Institute of Burn Surgery and Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
J Surg Res. 2012 May 15;174(2):326-33. doi: 10.1016/j.jss.2010.12.005. Epub 2011 Jan 5.
Splanchnic ischemia is common in critically ill patients, and it can result in injury not only of the intestine but also in distant organs, particularly in the lung. Local inflammatory changes play a pivotal role in the development of acute lung injury after intestinal ischemia, but the underlying molecular mechanisms are not fully understood. We sought to examine the role of Toll-like receptor 4 (TLR4) in the mouse model of intestinal ischemia-reperfusion (I/R)-induced lung injury and inflammation.
Adult male TLR4 mutant (C3H/HeJ) mice and TLR4 wild-type (WT) (C3H/HeOuJ) mice were subjected to 40 min of intestinal ischemia by clamping the superior mesenteric artery followed by 6 h of reperfusion. Lung histology was assessed and parameters of pulmonary microvascular permeability, inflammatory cytokine expression, and neutrophil infiltration were measured. Activation of mitogen-activated protein kinases (MAPKs) and the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in the lungs were also detected.
After intestinal I/R, lungs from TLR4 mutant mice demonstrated a significantly lower histological injury, a marked reduction of epithelial apoptosis associated with the decreased level of cleaved caspase-3 and the increased ratio of Bcl-xL to Bax proteins, and a large reduction in pulmonary vascular permeability and myeloperoxidase (MPO) activity in comparison with WT mice. TLR4 mutant mice also displayed marked decreases in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) expression. Following intestinal I/R, phosporylation of p38 MAPK and activation of NF-κB and AP-1 were significantly inhibited in lung tissue from TLR4 mutant mice compared with WT controls.
These data suggest that TLR4 plays an important role in the pathogenesis of intestinal I/R-induced acute lung injury and inflammation and that p38 kinase and NF-κB may be involved in TLR4 signaling-mediated lung inflammatory processes during intestinal I/R.
内脏缺血在危重病患者中很常见，它不仅会导致肠道损伤，还会导致远处器官损伤，特别是肺部。局部炎症变化在肠缺血后急性肺损伤的发展中起着关键作用，但潜在的分子机制尚不完全清楚。我们试图在肠缺血再灌注（I/R）诱导的肺损伤和炎症的小鼠模型中研究 Toll 样受体 4（TLR4）的作用。
成年雄性 TLR4 突变（C3H/HeJ）小鼠和 TLR4 野生型（WT）（C3H/HeOuJ）小鼠通过夹闭肠系膜上动脉进行 40 分钟的肠缺血，然后再灌注 6 小时。评估肺组织学，并测量肺微血管通透性、炎症细胞因子表达和中性粒细胞浸润的参数。还检测了肺中的丝裂原活化蛋白激酶（MAPKs）和转录因子核因子 κB（NF-κB）和激活蛋白-1（AP-1）的激活。
肠 I/R 后，TLR4 突变小鼠的肺组织显示出明显较低的组织损伤，与 cleaved caspase-3 水平降低和 Bcl-xL 与 Bax 蛋白比值增加相关的上皮细胞凋亡明显减少，肺血管通透性和髓过氧化物酶（MPO）活性也明显降低与 WT 小鼠相比。TLR4 突变小鼠的肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、单核细胞趋化蛋白-1（MCP-1）和巨噬细胞炎症蛋白-2（MIP-2）表达也明显减少。与 WT 对照组相比，肠 I/R 后 TLR4 突变小鼠肺组织中 p38 MAPK 的磷酸化和 NF-κB 和 AP-1 的激活明显受到抑制。
这些数据表明 TLR4 在肠 I/R 诱导的急性肺损伤和炎症的发病机制中起重要作用，并且 p38 激酶和 NF-κB 可能参与 TLR4 信号转导介导的肠 I/R 期间的肺炎症过程。
