Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome
Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome
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DOI：
10.1016/j.ejphar.2020.173754
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发表时间：
2021-01-09
影响因子：
5
通讯作者：
Nakazato, Masamitsu
中科院分区：
文献类型：
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作者：
Matsuo, Ayako;Tanida, Ryota;Nakazato, Masamitsu
纤维化瘢痕是急性呼吸窘迫综合征（ARDS）的重要预后因素。目前还没有抗纤维化药物或其他治疗ARDS的药物。赖氨酰氧化酶样2（L0 XL 2），一种胺氧化酶，通过促进胶原交联而促成纤维化瘢痕形成。最近的临床试验显示，针对LOXL 2的单克隆抑制性抗体在患有涉及肺的纤维化疾病的患者中未能显示出优于安慰剂的益处。这些临床结果提高了靶向L0 XL 2的细胞外酶活性本身不足以预防纤维化瘢痕形成的可能性。我们研究了LOXL 2在体内、体外和来自ARDS患者的样品中在ARDS发病机制中的作用。肺损伤后，LOXL 2在纤维化阶段的肺成纤维细胞和肌成纤维细胞的细胞核中不均匀地表达。在转化生长因子β 1（TGF-β 1）处理后，肺成纤维细胞的核LOXL 2表达上调。L0 XL 2沉默消除了TGF-β 1诱导的肌纤维化祖细胞标志物的表达、原肌成纤维细胞的出现以及肺成纤维细胞中分化的肌成纤维细胞的进化。在肺损伤后的纤维化阶段，肌成纤维细胞中Snail的核上调是明显的。我们在ARDS患者的肺中检测到高水平的LOXL 2蛋白，特别是在增殖和纤维化阶段。我们的研究结果强调了成纤维细胞中的核LOXL 2作为细胞命运决定肌成纤维细胞和纤维化瘢痕进展的主要原因驱动因素。核-L0 XL 2-靶向剂可能是针对纤维化疾病（包括ARDS）的有希望的治疗策略。
Fibrotic scarring is an important prognostic factor of acute respiratory distress syndrome (ARDS). There are currently no antifibrotic drugs or other therapeutic agents for ARDS. Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring by facilitating collagen cross-linking. Recent clinical trials revealed that a monoclonal inhibitory antibody against LOXL2 failed to show benefit over placebo in patients with fibrotic disorders involving the lungs. These clinical results raise the possibility that targeting the extracellular enzymic activity of LOXL2 is not in itself sufficient to prevent fibrotic scarring. We investigated the role of LOXL2 in the pathogenesis of ARDS in vivo, in vitro, and in samples from patients with ARDS. After lung injury, LOXL2 was unevenly expressed in the nuclei of lung fibroblasts and myofibroblasts in the fibrotic phase. Nuclear LOXL2 expression was upregulated in lung fibroblasts after transforming growth factor-betal (TGF-beta 1)-treatment. LOXL2 silencing abrogated the TGF-beta 1-induced expression of a myofibrogenic-progenitor marker, the appearance of proto-myofibroblasts, and the evolution of differentiated myofibroblasts in lung fibroblasts. Nuclear upregulation of Snail was evident in myofibroblasts during the fibrotic phase after lung injury. We detected high levels of LOXL2 protein in the lungs of ARDS patients, specifically during the proliferative and fibrotic phases. Our results highlight nuclear LOXL2 in fibroblasts as a primary causative driver of cell-fate decision toward myofibroblasts and of the progression of fibrotic scarring. A nuclear-LOXL2-targeted agent could be a promising therapeutic strategy against fibrotic disorders including ARDS.