Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model
Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model
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DOI：
10.5114/fn.2019.83830
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发表时间：
2019-01-01
影响因子：
2
通讯作者：
Lucas, Alexandra R.
中科院分区：
文献类型：
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作者：
Kwiecien, Jacek M.;Dabrowski, Wojciech;Lucas, Alexandra R.
用抗炎药物治疗脊髓损伤（SCI）性炎症。我们比较了脊髓局部或腹腔内输注两种黏液瘤病毒衍生的免疫调节蛋白Serp-1和M-T7与地塞米松（DEX）的疗效。脊髓损伤后出血和坏死启动了一个复杂的发病机制，以早期、严重和高度破坏性的炎性巨噬细胞浸润为主。我们研究了持续7天的硬膜下输注M-T7（一种化学因子调节剂）或Serp-1（一种纤溶酶原激活剂和因子抑制剂）。成熟雄性大鼠硬膜外球囊挤压脊髓损伤，经渗透泵持续硬膜下灌注Serp-1、M-T7、DEX或生理盐水7天。另一组脊髓损伤大鼠腹腔内输注。临床评价包括终点监测体重、出血性膀胱炎和双侧脚趾夹痛反应。对脊髓切片进行组织学分析，并对损伤腔（COI）内巨噬细胞数量进行标准化计数。给予DEX的大鼠表现出明显的体重减轻、脱水和皮肤萎缩，与类固醇毒性一致，而给予Serp-1和M-T7的大鼠没有毒性。Serp-1改善戒断反应。硬膜下灌注Serp-1、M-T7和DEX可显著减少吞噬细胞和cd68阳性巨噬细胞的数量。腹腔注射M-T7可降低巨噬细胞计数，Serp-1仅呈趋势。局部输注高活性免疫调节蛋白；针对丝氨酸蛋白酶和趋化因子途径的Serp-1和M-T7在严重脊髓损伤大鼠模型中显示出良好的神经保护潜力，且无不良副作用。持续硬膜下输注为脊髓损伤的治疗提供了另一种给药途径。
Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX).Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and highly destructive inflammatory macrophage infiltration. We examined sustained, 7-day, subdural infusion of either M-T7, a chemo-kine modulator or Serp-1, a plasminogen activator and factor inhibitor. Mature male rats had epidural balloon crush SCI and sustained subdural infusion of Serp-1, M-T7, DEX or saline for 7 days via the osmotic pump. A separate group of rats with SCI had intra-peritoneal infusion. Clinical evaluation included endpoint monitoring with body weight, hemorrhagic cystitis and bilateral toe pinch response. Sections of the spinal cord were analyzed histologically and macrophage numbers counted by standardized protocol in the cavity of injury (COI).While the rats administered DEX demonstrated substantial body weight loss, dehydration and dermal atrophy consistent with steroid toxicity, rats infused with Serp-1 and M-T7 had no toxicity. Serp-1 improved withdrawal responses. Subdural infusion of Serp-1, M-T7 and DEX significantly reduced numbers of phagocytic, CD68-positive macrophages. With intraperitoneal infusion only M-T7 reduced macrophage counts, Serp-1 showed only a trend. Local infusion of highly active immune modulating proteins; Serp-1 and M-T7, targeting serine protease and chemokine pathways demonstrated excellent potential for neuroprotection after severe SCI in a rat model, without adverse side effects. Sustained subdural infusion offers an alternative route of administration for treatment of SCI.