AAV6-Mediated IL-10 Expression in the Lung Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice
AAV6-Mediated IL-10 Expression in the Lung Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice
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DOI：
10.1089/hum.2018.024
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发表时间：
2018-05-14
影响因子：
4.2
通讯作者：
Kume, Akihiro
中科院分区：
文献类型：
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作者：
Kurosaki, Fumio;Uchibori, Ryosuke;Kume, Akihiro
特发性肺纤维化（IPF）是一种纤维增生性疾病，治疗选择有限。重复性肺损伤的异常伤口愈合过程已被认为是其发病机制，包括转化生长因子1在内的许多细胞因子在纤维化的诱导和进展中起关键作用。因此，调节这些促炎条件可能会减少IPF的进展并改善患者的症状。白细胞介素-10 （IL-10）是一种多效细胞因子，在许多生物环境中发挥抗炎和抗纤维化作用。在本研究中，我们通过腺相关病毒血清型6载体连续表达IL-10细胞因子，研究了IL-10对博莱霉素诱导的小鼠肺纤维化的预防作用。小鼠经气管内注射编码小鼠IL-10的腺相关病毒血清型6载体，7天后皮下植入含博来霉素的渗透微型泵。然后分析肺组织学和促炎细胞因子和纤维化细胞因子的表达水平。在第35天IL-10持续表达的小鼠中，肺组织中浸润的炎症细胞数量和纤维化的发生明显减少。在治疗动物中，转化生长因子1的增加和IFN-的减少也受到抑制，这些细胞因子的变化在肺纤维化的发病机制中起重要作用。此外，IL-10显著提高了博莱霉素诱导小鼠的存活率。我们的研究结果为IL-10作为一种新的IPF治疗方法的抗纤维化作用的潜在益处提供了见解。
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder with limited therapeutic options. An aberrant wound healing process in response to repetitive lung injury has been suggested for its pathogenesis, and a number of cytokines including transforming growth factor 1 play pivotal roles in the induction and progression of fibrosis. Thus, the regulation of these pro-inflammatory conditions may reduce the progression of IPF and ameliorate its symptoms in patients. Interleukin-10 (IL-10), a pleiotropic cytokine, exerts anti-inflammatory and anti-fibrotic effects in numerous biological settings. In the present study, we investigated the preventive effects of IL-10 on bleomycin-induced pulmonary fibrosis in mice with the continuous expression of this cytokine via an adeno-associated virus serotype 6 vector. Mice were administered the adeno-associated virus serotype 6 vector encoding mouse IL-10 by intratracheal injection, and osmotic minipumps containing bleomycin were subcutaneously implanted seven days later. Lung histology and the expression levels of pro-inflammatory cytokines and fibrogenic cytokines were then analyzed. In mice exhibiting persistent IL-10 expression on day 35, the number of infiltrated inflammatory cells and the development of fibrosis in lung tissues were significantly reduced. Increases in transforming growth factor 1 and decreases in IFN- were also suppressed in treated animals, with changes in these cytokines playing important roles in the pathogenesis of pulmonary fibrosis. Furthermore, IL-10 significantly improved survival in bleomycin-induced mice. Our results provide insights into the potential benefit of the anti-fibrotic effects of IL-10 as a novel therapeutic approach for IPF.