Moses Tiffany, Wagner Lynn, Fleming Sherry D
Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
J Leukoc Biol. 2009 Oct;86(4):971-80. doi: 10.1189/jlb.0708396. Epub 2009 Jun 29.
Mesenteric IR induces significant inflammation and immune-mediated mucosal damage. TLR4 is a critical receptor in the induction of the inflammatory response and plays a role in intestinal homeostasis. To determine the role of TLR4 in IR-induced epithelial damage, we performed IR studies using TLR4(lps-def) and TLR4(lps-n) mice and analyzed mucosal damage and inflammation. We found that the absence of TLR4 or TLR4-induced signaling attenuated local mucosal damage with significantly decreased cytokine and eicosanoid secretion including PGE2 production. Similar results were seen in MyD88-/- mice. Wild-type mice treated with NS-398 (a Cox-2 inhibitor) not only decreased PGE2 production but also attenuated tissue damage. In contrast, PGE2 was not sufficient to induce damage in the TLR4(lps-def) mice. Together, these data indicate that TLR4 stimulation of Cox-2 activation of PGE2 production is necessary but not sufficient for intestinal IR-induced damage and inflammation.
肠系膜缺血再灌注（IR）会引发显著的炎症反应以及免疫介导的黏膜损伤。Toll样受体4（TLR4）是诱导炎症反应的关键受体，在肠道内环境稳态中发挥作用。为了确定TLR4在缺血再灌注诱导的上皮损伤中的作用，我们使用TLR4（lps缺陷型）和TLR4（lps正常型）小鼠进行了缺血再灌注研究，并分析了黏膜损伤和炎症情况。我们发现，TLR4缺失或TLR4诱导的信号传导减弱会减轻局部黏膜损伤，细胞因子和类花生酸分泌显著减少，包括前列腺素E2（PGE2）的产生。在髓样分化因子88（MyD88）基因敲除小鼠中也观察到了类似结果。用NS - 398（一种环氧化酶-2（Cox - 2）抑制剂）处理的野生型小鼠不仅减少了PGE2的产生，还减轻了组织损伤。相反，PGE2不足以在TLR4（lps缺陷型）小鼠中诱导损伤。综上所述，这些数据表明，TLR4刺激Cox - 2激活PGE2产生对于肠道缺血再灌注诱导的损伤和炎症是必要的，但并不充分。
