因呼吸衰竭死亡。LAM细胞肺转移后形成的薄壁囊性肺结构是造成进行性呼吸困难的主要原因，因此深入探讨LAM导致肺损伤的机制有重要临床意义。我们的前期工作提示：雌激素能够刺激LAM细胞分泌基质金属蛋白酶2破坏肺细胞外基质成分；TSC2的缺失激活了Toll样受体信号通路，产生大量细胞因子，产生免疫反应。本项目拟在前期研究结果的基础上，通过细胞实验和动物模型，探讨LAM导致肺损伤的具体机制。目前LAM肺损伤的动物模型仍是空白，我们通过多次注射LAM细胞，使少数细胞进入肺部生长，形成结节，并造成肺组织损伤，成功构建了LAM导致肺损伤的小鼠模型。本项目有助于阐明LAM导致肺损伤的具体机制，明确相关信号通路为LAM的治疗和新药研发提供有效的靶点和理论基础。

淋巴管肌瘤病（LAM）是一种罕见病，几乎都发生于孕龄期妇女。LAM以不典型淋巴管平滑肌细胞过度增生为特征，随疾病进展出现进行加重的呼吸困难，最终常因呼吸衰竭死亡。LAM细胞肺转移后形成的薄壁囊性肺结构是造成进行性呼吸困难的主要原因，因此深入探讨LAM导致肺损伤的机制有重要临床意义。我们的前期工作提示：雌激素能够刺激LAM细胞分泌基质金属蛋白酶2破坏肺细胞外基质成分；TSC2的缺失激活了Toll样受体信号通路，产生大量细胞因子，产生免疫反应。本项目拟在前期研究结果的基础上，通过细胞实验和动物模型，探讨LAM导致肺损伤的具体机制。目前LAM肺损伤的动物模型仍是空白，我们通过多次注射LAM细胞，使少数细胞进入肺部生长，形成结节，并造成肺组织损伤，成功构建了LAM导致肺损伤的小鼠模型。本项目有助于阐明LAM导致肺损伤的具体机制，明确相关信号通路为LAM的治疗和新药研发提供有效的靶点和理论基础。