Montesinos M Carmen, Desai Avani, Chen Jiang-Fan, Yee Herman, Schwarzschild Michael A, Fink J Stephen, Cronstein Bruce N
Department of Medicine, New York University School of Medicine, New York, New York, USA.
Am J Pathol. 2002 Jun;160(6):2009-18. doi: 10.1016/S0002-9440(10)61151-0.
Recent evidence indicates that topical application of adenosine A(2A) receptor agonists, unlike growth factors, increases the rate at which wounds close in normal animals and promotes wound healing in diabetic animals as well as growth factors, yet neither the specific adenosine receptor involved nor the mechanism(s) by which adenosine receptor occupancy promotes wound healing have been fully established. To determine which adenosine receptor is involved and whether adenosine receptor-mediated stimulation of angiogenesis plays a role in promotion of wound closure we compared the effect of topical application of the adenosine receptor agonist CGS-21680 (2-p-[2-carboxyethyl]phenethyl-amino-5'-N-ethylcarboxamido-adenosine) on wound closure and angiogenesis in adenosine A(2A) receptor knockout mice and their wild-type littermates. There was no change in the rate of wound closure in the A(2A) receptor knockout mice compared to their wild-type littermates although granulation tissue formation was nonhomogeneous and there seemed to be greater inflammation at the base of the wound. Topical application of CGS-21680 increased the rate of wound closure and increased the number of microvessels in the wounds of wild-type mice but did not affect the rate of wound closure in A(2A) receptor knockout mice. Similarly, in a model of internal trauma and repair (murine air pouch model), endogenously produced adenosine released into areas of internal tissue injury stimulates angiogenesis because there was a marked reduction in blood vessels in the walls of healing air pouches of A(2A) receptor knockout mice compared to their wild-type controls. Inflammatory vascular leakage and leukocyte accumulation in the inflamed air pouch were similarly reduced in the A(2A) receptor knockout mice reflecting the reduced vascularity. Thus, targeting the adenosine A(2A) receptor is a novel approach to promoting wound healing and angiogenesis in normal individuals and those suffering from chronic wounds.
最近的证据表明，与生长因子不同，局部应用腺苷A(2A)受体激动剂可提高正常动物伤口愈合的速度，并促进糖尿病动物的伤口愈合，其效果与生长因子相当。然而，目前尚未完全明确具体涉及的腺苷受体以及腺苷受体激活促进伤口愈合的机制。为了确定参与其中的腺苷受体以及腺苷受体介导的血管生成刺激是否在促进伤口闭合中发挥作用，我们比较了局部应用腺苷受体激动剂CGS-21680（2-p-[2-羧乙基]苯乙胺基-5'-N-乙基羧酰胺腺苷）对腺苷A(2A)受体敲除小鼠及其野生型同窝小鼠伤口闭合和血管生成的影响。与野生型同窝小鼠相比，A(2A)受体敲除小鼠的伤口闭合速度没有变化，尽管肉芽组织形成不均匀，且伤口底部似乎有更严重的炎症。局部应用CGS-21680可提高野生型小鼠伤口的闭合速度，并增加伤口中的微血管数量，但对A(2A)受体敲除小鼠的伤口闭合速度没有影响。同样，在内部创伤和修复模型（小鼠气袋模型）中，内源性产生的腺苷释放到内部组织损伤区域会刺激血管生成，因为与野生型对照相比，A(2A)受体敲除小鼠愈合气袋壁中的血管明显减少。A(2A)受体敲除小鼠炎症气袋中的炎症性血管渗漏和白细胞积聚也同样减少，这反映了血管生成的减少。因此，靶向腺苷A(2A)受体是促进正常个体和患有慢性伤口的个体伤口愈合和血管生成的一种新方法。
