Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice.
Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice.
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DOI：
10.1016/j.ajpath.2016.04.014
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
T. Zhao;Xinchun Ding;H. Du;Cong Yan
中科院分区：
文献类型：
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作者：
T. Zhao;Xinchun Ding;H. Du;Cong Yan
溶酶体酸性脂肪酶（lysosomalacidlipase，LAL）是中性脂质代谢途径中的关键酶，与炎症和肿瘤的发生发展密切相关。LAL缺陷（利帕−/−）小鼠的一个主要表现是与髓源性抑制细胞扩增相关的肿瘤生长和转移增加。在肺中，LAL在肺泡II型上皮细胞中高度表达。为了评估肺上皮细胞中的LAL如何在这种炎症相关的致病过程中发挥作用，通过将CCSP驱动的rtTA转基因和（TetO）7-CMV-hLAL转基因杂交到Lipa −/−小鼠（CCSP-Tg/KO）中，建立了Lipa −/−小鼠中肺泡II型上皮细胞特异性表达人LAL（hLAL）。hLAL在肺上皮细胞中的表达不仅减少了肺中促肿瘤的髓源性抑制细胞，而且下调了促肿瘤细胞因子和趋化因子的合成和分泌到Lipa −/−小鼠的支气管肺泡灌洗液中。hLAL表达降低支气管肺泡灌洗液细胞的免疫抑制功能，抑制骨髓细胞跨内皮迁移，并抑制Lipa −/−小鼠内皮细胞增殖和迁移。结果表明，hLAL在CCSP-Tg/KO小鼠中的表达可纠正肺损伤，抑制体外肿瘤细胞增殖和迁移，抑制体内肿瘤向肺转移。这些结果支持了这样一个概念，即LAL是肺上皮细胞中调节肺稳态、免疫应答和肿瘤转移的关键代谢酶。
Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa−/−) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell–specific expression of human LAL (hLAL) inLipa−/−mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene intoLipa−/−mice (CCSP-Tg/KO). hLAL expression in lung epithelial cells not only reduced tumor-promoting myeloid-derived suppressor cells in the lung, but also down-regulated the synthesis and secretion of tumor-promoting cytokines and chemokines into the bronchoalveolar lavage fluid ofLipa−/−mice. hLAL expression reduced the immunosuppressive functions of bronchoalveolar lavage fluid cells, inhibited bone marrow cell transendothelial migration, and inhibited endothelial cell proliferation and migration inLipa−/−mice. As a result, hLAL expression in CCSP-Tg/KO mice corrected pulmonary damage, and inhibited tumor cell proliferation and migrationin vitro, and tumor metastasis to the lungin vivo. These results support a concept that LAL is a critical metabolic enzyme in lung epithelial cells that regulates lung homeostasis, immune response, and tumor metastasis.