Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
J Immunol. 2011 Oct 1;187(7):3831-9. doi: 10.4049/jimmunol.1003238. Epub 2011 Sep 2.
Reperfusion of ischemic organs induces a potent inflammatory response initiated by the generation of reactive oxygen species that directly damage tissue and promote leukocyte infiltration and activation that also mediate tissue injury. We recently found that radiation-induced tissue injury, which is caused by radiation-induced reactive oxygen species, is attenuated by administration of CBLB502, a pharmacologically optimized derivative of the TLR5 agonist flagellin. Therefore, we tested the ability of CBLB502 to attenuate injury in a murine model of acute ischemic renal failure. CBLB502 given 30 min before imposition of bilateral renal pedicle occlusion provided marked protection against the renal dysfunction and inflammation that follows reperfusion of ischemic kidneys, including marked decreases in leukocyte infiltration, proinflammatory cytokine production, and tubular injury. Importantly, CBLB502 given within 30 min after ischemic kidney reperfusion reproduced the protective effects of pretreatment with the TLR5 agonist, indicating a window following reperfusion in which CBLB502 administration abrogates acute renal ischemic failure. Bone marrow-reconstituted chimeras were used to show that the protective effects of CBLB502 could be delivered by intact MyD88 signaling on renal parenchymal cells. Consistent with this, Ab staining of kidney sections indicated that cells lining the renal vasculature expressed TLR5. Overall, these results indicate the use of TLR5 agonists as mitigators and protectants of acute renal ischemic failure.
缺血器官的再灌注会引发强烈的炎症反应，这是由活性氧的产生引发的，活性氧会直接损伤组织，并促进白细胞浸润和激活，进而介导组织损伤。我们最近发现，由辐射诱导的活性氧引起的组织损伤，会被 CBLB502 减弱，CBLB502 是 TLR5 激动剂鞭毛蛋白的药理学优化衍生物。因此，我们测试了 CBLB502 在急性缺血性肾衰竭的小鼠模型中减弱损伤的能力。在双侧肾蒂夹闭前 30 分钟给予 CBLB502，可显著防止缺血肾脏再灌注后的肾功能障碍和炎症，包括白细胞浸润、促炎细胞因子产生和肾小管损伤的显著减少。重要的是，在缺血性肾再灌注后 30 分钟内给予 CBLB502 可重现 TLR5 激动剂预处理的保护作用，表明再灌注后存在一个窗口，在此期间给予 CBLB502 可消除急性肾缺血性衰竭。骨髓重建嵌合体被用来表明 CBLB502 的保护作用可以通过完整的 MyD88 信号传递到肾实质细胞上。与这一观点一致的是，肾脏切片的 Ab 染色表明，肾血管壁细胞表达 TLR5。总的来说，这些结果表明 TLR5 激动剂可作为急性肾缺血性衰竭的缓解剂和保护剂。
