Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns
Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns
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DOI：
10.1073/pnas.1214099110
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发表时间：
2013-02-26
影响因子：
11.1
通讯作者：
Yarmush, Martin L.
中科院分区：
文献类型：
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作者：
Bohr, Stefan;Patel, Suraj J.;Yarmush, Martin L.
通过由EPO受体和β-共同受体（CD 131）组成的异聚体受体的交替促红细胞生成素（EPO）介导的信号传导在各种类型的损伤中发挥EPO的组织保护作用。在此，我们研究了EPO衍生物螺旋β表面肽（同义词：ARA 290）对皮肤烧伤后继发性组织损伤进展的影响，所述EPO衍生物螺旋β表面肽特异性地触发交替EPO介导的信号传导，但不结合红细胞生成性EPO受体同型二聚体。为此目的，在小鼠背部施加深度部分厚度皮肤烧伤，然后在烧伤后1、12和24 h全身给予溶媒或ARA 290。在仅用溶剂处理的情况下，伤口在烧伤后24小时内表现出继发性微血管血栓形成，随后周围组织坏死，从而在48小时内转化为全层损伤。另一方面，当全身给予ARA 290时，维持了微血管的通畅性。此外，ARA 290减轻了先天性炎症反应，最显著的是肿瘤坏死因子-α介导的信号传导。这些发现与最初受损但存活的组织成分的长期恢复相关。总之，ARA 290可能是一种有前途的治疗方法，以防止转换的部分到全层烧伤。在临床环境中，烧伤深度和面积的减少可能会减少广泛的外科清创术以及通过皮肤移植进行二次伤口闭合的必要性。ARA 290的这种使用与之前在其他损伤模型（如心肌梗死和出血性休克）中报道的组织保护特性一致。
Alternate erythropoietin (EPO)-mediated signaling via the heteromeric receptor composed of the EPO receptor and the beta-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue cornponents. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.