Aschermann Ilknur, Noor Seema, Venturelli Sascha, Sinnberg Tobias, Mnich Christian D, Busch Christian
Cell Physiol Biochem. 2017;41(3):890-906. doi: 10.1159/000460503. Epub 2017 Feb 20.
BACKGROUND/AIMS: Chronic leg ulcers (CLUs) are globally a major cause of morbidity and mortality with increasing prevalence. Their treatment is highly challenging, and many conservative, surgical or advanced therapies have been suggested, but with little overall efficacy. Since the 1980s extracorporal shock wave therapy (ESWT) has gained interest as treatment for specific indications. Here, we report that patients with CLU showed wound healing after ESWT and investigated the underlying molecular mechanisms.
We performed cell proliferation and migration assays, FACS- and Western blot analyses, RT-PCR, and Affymetrix gene expression analyses on human keratinocytes and fibroblasts, and a tube formation assay on human microvascular endothelial cells to assess the impact of shock waves in vitro. In vivo, chronic therapy-refractory leg ulcers were treated with ESWT, and wound healing was assessed.
Upon ESWT, we observed morphological changes and increased cell migration of keratinocytes. Cell-cycle regulatory genes were upregulated, and proliferation induced in fibroblasts. This was accompanied by secretion of pro-inflammatory cytokines from keratinocytes, which are known to drive wound healing, and a pro-angiogenic activity of endothelial cells. These observations were transferred "from bench to bedside", and 60 consecutive patients with 75 CLUs with different pathophysiologies (e.g. venous, mixed arterial-venous, arterial) were treated with ESWT. In this setting, 41% of ESWT-treated CLUs showed complete healing, 16% significant improvement, 35% improvement, and 8% of the ulcers did not respond to ESWT. The induction of healing was independent of patient age, duration or size of the ulcer, and the underlying pathophysiology.
The efficacy of ESWT needs to be confirmed in controlled trials to implement ESWT as an adjunct to standard therapy or as a stand-alone treatment. Our results suggest that EWST may advance the treatment of chronic, therapy-refractory ulcers.
背景/目的：慢性腿部溃疡（CLU）在全球范围内是发病率和死亡率的主要原因，且患病率不断上升。其治疗极具挑战性，人们提出了许多保守、手术或先进的治疗方法，但总体疗效甚微。自20世纪80年代以来，体外冲击波疗法（ESWT）作为特定适应症的治疗方法受到关注。在此，我们报告CLU患者在ESWT后伤口愈合情况，并研究其潜在的分子机制。
我们对人角质形成细胞和成纤维细胞进行了细胞增殖和迁移试验、流式细胞术和蛋白质印迹分析、逆转录聚合酶链反应（RT-PCR）以及Affymetrix基因表达分析，并对人微血管内皮细胞进行了管腔形成试验，以评估冲击波在体外的影响。在体内，对慢性治疗难治性腿部溃疡进行ESWT治疗，并评估伤口愈合情况。
经ESWT治疗后，我们观察到角质形成细胞的形态变化和细胞迁移增加。细胞周期调节基因上调，成纤维细胞增殖诱导。这伴随着角质形成细胞分泌促炎细胞因子，已知这些因子可促进伤口愈合，以及内皮细胞的促血管生成活性。这些观察结果从实验室转化到临床，连续60例患有75处不同病理生理学（如静脉性、动静脉混合性、动脉性）CLU的患者接受了ESWT治疗。在此情况下，41%接受ESWT治疗的CLU完全愈合，16%显著改善，35%有所改善，8%的溃疡对ESWT无反应。愈合的诱导与患者年龄、溃疡持续时间或大小以及潜在的病理生理学无关。
ESWT的疗效需要在对照试验中得到证实，以便将ESWT作为标准治疗的辅助手段或作为独立治疗方法应用。我们的结果表明，ESWT可能会推动慢性治疗难治性溃疡的治疗。
