Atochina-Vasserman Elena N, Guo Chang-Jiang, Abramova Elena, Golden Thea N, Sims Michael, James Melane L, Beers Michael F, Gow Andrew J, Krymskaya Vera P
1 Airway Biology Initiative and.
2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
Am J Respir Cell Mol Biol. 2015 Jul;53(1):96-104. doi: 10.1165/rcmb.2014-0224OC.
Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations of the tumor suppressor genes, tuberous sclerosis complex (TSC) 1 or TSC2. LAM affects women almost exclusively, and it is characterized by neoplastic growth of atypical smooth muscle-like TSC2-null LAM cells in the pulmonary interstitium, cystic destruction of lung parenchyma, and progressive decline in lung function. In this study, we hypothesized that TSC2-null lesions promote a proinflammatory environment, which contributes to lung parenchyma destruction. Using a TSC2-null female murine LAM model, we demonstrate that TSC2-null lesions promote alveolar macrophage accumulation, recruitment of immature multinucleated cells, an increased induction of proinflammatory genes, nitric oxide (NO) synthase 2, IL-6, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and up-regulation of IL-6, KC, MCP-1, and transforming growth factor-β1 levels in bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid also contained an increased level of surfactant protein (SP)-D, but not SP-A, significant reduction of SP-B levels, and a resultant increase in alveolar surface tension. Consistent with the growth of TSC2-null lesions, NO levels were also increased and, in turn, modified SP-D through S-nitrosylation, forming S-nitrosylated SP-D, a known consequence of lung inflammation. Progressive growth of TSC2-null lesions was accompanied by elevated levels of matrix metalloproteinase-3 and -9. This report demonstrates a link between growth of TSC2-null lesions and inflammation-induced surfactant dysfunction that might contribute to lung destruction in LAM.
肺淋巴管平滑肌瘤病（LAM）是一种由肿瘤抑制基因结节性硬化复合物（TSC）1或TSC2突变引起的罕见肺部疾病。LAM几乎只影响女性，其特征是肺间质中出现非典型平滑肌样TSC2缺失的LAM细胞的肿瘤性生长、肺实质的囊性破坏以及肺功能的进行性下降。在本研究中，我们假设TSC2缺失的病变促进促炎环境，这导致肺实质破坏。使用TSC2缺失的雌性小鼠LAM模型，我们证明TSC2缺失的病变促进肺泡巨噬细胞积聚、未成熟多核细胞的募集、促炎基因、一氧化氮（NO）合酶2、白细胞介素-6、趋化因子（C-C基序）配体2（CCL2）/单核细胞趋化蛋白1（MCP1）、趋化因子（C-X-C基序）配体1（CXCL1）/角质形成细胞趋化因子（KC）的诱导增加，以及支气管肺泡灌洗液中白细胞介素-6、KC、MCP-1和转化生长因子-β1水平的上调。支气管肺泡灌洗液中表面活性蛋白（SP）-D水平也升高，但SP-A水平未升高，SP-B水平显著降低，导致肺泡表面张力增加。与TSC2缺失病变的生长一致，NO水平也升高，进而通过S-亚硝基化修饰SP-D，形成S-亚硝基化SP-D，这是肺部炎症的已知后果。TSC2缺失病变的进行性生长伴随着基质金属蛋白酶-3和-9水平的升高。本报告证明了TSC2缺失病变的生长与炎症诱导的表面活性物质功能障碍之间的联系，这可能导致LAM中的肺破坏。
