Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase
Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase
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DOI：
10.4049/jimmunol.172.9.5664
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Hogan, SP
中科院分区：
文献类型：
--
作者：
Forbes, E;Murase, T;Hogan, SP
个体炎症细胞和介质在溃疡性结肠炎（UC）胃肠道（GI）功能障碍和肠外临床表现的发展中所起的确切作用尚不清楚。在这项研究中，我们使用UC的小鼠模型来确定eotaxin的中心作用，反过来，嗜酸性粒细胞在这种疾病的免疫发病机制的发展中。在这个模型中，给药葡聚糖硫酸钠（DSS）诱导了明显的结肠嗜酸性粒细胞炎症和胃肠道功能障碍（带血腹泻和结肠缩短），类似于UC患者。胃肠道功能障碍与嗜酸性细胞溶解脱颗粒和嗜酸性过氧化物酶（EPO）释放到结肠腔有关。通过使用IL-5或eotaxin缺乏的小鼠，我们发现eotaxin在实验性UC期间嗜酸性粒细胞募集到结肠中的重要作用。此外，利用EPO缺陷小鼠和EPO抑制剂间苯二酚，我们证明嗜酸性粒细胞衍生的过氧化物酶在实验性UC中GI功能障碍的发展中至关重要。这些发现为嗜酸性粒细胞和EPO在胃肠道功能障碍和UC的潜在免疫发病机制中发挥核心作用提供了直接证据。
The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and, shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.