Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair.
Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair.
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DOI：
10.3389/fmed.2015.00086
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发表时间：
2015
影响因子：
3.9
通讯作者：
Wagener FA
中科院分区：
文献类型：
--
作者：
Cremers NA;Suttorp M;Gerritsen MM;Wong RJ;van Run-van Breda C;van Dam GM;Brouwer KM;Kuijpers-Jagtman AM;Carels CE;Lundvig DM;Wagener FA
手术或损伤后的机械应力可促进病理性伤口愈合和纤维化，并导致功能丧失和审美问题。夹板切除创面可作为诱导机械应力的模型。细胞保护酶血红素加氧酶-1(HO-1)被认为是协调防御炎症和氧化侮辱，推动纤维化。在这里，我们研究了HO-1-Luc转基因小鼠在夹板和非夹板全层切除创面模型中HO-1系统的激活。评估夹板对伤口闭合、HO-1启动子活性以及炎症和纤维化标志物的影响。七天后，夹板伤口比非夹板伤口大三倍以上，显示伤口闭合延迟。HO-1启动子活性在去除真皮后迅速下降，但在夹板和非夹板伤口的皮肤修复过程中均被诱导。夹板固定诱导7天创面HO-1基因表达增加，但HO-1蛋白在表皮中的表达较低，可能是由于再上皮化组织中角质形成细胞数量较少所致。在7天的夹板创面中，F4/80阳性的巨噬细胞、αSMA阳性的肌成纤维细胞以及炎症基因IL-1β、α和COX-2的水平增加。令人惊讶的是，夹板后7d创面新生胶原(III型)的mRNA表达较低，而血管内皮生长因子(VEGF)和基质金属蛋白酶-9(MMP9)的表达增加。综上所述，这些数据表明夹板延迟皮肤伤口的闭合和HO-1蛋白的诱导。夹板后的促炎环境可能有助于增加肌成纤维细胞的数量，并增加纤维化和瘢痕形成的风险。因此，诱导HO-1活性对抗机械应激引起的炎症和纤维化可能是一种有趣的策略，可以防止手术对口腔裂伤患者或烧伤患者的生长和功能产生负面影响。
Mechanical stress following surgery or injury can promote pathological wound healing and fibrosis, and lead to functional loss and esthetic problems. Splinted excisional wounds can be used as a model for inducing mechanical stress. The cytoprotective enzyme heme oxygenase-1 (HO-1) is thought to orchestrate the defense against inflammatory and oxidative insults that drive fibrosis. Here, we investigated the activation of the HO-1 system in a splinted and non-splinted full-thickness excisional wound model using HO-1-luc transgenic mice. Effects of splinting on wound closure, HO-1 promoter activity, and markers of inflammation and fibrosis were assessed. After seven days, splinted wounds were more than three times larger than non-splinted wounds, demonstrating a delay in wound closure. HO-1 promoter activity rapidly decreased following removal of the (epi)dermis, but was induced in both splinted and non-splinted wounds during skin repair. Splinting induced more HO-1 gene expression in 7-day wounds; however, HO-1 protein expression remained lower in the epidermis, likely due to lower numbers of keratinocytes in the re-epithelialization tissue. Higher numbers of F4/80-positive macrophages, αSMA-positive myofibroblasts, and increased levels of the inflammatory genes IL-1β, TNF-α, and COX-2 were present in 7-day splinted wounds. Surprisingly, mRNA expression of newly formed collagen (type III) was lower in 7-day wounds after splinting, whereas, VEGF and MMP-9 were increased. In summary, these data demonstrate that splinting delays cutaneous wound closure and HO-1 protein induction. The pro-inflammatory environment following splinting may facilitate higher myofibroblast numbers and increase the risk of fibrosis and scar formation. Therefore, inducing HO-1 activity against mechanical stress-induced inflammation and fibrosis may be an interesting strategy to prevent negative effects of surgery on growth and function in patients with orofacial clefts or in patients with burns.