Bae Jong-Sup, Kim Yong-Ung, Park Moon-Ki, Rezaie Alireza R
Department of Herbal Pharmaceutical Engineering, College of Herbal Bio-Industry, Daegu Haany University, Gyeongsan, Republic of Korea.
J Cell Physiol. 2009 Jun;219(3):744-51. doi: 10.1002/jcp.21718.
Disruption of endothelial barrier is a critical pathophysiological factor in inflammation. Thrombin exerts a variety of cellular effects including inflammation and apoptosis through activation of the protease activated receptors (PARs). The activation of PAR-1 by thrombin is known to have a bimodal effect in endothelial cell permeability with a low concentration (pM levels) eliciting a barrier protective and a high concentration (nM levels) eliciting a barrier disruptive response. It is not known whether this PAR-1-dependent activity of thrombin is a unique phenomenon specific for the in vitro assay or it is part of a general anti-inflammatory effect of low concentrations of thrombin that may have a physiological relevance. Here, we report that low concentrations of thrombin or of PAR-1 agonist peptide induced significant anti-inflammatory activities. However, relatively high concentration of thrombin or of PAR-1 agonist peptide showed pro-inflammatory activities. By using function-blocking anti-PAR-1 antibodies and PI3 kinase inhibitor, we show that the direct anti-inflammatory effects of low concentrations of thrombin are dependent on the activation of PAR-1 and PI3 kinase. These results suggest a role for cross communication between PAR-1 activation and PI3 kinase pathway in mediating the cytoprotective effects of low concentrations of thrombin in the cytokine-stimulated endothelial cells. J. Cell. Physiol. 219: 744-751, 2009. (c) 2009 Wiley-Liss, Inc.
内皮屏障的破坏是炎症中的一个关键病理生理因素。凝血酶通过激活蛋白酶激活受体（PARs）发挥多种细胞效应，包括炎症和凋亡。已知凝血酶激活PAR-1对内皮细胞通透性具有双峰效应，低浓度（皮摩尔水平）引起屏障保护作用，高浓度（纳摩尔水平）引起屏障破坏反应。目前尚不清楚凝血酶的这种PAR-1依赖性活性是体外试验特有的现象，还是低浓度凝血酶一般抗炎作用的一部分，而这种抗炎作用可能具有生理相关性。在此，我们报告低浓度的凝血酶或PAR-1激动剂肽可诱导显著的抗炎活性。然而，相对高浓度的凝血酶或PAR-1激动剂肽则表现出促炎活性。通过使用功能阻断性抗PAR-1抗体和PI3激酶抑制剂，我们表明低浓度凝血酶的直接抗炎作用依赖于PAR-1和PI3激酶的激活。这些结果表明PAR-1激活与PI3激酶途径之间的交叉通讯在介导低浓度凝血酶对细胞因子刺激的内皮细胞的细胞保护作用中发挥作用。《细胞生理学杂志》2009年第219卷：744 - 751页。（c）2009年威利 - 利斯公司。
