Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y(12) Receptor Activation.
Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y(12) Receptor Activation.
复制标题
二磷酸腺苷通过激活P2Y（12）受体促进糖尿病小鼠伤口愈合。
DOI：
10.3389/fimmu.2021.651740
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发表时间：
2021
影响因子：
7.3
通讯作者：
Benjamim CF
中科院分区：
文献类型：
--
作者：
Borges PA;Waclawiak I;Georgii JL;Fraga-Junior VDS;Barros JF;Lemos FS;Russo-Abrahão T;Saraiva EM;Takiya CM;Coutinho-Silva R;Penido C;Mermelstein C;Meyer-Fernandes JR;Canto FB;Neves JS;Melo PA;Canetti C;Benjamim CF
慢性伤口是世界范围内的一个公共卫生问题，尤其是与糖尿病相关的伤口。除了给患者带来巨大负担之外，它还对伤口护理专业人员提出了挑战，并给卫生系统带来了巨大的财务成本。考虑到慢性伤口缺乏有效的治疗方法，我们的目的是更好地了解糖尿病组织修复的病理生理学，以便找到加速伤口愈合的替代策略。核苷酸被描述为不同炎症过程（包括组织修复）中的细胞外信号分子。 5'-二磷酸腺苷 (ADP) 在血管和细胞反应中发挥重要作用，在组织损伤后立即释放，主要从血小板中释放。然而，尽管对炎症和损伤过程中血小板聚集的影响已有充分描述，但人们对 ADP 在组织修复多个步骤中的作用知之甚少，特别是在皮肤伤口中。因此，我们采用全层切除伤口模型来评价局部ADP应用在糖尿病小鼠伤口中的效果。 ADP 加速皮肤伤口愈合，改善新组织形成，并增加伤口中胶原蛋白沉积和转化生长因子-β (TGF-β) 的产生。这些作用是由 P2Y12 受体激活介导的，因为它们被 P2Y12 受体拮抗剂氯吡格雷 (Clop) 治疗所抑制。此外，P2Y1 受体拮抗剂还可阻断 ADP 诱导的伤口闭合直至第 7 天，表明其参与修复过程的早期。有趣的是，ADP 治疗增加了伤口中 P2Y12 和 P2Y1 受体的表达。与此同时，ADP 减少了活性氧 (ROS) 的形成和肿瘤坏死因子-α (TNF-α) 的水平，同时增加了皮肤中 IL-13 的水平。此外，ADP 增加了中性粒细胞、嗜酸性粒细胞、肥大细胞和 γδ (γδ) T 细胞（γδ+ T 细胞的 Vγ4+ 和 Vγ5+ 细胞亚型）的计数，但减少了病变中的调节性 T (Treg) 细胞。相应地，ADP 增加成纤维细胞增殖和迁移、肌成纤维细胞分化和角质形成细胞增殖。总之，我们提供了强有力的证据，表明 ADP 在糖尿病相关皮肤伤口中发挥着促消退调节作用，并且是解决这一全球性问题的有希望的干预目标。
Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5’-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.
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影响因子：
2.2
作者：
Brubaker, Aleah L.;Schneider, David F.;Kovacs, Elizabeth J.
通讯作者：
Kovacs, Elizabeth J.
影响因子：
3.5
作者：
Gendaszewska-Darmach, Edyta;Kucharska, Marta
通讯作者：
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影响因子：
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作者：
Chia JS;McRae JL;Cowan PJ;Dwyer KM
通讯作者：
Dwyer KM
影响因子：
2.9
作者：
DiPietro, LA;Reintjes, MG;Gamelli, RL
通讯作者：
Gamelli, RL
影响因子：
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作者：
Choi, HS;Kim, JW;Kim, C
通讯作者：
Kim, C