Delayed onset of inflammation in protease-activated receptor-2-deficient mice
Delayed onset of inflammation in protease-activated receptor-2-deficient mice
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DOI：
10.4049/jimmunol.165.11.6504
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发表时间：
2000-12-01
影响因子：
4.4
通讯作者：
Ley, K
中科院分区：
文献类型：
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作者：
Lindner, JR;Kahn, ML;Ley, K
肥大细胞衍生的组胺和凝血酶与蛋白酶激活的受体-1(PAR1)结合可诱导内皮细胞表面P-选择素的表达以及随后的白细胞在小静脉中滚动。我们假设肥大细胞类胰蛋白酶或其他蛋白酶激活内皮细胞PAR2也有助于炎症反应。通过活体显微镜观察静脉周围注射对照(LSIGRL)或PAR2激活(SLIGRL)寡肽后野生型小鼠提睾肌的白细胞滚动通量和滚动速度。注射SLIGRL后，平均滚动白细胞流量分数由34+/-11升至71+/-24%(p<；0.05)，平均滚动速度由63+/-29降至32+/-2 m/S(p<；0.05)。对照多肽注射剂无明显变化。为了进一步评价PAR2在炎症反应中的作用，通过基因打靶和同源重组的方法建立了PAR2缺陷小鼠。静脉注射SLIGRL仅使滚转的白细胞流量分数略有增加(从21+/-8增加到30+/-2%)，而滚转速度没有变化。对9只PAR2缺陷小鼠和12只野生型小鼠的手术创伤后的白细胞滚动进行了评估。创伤后早期(0~15min)，PAR2基因缺陷小鼠的白细胞平均滚动通量分数低于对照组(10+/-3vs30+/-6%，p<0.05)，平均滚动速度高于对照组(67+/-46vs52+/-36um/S，p<；0.01)。在手术创伤后，PAR2缺陷小鼠的白细胞滚动缺陷没有持续超过30分钟。这些结果表明，PAR2的激活通过快速诱导P-选择素介导的白细胞滚动而产生微血管炎症。在缺乏PAR2的情况下，炎症的发生被推迟。
Endothelial surface expression of P-selectin and subsequent leukocyte rolling in venules can be induced by mast cell-derived histamine and binding of thrombin to protease-activated receptor-1 (PAR1), We hypothesized that activation of endothelial PAR2 by mast cell tryptase or other proteases also contributes to inflammatory responses. Leukocyte rolling flux and rolling velocity were assessed by intravital microscopy of the cremaster muscles of wild-type mice following perivenular micropipette injections of a control (LSIGRL) or PAR2-activating (SLIGRL) oligopeptide. Injection of SLIGRL increased mean rolling leukocyte flux fraction from 34 +/- 11 to 71 +/- 24% (p < 0.05) and decreased mean rolling velocity from 63 +/- 29 to 32 +/- 2 m/s (p < 0.05). No significant changes occurred with control peptide injection. To further evaluate the role of PAR2 in inflammatory responses, PAR2 deficient mice were generated by gene targeting and homologous recombination. Perivenular injections of SLIGRL resulted in only a small increase in rolling leukocyte flux fraction (from 21 +/- 8 to 30 +/- 2%) and no change in rolling velocity. Leukocyte rolling after surgical trauma was assessed in 9 PAR2 deficient and 12 wild-type mice. Early (0-15 min) after surgical trauma, the mean leukocyte rolling flux fraction was lower (10 +/- 3 vs 30 +/- 6%,p < 0.05) and mean rolling velocity was higher (67 +/- 46 vs 52 +/- 36 mum/s, p < 0.01) in PAR2-deficient compared with control mice. The defect in leukocyte rolling in PAR2-deficient mice did not persist past 30 min following surgical trauma. These results indicate that activation of PAR2 produces microvascular inflammation by rapid induction of P-selectin-mediated leukocyte rolling. In the absence of PAR2, the onset of inflammation is delayed.