Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.
Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.
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DOI：
10.1038/s41598-017-00270-0
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发表时间：
2017-03-10
影响因子：
4.6
通讯作者：
Kreuz S
中科院分区：
文献类型：
--
作者：
Aumiller V;Strobel B;Romeike M;Schuler M;Stierstorfer BE;Kreuz S
细胞外基质（ECM）的组成和硬度是纤维化疾病发展和持续的主要驱动力。赖氨酰氧化酶（LOX）和LOX样（LOXL）蛋白由于其胶原交联和细胞内功能而在ECM重塑中起关键作用。在这里，我们系统地研究了LOX/L在纤维化条件下，博莱霉素（BLM）诱导的肺纤维化和人IPF组织中的原代成纤维细胞和上皮细胞中的表达。在上皮细胞中检测到所有LOX/L家族成员的基础表达，在成纤维细胞中检测到更高水平的表达。各种促纤维化刺激广泛诱导LOX/L在成纤维细胞中的表达，而在上皮细胞中观察到LOXL 2和部分LOX的特异性诱导。来自14名IPF患者和健康供体的肺组织的免疫组织化学分析揭示了支气管和肺泡上皮以及成纤维细胞灶中LOX和LOXL 2的强烈诱导。使用siRNA实验，我们观察到LOXL 2和LOXL 3对于成纤维细胞向肌成纤维细胞转化（FMT）至关重要。由于FMT只能用具有酶活性的LOXL 2变体重建，因此我们得出结论，LOXL 2酶功能对于成纤维细胞转分化至关重要。总之，我们的研究提供了对纤维化肺病中LOX/L家族的全面分析，并表明L0 XL 2/3在成纤维细胞活化中以及LOX/L0 XL 2在IPF中的突出作用。
Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts. Various pro-fibrotic stimuli broadly induced LOX/L expression in fibroblasts, whereas specific induction of LOXL2 and partially LOX was observed in epithelial cells. Immunohistochemical analysis of lung tissue from 14 IPF patients and healthy donors revealed strong induction of LOX and LOXL2 in bronchial and alveolar epithelium as well as fibroblastic foci. Using siRNA experiments we observed that LOXL2 and LOXL3 were crucial for fibroblast-to-myofibroblast transition (FMT). As FMT could only be reconstituted with an enzymatically active LOXL2 variant, we conclude that LOXL2 enzymatic function is crucial for fibroblast transdifferentiation. In summary, our study provides a comprehensive analysis of the LOX/L family in fibrotic lung disease and indicates prominent roles for LOXL2/3 in fibroblast activation and LOX/LOXL2 in IPF.