Therapeutic Effect of Blocking CXCR2 on Neutrophil Recruitment and Dextran Sodium Sulfate-Induced Colitis
Therapeutic Effect of Blocking CXCR2 on Neutrophil Recruitment and Dextran Sodium Sulfate-Induced Colitis
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DOI：
10.1124/jpet.108.145862
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Stadnyk, Andrew W.
中科院分区：
文献类型：
--
作者：
Farooq, Shukkur Muhammed;Stillie, RoseMarie;Stadnyk, Andrew W.
葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的特征是多形核中性粒细胞（PMN）浸润到结肠粘膜和管腔中。发生这种情况的机制尚不清楚。为了开始理解其机制，我们通过使用CXCR 2（-/-）小鼠或通过中和CXCR 2来确定PMN趋化因子受体CXCR 2在DSS诱导的结肠炎中的作用。DSS通过饮用水给予CXCR 2（-/-）和BALB/c小鼠5天，然后常规水给药1天。在中和研究中，向小鼠注射对照血清或山羊抗CXCR 2抗血清。接受DSS的BALB/c小鼠和接受DSS的对照血清注射小鼠体重减轻，并显示出相当大的临床疾病。组织学观察显示粘膜下水肿，PMN浸润到粘膜下和粘膜，广泛的隐窝损伤伴肿胀和溃疡。相反，CXCR 2（-/-）和抗CXCR 2抗血清治疗的小鼠体重增加，症状评分显著降低。这些小鼠的组织学显示粘膜下水肿，但隐窝结构相对完整，溃疡很少。与对照血清注射的发炎小鼠相比，在抗CXCR 2抗血清中的粘膜中发现了显著较少的PMN，但在各组之间观察到嗜酸性粒细胞浸润没有显著差异。我们的实验确定了CXCR 2在DSS诱导的结肠炎中的作用，并表明拮抗CXCR 2可能通过阻止PMN募集到粘膜中来提供一定的治疗效果。拮抗CXCR 2可以形成针对控制结肠炎的治疗药物的基础。
Dextran sodium sulfate (DSS)-induced colitis in mice is characterized by polymorphonuclear neutrophil (PMN) infiltration into the colonic mucosa and lumen. The mechanism by which this occurs is unclear. To begin to understand the mechanism, we determined the role of the PMN chemokine receptor, CXCR2, in DSS-induced colitis by using CXCR2(-/-) mice or by neutralizing CXCR2. DSS was administered through drinking water to CXCR2(-/-) and BALB/c mice for 5 days followed by regular water for 1 day. In the neutralization study, mice were injected with control serum or goat anti-CXCR2 antiserum. BALB/c mice receiving DSS and control serum-injected mice receiving DSS lost weight and showed considerable clinical illness. Histological observation revealed submucosal edema, PMN infiltration into the submucosa and mucosa, extensive crypt damage with abscesses, and ulceration. In contrast, both the CXCR2(-/-) and anti-CXCR2 antiserum-treated mice gained weight and had significantly lower symptom scores. Histology of these mice showed submucosal edema but relatively intact crypt architecture and very few ulcers. Significantly fewer PMNs were found in the mucosa in anti-CXCR2 antiserum compared with control serum-injected inflamed mice, but no significant difference in eosinophil infiltration was observed between the groups. Our experiments identify a role for CXCR2 in DSS-induced colitis and suggest that antagonizing CXCR2 provides some therapeutic efficacy, possibly by impeding PMN recruitment into the mucosa. Antagonizing CXCR2 may form the basis for therapeutic drugs directed at controlling colitis.