Infectious Disease Division, Memorial Hospital of RI, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island, USA.
Shock. 2011 May;35(5):492-8. doi: 10.1097/SHK.0b013e31820b2e1c.
The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.
晚期糖基化终产物受体（RAGE）被认为通过持续炎症反应在脓毒症中发挥作用。RAGE 与各种宿主衍生配体相互作用，这些配体在应激和炎症期间积累，进一步诱导 RAGE 的表达。先前的研究表明，一种抗 RAGE 单克隆抗体可保护小鼠免受盲肠结扎和穿刺模型的致死性影响。我们研究了一种人源化抗 RAGE 单克隆抗体在脓毒症的肺炎球菌性肺炎小鼠模型中的作用。此外，我们对接受盲肠结扎和穿刺并接受抗 RAGE 单克隆抗体治疗的动物的肺组织进行了基因表达分析，并与对照组进行了比较。在经气管内感染肺炎链球菌后 6 小时给予人源化抗 RAGE mAb，无论联合使用抗生素的剂量为 7.5mg/kg（P<0.01）还是 15mg/kg（P<0.01），均可改善 BALB/c 小鼠的死亡率。基因表达分析表明，抗 RAGE 抗体治疗调节的许多基因是那些在调节炎症中起重要作用的基因。抗 RAGE 单克隆抗体为脓毒症小鼠提供了生存优势。在治疗动物中观察到的参与脓毒症和炎症的基因表达谱变化支持了这种保护作用。
