Anti-inflammatory effects of αv integrin antagonism in acute kidney allograft rejection
Anti-inflammatory effects of αv integrin antagonism in acute kidney allograft rejection
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DOI：
10.2353/ajpath.2007.070329
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发表时间：
2007-10-01
影响因子：
6
通讯作者：
Groene, Hermann-Josef
中科院分区：
文献类型：
--
作者：
Bedke, Jens;Kiss, Eva;Groene, Hermann-Josef
整合素介导的细胞粘附和信号传导对血管发育和炎症过程至关重要。在缺血再灌注损伤和排斥性心脏移植物中检测到整合素α（v）β（3）的表达升高。因此，我们假设α（v）相关整合素的抑制可能在急性肾移植排斥反应中具有有效的抗炎作用。我们研究了α（V）整合素的拟肽拮抗剂在两种大鼠同种异体肾移植模型中的作用，主要组织相容性复合物错配程度不同。整合素α（v）β（3）在排斥性肾移植中表达上调。整合素拮抗剂可减轻移植肾急性排斥反应的组织学表现、单个核细胞浸润强度和细胞增殖。这可能与减少白细胞-内皮细胞相互作用和改善管周微循环活体显微镜观察。在体外层流条件下，单核细胞对白细胞介素-1 β激活的内皮细胞的阻滞减少。此外，在共培养模型中，由肾小管上皮细胞诱导的单核细胞/巨噬细胞、内皮细胞和成纤维细胞的增殖和迁移被α（v）整合素拮抗剂有效地抑制。这些数据揭示了这种整合素亚类在白细胞募集和急性排斥反应的发展和维持中的重要作用;阻断α（V）整合素可能提供一种新的治疗策略来减轻急性同种异体移植排斥反应。
Integrin-mediated cell adhesion and signaling is essential to vascular development and inflammatory processes. Elevated expression of integrin alpha(v)beta(3) has been detected in ischemia-reperfusion injury and rejecting heart allografts. We thus hypothesized that the inhibition of alpha(v)-associated integrins may have potent anti-inflammatory effects in acute kidney allograft rejection. We studied the effects of a peptidomimetic antagonist of alpha(v) integrins in two rat models of renal allotransplantation, differing in degree of major histocompatibility complex mismatch. Integrin alpha(v)beta(3) was up-regulated in rejecting renal allografts. Integrin antagonist reduced the histological signs of acute rejection, the intensity of the mononuclear cell infiltration, and cell proliferation in the grafted kidneys. This could be correlated to a reduced leukocyte-endothelial interaction and an improved peritubular microcirculation observed by intravital microscopy. In vitro under laminar flow conditions, the arrest of monocytes to interleukin-1 beta-activated endothelium was decreased. Furthermore, in co-culture models the proliferation and transmigration of monocytes/macrophages, endothelium, and fibroblasts induced by renal tubular epithelia was efficiently inhibited by alpha(v) integrin antagonism. These data reveal an important role of this integrin subclass in leukocyte recruitment and development and maintenance of acute rejection; blockade of alpha(v) integrins may provide a new therapeutic strategy to attenuate acute allograft rejection.