CXCR2/CXCR2 ligand biology ischemia-reperfusion injury
CXCR2/CXCR2 ligand biology ischemia-reperfusion injury
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DOI：
10.4049/jimmunol.175.10.6931
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Strieter, RM
中科院分区：
文献类型：
--
作者：
Belperio, JA;Keane, MP;Strieter, RM
肺移植是许多终末期肺部疾病的一种治疗选择。早期同种异体肺移植功能障碍（缺血再灌注损伤）仍然是肺移植后早期死亡的最常见原因，也是闭塞性细支气管炎综合征发生的重要危险因素。缺血再灌注损伤的组织病理学特征是肺水肿和以中性粒细胞为主的白细胞外渗。在肺移植后缺血再灌注损伤期间将白细胞募集至肺的具体机制尚未完全阐明。由于 ELR+ CXC 趋化因子是有效的中性粒细胞趋化因子，因此我们研究了它们在肺移植后缺血再灌注损伤中的作用。我们发现缺血再灌注损伤患者的人支气管肺泡灌洗液中多种 ELR+ CXC 趋化因子水平升高。使用“冷”缺血再灌注损伤的大鼠原位肺移植模型进行的概念验证研究表明，肺移植物中性粒细胞隔离和损伤增加。此外，CXCL1、CXCL2/3 及其共有受体 CXCR2 的肺表达与肺中性粒细胞浸润和损伤平行。重要的是，体内CXCR2/CXCR2配体相互作用的抑制导致肺中性粒细胞隔离和移植物损伤显着减少。总之，这些实验支持这样的观点：ELR+CXC趋化因子的表达增加及其与CXCR2的相互作用在肺移植后冷缺血再灌注损伤的发病机制中发挥重要作用。
Lung transplantation is a therapeutic option for a number of end-stage pulmonary disorders. Early lung allograft dysfunction (ischemia-reperfusion injury) continues to be the most common cause of early mortality after lung transplantation and a significant risk factor for the development of bronchiolitis obliterans syndrome. Ischemia-reperfusion injury is characterized histopathologically by lung edema and a neutrophil predominate leukocyte extravasation. The specific mechanism(s) that recruit leukocytes to the lung during post-lung transplantation ischemia-reperfusion injury have not been fully elucidated. Because the ELR+ CXC chemokines are potent neutrophil chemoattractants, we investigated their role during post-lung transplantation ischemic-reperfusion injury. We found elevated levels of multiple ELR+ CXC chemokines in human bronchoalveolar lavage fluid from patients with ischemia-reperfusion injury. Proof of concept studies using a rat orthotopic lung transplantation model of "cold" ischemic-reperfusion injury demonstrated an increase in lung graft neutrophil sequestration and injury. In addition, lung expression of CXCL1, CXCL2/3, and their shared receptor CXCR2 paralleled lung neutrophil infiltration and injury. Importantly, inhibition of CXCR2/CXCR2 ligand interactions in vivo led to a marked reduction in lung neutrophil sequestration and graft injury. Taken together these experiments support the notion that increased expression of ELR+ CXC chemokines and their interaction with CXCR2 plays an important role in the pathogenesis of post-lung transplantation cold ischemia-reperfusion injury.