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首页> 外文期刊>American Journal of Physiology >Immunoblockade of PSGL-1 attenuates established experimental murine colitis by reduction of leukocyte rolling.
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Immunoblockade of PSGL-1 attenuates established experimental murine colitis by reduction of leukocyte rolling.

机译：PSGL-1的免疫阻断作用通过减少白细胞滚动来减轻已建立的实验性小鼠结肠炎。

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Recruitment of circulating leukocytes into the colonic tissue is a key feature of intestinal inflammation. P-selectin glycoprotein ligand-1 (PSGL-1) and very late antigen-4 (VLA-4) are expressed on leukocytes and play an important role in leukocyte-endothelial cell adhesive interactions. We examined the effects of immunoneutralization of PSGL-1 and VLA-4 on leukocyte recruitment in vivo in the development and treatment of experimental colitis. Chronic colitis was induced in balb/c mice by oral administration of dextran sodium sulfate (DSS). Monoclonal antibodies 2PH1 (anti-PSGL-1) and PS/2 (anti-VLA-4) or the combination of both were injected intravenously, and leukocyte adhesion was observed for 60 min in colonic submucosal venules by intravital microscopy (IVM) under isoflurane/N(2)O anesthesia. In addition, mice with established colitis were treated by daily intraperitoneal injections of 2PH1, PS/2, or the combination of both over 5 days. Disease activity index (DAI), histology, and myeloperoxidase (MPO) levels were compared with sham-treated DSS controls. We found that 2PH1 reduced the number of rolling leukocytes (148.7 +/- 29.8 vs. 36.9 +/- 8.7/0.01 mm(2)/30 s, P < 0.05), whereas leukocyte velocity was increased (24.0 +/- 3.6 vs. 127.8 +/- 11.7 microm/s, P < 0.05). PS/2 reduced leukocyte rolling to a lesser extent. Leukocyte firm adhesion was not influenced by 2PH1 but was strongly reduced by PS/2 (24.1 +/- 2 vs. 4.4 +/- 0.9/0.01 mm(2)/30 s, P < 0.05). Combined application did not cause additional effects on leukocyte adhesion. Treatment of chronic colitis with 2PH1 or PS/2 reduced DAI, mucosal injury, and MPO levels significantly. Combined treatment led to a significantly better reduction of DAI (0.4 +/- 0.1 vs. 2.1 +/- 0.2 points) and histology (9.7 +/- 0.9 vs. 21.4 +/- 4.6 points). In conclusion, PSGL-1 and VLA-4 play an important role for leukocyte recruitment during intestinal inflammation. Therapeutic strategies designed to disrupt interactions mediated by PSGL-1 and/or VLA-4 may prove beneficial in treatment of chronic colitis.
机译：循环白细胞进入结肠组织的募集是肠道炎症的关键特征。 P-选择蛋白糖蛋白配体1（PSGL-1）和晚期抗原4（VLA-4）在白细胞上表达，并在白细胞-内皮细胞粘附相互作用中起重要作用。在实验性结肠炎的发生和治疗中，我们检查了PSGL-1和VLA-4免疫中和对体内白细胞募集的影响。通过口服右旋糖酐硫酸钠（DSS）在balb / c小鼠中诱发慢性结肠炎。静脉注射单克隆抗体2PH1（抗PSGL-1）和PS / 2（抗VLA-4）或两者的组合，并在异氟烷下通过活体显微镜检查（IVM）在结肠粘膜下小静脉中观察白细胞粘附60分钟/ N（2）O麻醉。另外，患有结肠炎的小鼠在5天内每天进行腹膜内注射2PH1，PS / 2或两者的组合治疗。将疾病活动指数（DAI），组织学和髓过氧化物酶（MPO）水平与假治疗的DSS对照进行比较。我们发现2PH1减少了滚动白细胞的数量（148.7 +/- 29.8 vs. 36.9 +/- 8.7 / 0.01 mm（2）/ 30 s，P <0.05），而白细胞速度增加了（24.0 +/- 3.6 vs 127.8 +/- 11.7 microm / s，P <0.05）。 PS / 2降低了白细胞滚动的程度。白细胞牢固粘附不受2PH1的影响，但被PS / 2强烈降低（24.1 +/- 2与4.4 +/- 0.9 / 0.01 mm（2）/ 30 s，P <0.05）。联合应用不会对白细胞粘附产生额外影响。用2PH1或PS / 2治疗慢性结肠炎可显着降低DAI，粘膜损伤和MPO水平。联合治疗导致DAI（0.4 +/- 0.1 vs. 2.1 +/- 0.2点）和组织学（9.7 +/- 0.9 vs. 21.4 +/- 4.6点）明显更好的降低。总之，PSGL-1和VLA-4在肠道炎症过程中对白细胞募集起着重要作用。旨在破坏PSGL-1和/或VLA-4介导的相互作用的治疗策略可能对慢性结肠炎的治疗有益。

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