Receptor cleavage and P-select-independent reduction of leukocyte adhesion in the spontaneously hypertensive rat
Receptor cleavage and P-select-independent reduction of leukocyte adhesion in the spontaneously hypertensive rat
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DOI：
10.1189/jlb.0112010
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发表时间：
2012-07-01
影响因子：
5.5
通讯作者：
Schmid-Schoenbein, Geert W.
中科院分区：
文献类型：
--
作者：
Chen, Angela Y.;Ha, Jessica N.;Schmid-Schoenbein, Geert W.
SHR是高血压和代谢综合征的遗传模型，它通过一种未知的机制减弱了白细胞与毛细血管后内皮的粘附。基于最近的证据表明，血浆中的MMPs水平升高，并对SHR的微血管内皮细胞与几种受体类型的裂解，我们假设，减少白细胞-内皮细胞的相互作用是增强的蛋白水解裂解的P-选择素对毛细血管后内皮细胞和PSGL-1对白细胞。通过使用广谱MMP抑制剂（CGS）长期治疗24周，SHR白细胞与内皮细胞的减弱的滚动相互作用得以恢复。SHR血浆和肠系膜中MMP水平以及收缩压均随治疗而显著降低。在SHR肠系膜，标记的P-选择素在毛细血管后微静脉的免疫组化显示，平均而言，31%的细胞外P-选择素密度低于血压正常的WKY。与WKY相比，SHR中性粒细胞膜上的细胞外PSGL-1密度显着降低也支持了我们的假设。在体内的肠系膜毛细血管后微静脉组胺刺激表明，SHR有一个衰减的反应，作为测量白细胞滚动速度的内皮。降低P-选择素和PSGL-1密度，SHR毛细血管后内皮细胞和SHR白细胞，分别恢复显着的慢性MMP抑制。SHR白细胞在炎症刺激后降低滚动速度的能力受损，导致更少的牢固粘附到内皮的白细胞作为免疫抑制的贡献者。J. Leukoc.生物学92：183-194; 2012年。
The SHR,a genetic model for hypertension and the metabolic syndrome, has attenuated leukocyte adhesion to the postcapillary endothelium by an unknown mechanism. Based on recent evidence of elevated levels of MMPs in plasma and on microvascular endothelium of the SHR with cleavage of several receptor types, we hypothesize that the reduced leukocyte-endothelial interaction is a result of enhanced proteolytic cleavage of P-selectin on the postcapillary endothelium and PSGL-1 on leukocytes. The attenuated rolling interactions of SHR leukocytes with the endothelium were restored by chronic treatment with a broad-spectrum MMP inhibitor (CGS) for 24 weeks. The SHR MMP levels, in plasma and mesentery, as well as the systolic blood pressure, decreased significantly with treatment. In the SHR mesentery, labeling of P-selectin in the post-capillary venules by immunohistochemistry demonstrated, on average, a 31% lower extracellular P-selectin density compared with the normotensive WKY. A significantly lower extracellular PSGL-1 density on the membranes of SHR neutrophils compared with the WKY also supported our hypothesis. In vivo stimulation of the mesenteric postcapillary venules with histamine demonstrated that the SHR had an attenuated response, as measured by leukocyte rolling velocity on the endothelium. The reduced P-selectin and PSGL-1 density, on SHR postcapillary endothelium and on SHR leukocytes, respectively, was restored significantly by chronic MMP inhibition. The impaired ability of SHR leukocytes to reduce rolling velocity upon inflammatory stimulation led to fewer firmly adhered leukocytes to the endothelium as a contributor to immune suppression. J. Leukoc. Biol. 92: 183-194; 2012.