Recombinant human ADAMTS13 treatment and anti-NET strategies enhance skin allograft survival in mice
Recombinant human ADAMTS13 treatment and anti-NET strategies enhance skin allograft survival in mice
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DOI：
10.1111/ajt.15703
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发表时间：
2019-12-12
影响因子：
8.8
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
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作者：
Wong, Siu Ling;Goverman, Jeremy;Wagner, Denisa D.
提高同种异体皮肤移植的寿命减少了在最佳干预可用之前对新的同种异体移植的需求。ADAMTS13（一种分裂促血栓和促炎血管性血液病因子的酶）活性降低和中性粒细胞细胞外陷阱（NETs）的存在与肝和肺同种异体移植失败有关。然而，ADAMTS13治疗的效果和NETs对同种异体皮肤移植物的影响仍未被探索。本研究采用BALB/c小鼠背侧皮肤移植至C57BL/6J背景小鼠，建立小鼠完全错配全层皮肤移植模型。重组人ADAMTS13 （rhADAMTS13）处理可提高同种异体移植物的存活率。Western blot和免疫荧光显微镜显示异体移植物中存在NETs，但令人惊讶的是，术后3天，在rhadamts13治疗的小鼠中没有NETs。总结在小鼠中的观察结果，在所有烧伤患者的同种异体移植物中也观察到NETs。有趣的是，敲除肽精氨酸脱亚胺酶4 （PAD4， NET形成的关键酶）或dna酶1（切割NET）也延长了同种异体移植物的存活时间。综上所述，rhADAMTS13通过减少NET负担减轻同种异体移植物的炎症，从而提高同种异体移植物的存活率。RhADAMTS13和抗net治疗可能是促进同种异体皮肤移植寿命的新治疗策略，从而提高严重烧伤患者的生存率。
Enhancing skin allograft longevity lessens the need for new allografts before optimal intervention is available. Reduced activity of ADAMTS13 (an enzyme that cleaves the pro-thrombotic and proinflammatory von Willebrand factor) and presence of neutrophil extracellular traps (NETs) have been implicated in liver and lung allograft failures. The effect of ADAMTS13 treatment and the impact of NETs on skin allografts, however, remain unexplored. Here, we adopted a murine model of complete mismatch full-thickness skin transplant by grafting dorsal skin from BALB/c mice to C57BL/6J background mice. Recombinant human ADAMTS13 (rhADAMTS13) treatment of graft recipients increased allograft survival. Western blot and immunofluorescence microscopy revealed the presence of NETs in allografts of vehicle, but surprisingly, not in rhADAMTS13-treated mice, 3 days after surgery. Recapitulating the observations in mice, NETs were also observed in all the examined allografts from burn patients. Intriguingly, knocking out peptidylarginine deiminase 4 (PAD4, a key enzyme for NET formation) or DNase 1 treatment (which cleaves NETs) also prolonged allograft survival. In summary, rhADAMTS13 lessens inflammation in allografts by reducing NET burden, resulting in enhanced allograft survival. RhADAMTS13 and anti-NET treatments could be new therapeutic strategies to promote skin allograft longevity and, hence, the survival of patients with severe burns.