Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2 deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2 deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2 deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.

中文翻译：

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在caveolin-2整体缺乏的小鼠中，缺血后组织损伤和白细胞-内皮粘附相互作用升高：PAI-1的作用

缺血/再灌注 (I/R) 诱导的快速炎症涉及激活白细胞-内皮粘附相互作用和白细胞浸润到组织中，是造成缺血后组织损伤的主要因素。然而，参与这一病理过程的分子介质尚不完全清楚。我们之前曾报道过小窝蛋白 2 (Cav-2) 是质膜小窝的蛋白质成分，可调节小鼠肺癌肿瘤中的白细胞浸润。当前研究的目标是检查 Cav-2 是否在 I/R 损伤和相关的急性白细胞介导的炎症中起作用。使用小鼠小肠 I/R 模型，我们证明 I/R 下调小肠中的 Cav-2 蛋白水平。使用 Cav-2 缺陷小鼠的进一步研究显示，通过对 H&E 染色组织切片中的绒毛长度进行评分确定的缺血后组织损伤加重，这与通过 IHC 染色确定的 MPO 阳性组织浸润白细胞数量增加有关。与白细胞迁移和组织浸润相关的上游事件的活体显微镜分析表明，在 Cav-2 缺陷小鼠中，毛细血管后微静脉中的白细胞 - 内皮细胞粘附相互作用，即白细胞滚动和粘附也增强了。从机制上讲，Cav-2 缺乏会增加肠组织中纤溶酶原激活物抑制剂-1 (PAI-1) 蛋白水平，并且 PAI-1 的药理学抑制对加重的 I/R 组织损伤和毛细血管后白细胞-内皮相互作用增强具有更大的抑制作用Cav-2缺陷小鼠的小静脉。总之，我们的数据表明，Cav-2 蛋白通过抑制 PAI-1 蛋白水平来减轻 I/R 对组织损伤的反应，从而减少白细胞-内皮粘附相互作用。