PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases
PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases
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DOI：
10.1172/jci35874
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发表时间：
2008-11-01
影响因子：
15.9
通讯作者：
Colgan, Sean P.
中科院分区：
文献类型：
--
作者：
Weissmueller, Thomas;Campbell, Eric L.;Colgan, Sean P.
粘膜疾病通常以炎症浸润为特征，其中包括多形核白细胞 (PMN)、单核细胞、淋巴细胞和血小板。许多研究表明血小板与白细胞的相互作用具有重要的促炎作用。在这里，我们检查了血小板是否像众所周知的中性粒细胞那样迁移穿过粘膜上皮，以及血小板是否影响上皮细胞功能。初步研究表明，人血小板不能有效地跨过人上皮细胞单层。然而，在人类中性粒细胞存在的情况下，血小板穿过上皮的运动与中性粒细胞迁移的程度成正比，而阻止中性粒细胞迁移的策略会减少血小板运动。此外，在人类炎症性肠病（IBD）患者的肠道组织中观察到血小板-PMN 共迁移。研究发现，转位的血小板释放大量 ATP，通过胞外核苷酸酶（包括表达于肠上皮细胞顶膜的 CD73 和胞外核苷三磷酸二磷酸水解酶 (胞外-NTPDases)）介导的两步酶反应，将其代谢为腺苷。采用体外研究和小鼠肠道炎症模型来确定一种机制，涉及腺苷介导的电化学氯化物分泌诱导，同时水运动进入肠腔。这些研究表明，ecto-NTPDase 在上皮细胞的顶膜上表达，并参与了我们认为以前未认识到的炎症肠道中血小板的功能，这可能会促进炎症条件下的细菌清除。
Mucosal diseases are often characterized by an inflammatory infiltrate that includes polymorphonuclear leukocytes (PMNs), monocytes, lymphocytes, and platelets. A number of studies have suggested that the interaction of platelets with leukocytes has an essential proinflammatory role. Here, we examined whether platelets migrate across mucosal epithelium, as PMNs are known to do, and whether platelets influence epithelial cell function. Initial studies revealed that human platelets did not efficiently transmigrate across human epithelial cell monolayers. However, in the presence of human PMNs, platelet movement across the epithelium was proportional to the extent of PMN transmigration, and strategies that blocked PMN transmigration diminished platelet movement. Furthermore, platelet-PMN comigration was observed in intestinal tissue derived from human patients with inflammatory bowel disease (IBD). The translocated platelets were found to release large quantities of ATP, which was metabolized to adenosine via a 2-step enzymatic reaction mediated by ecto-nucleotidases, including CD73 and ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases), expressed on the apical membrane of the intestinal epithelial cells. In vitro studies and a mouse model of intestinal inflammation were employed to define a mechanism involving adenosine-mediated induction of electrogenic chloride secretion, with concomitant water movement into the intestinal lumen. These studies demonstrate that ecto-NTPDases are expressed on the apical membrane of epithelial cells and are involved in what we believe to be a previously unappreciated function for platelets in the inflamed intestine, which might promote bacterial clearance under inflammatory conditions.