Zhang Liqiang, Yaron Jordan R, Tafoya Amanda M, Wallace Sarah E, Kilbourne Jacquelyn, Haydel Shelley, Rege Kaushal, McFadden Grant, Lucas Alexandra R
Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Center for Bioelectronics and Biosensors, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
J Clin Med. 2019 Oct 4;8(10):1626. doi: 10.3390/jcm8101626.
Numerous treatments have been developed to promote wound healing based on current understandings of the healing process. Hemorrhaging, clotting, and associated inflammation regulate early wound healing. We investigated treatment with a virus-derived immune modulating serine protease inhibitor (SERPIN), Serp-1, which inhibits thrombolytic proteases and inflammation, in a mouse excisional wound model. Saline or recombinant Serp-1 were applied directly to wounds as single doses of 1 μg or 2 µg or as two 1 µg boluses. A chitosan-collagen hydrogel was also tested for Serp-1 delivery. Wound size was measured daily for 15 days and scarring assessed by Masson's trichrome, Herovici's staining, and immune cell dynamics and angiogenesis by immunohistochemistry. Serp-1 treatment significantly accelerated wound healing, but was blocked by urokinase-type plasminogen activator (uPAR) antibody. Repeated dosing at a lower concentration was more effective than single high-dose serpin. A single application of Serp-1-loaded chitosan-collagen hydrogel was as effective as repeated aqueous Serp-1 dosing. Serp-1 treatment of wounds increased arginase-1-expressing M2-polarized macrophage counts and periwound angiogenesis in the wound bed. Collagen staining also demonstrated that Serp-1 improves collagen maturation and organization at the wound site. Serp-1 has potential as a safe and effective immune modulating treatment that targets thrombolytic proteases, accelerating healing and reducing scar in deep cutaneous wounds.
基于目前对愈合过程的理解，已经开发出许多促进伤口愈合的治疗方法。出血、凝血及相关炎症调节早期伤口愈合。我们在小鼠切除伤口模型中研究了一种病毒衍生的免疫调节丝氨酸蛋白酶抑制剂（SERPIN）Serp-1的治疗效果，该抑制剂可抑制溶栓蛋白酶和炎症。将生理盐水或重组Serp-1以1μg或2μg的单剂量或两次1μg的推注直接应用于伤口。还测试了一种壳聚糖-胶原蛋白水凝胶用于递送Serp-1。连续15天每天测量伤口大小，并通过Masson三色染色法、Herovici染色法评估瘢痕形成，通过免疫组织化学评估免疫细胞动力学和血管生成。Serp-1治疗显著加速了伤口愈合，但被尿激酶型纤溶酶原激活剂（uPAR）抗体阻断。较低浓度的重复给药比较高剂量的单一丝氨酸蛋白酶抑制剂更有效。单次应用负载Serp-1的壳聚糖-胶原蛋白水凝胶与重复给予Serp-1水溶液的效果相同。Serp-1治疗伤口可增加伤口床中表达精氨酸酶-1的M2极化巨噬细胞数量和伤口周围血管生成。胶原蛋白染色还表明，Serp-1可改善伤口部位胶原蛋白的成熟和组织化。Serp-1作为一种安全有效的免疫调节治疗方法具有潜力，它靶向溶栓蛋白酶，可加速深层皮肤伤口的愈合并减少瘢痕形成。
