Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model.
Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model.
复制标题
截短的纤溶酶原激活剂抑制剂-1蛋白可以保护鼠模型中辐射介导的肺纤维化。
DOI：
10.1016/j.ijrobp.2015.11.044
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Citrin D
中科院分区：
文献类型：
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作者：
Chung EJ;McKay-Corkum G;Chung S;White A;Scroggins BT;Mitchell JB;Mulligan-Kehoe MJ;Citrin D
纤维化是胸部照射的一种晚期毒性，可导致大量发病。纤溶酶原激活物抑制剂-1（派-1）是细胞衰老和纤维蛋白稳定的关键介质。我们试图确定重组截短派-1蛋白（rPAI-123）的递送是否会防止辐射诱导的肺损伤的发展。C57 B1/6小鼠在辐射暴露前两天开始接受腹膜内注射rPAI-123（5.4 μg/kg/天）或媒介物18周（每天5次，每次6戈伊）。跟踪小鼠队列的存活率（每个处理n=8）和组织收集（每个处理和时间点n=3）。采用Masson三色染色和羟脯氨酸含量测定评价肺纤维化。通过肺和原代肺细胞中β-半乳糖苷酶活性的染色评估衰老。与接受媒介物的小鼠相比，接受rPAI-123的小鼠中照射的肺中的羟脯氨酸含量显著降低（IR+媒介物：84.97，IR+rPAI-123：56.2 μg/肺，p=0.001）。暴露于IR+媒介物的C57 B1/6小鼠在19周时具有胸膜下纤维化的致密病灶，而暴露于IR+rPAI-123的小鼠的肺基本上没有纤维化病灶。细胞衰老显着降低rPAI-123治疗在原代肺细胞培养物和肺在多个时间点后IR。这些研究表明，rPAI-123能够防止辐射诱导的小鼠肺纤维化。这些抗纤维化作用与II型肺细胞中纤维蛋白代谢增加、基质金属蛋白酶-3（MMP-3）表达增强和衰老减少相关。rPAI-123是治疗放射性纤维化的新选择。
Fibrosis is a late toxicity of thoracic irradiation that can result in substantial morbidity. Plasminogen activator inhibitor-1 (PAI-1) is a critical mediator of cellular senescence and fibrin stabilization. We sought to determine if the delivery of recombinant truncated PAI-1 protein (rPAI-123) would protect from the development of radiation-induced lung injury. C57Bl/6 mice received intraperitoneal injections of rPAI-123 (5.4 μg/kg/day) or vehicle for 18 weeks beginning two days prior to radiation exposure (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson-Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for beta-galactosidase activity in lung and primary pneumocytes. Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-123 compared to mice that received vehicle (IR+vehicle: 84.97, IR+rPAI-123: 56.2 μg/lung, p=0.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-123 were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-123 treatment in primary pneumocyte cultures and in lung at multiple time points after IR. These studies identify that rPAI-123 is capable of preventing radiation-induced fibrosis in murine lungs. These anti-fibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 (MMP-3) expression and reduced senescence in type II pneumocytes. rPAI-123 is a novel therapeutic option for radiation-induced fibrosis.