Toll样受体4在急性肺损伤中的作用

Effects of Toll-like receptor 4 in lipopolysaccharide induced acute lung injury

目的观察Toll样受体4(toll-like receptor 4,TLR4)基因突变型小鼠与野生型小鼠内毒素攻击致急性肺损伤(acute lung injury,ALI)的差异,分析TLR4在ALI中的作用。方法采用TLR4基因突变小鼠(C3H/HeJ品系,TLR4^(-/-)及野生型小鼠(CBA品系,TLR4^(+/+)),用内毒素攻击复制小鼠ALI模型,用显微病理及肺干湿重比(W/D)分析肺损伤程度,检测肺组织髓过氧化物酶(MPO)水平,探讨损伤差异的可能机制。结果用1,5 mg·kg^(-1)LPS溶液经尾静脉注射复制ALI模型,结果示TLR4突变小鼠肺组织大体及显微病理损伤较野生型小鼠减轻,同时肺组织水肿(W/D)亦较野生小鼠减轻,尤其是在大剂量(5mg·kg^(-1))时,差异有显著性[(4．08±0．1)vs．(4．55±0．2),n=10,t=12．71,P＜0．01]。突变小鼠肺组织PMN浸润水平较野生型低[MPO：1 mg·kg^(-1)组,(20．73±4．58)vs．(39．97±3．66),n=10,t=13．43,P＜0．01]；5 mg·kg^(-1)组,[(24．0±3．94)vs．(48．5±4．07),n=10,t=15．33,P＜0．01],且两者均较假手术组高。结论TLR4可能通过介导中性粒细胞肺内聚集而导致ALI的发生发展。

Objective To observe the difference of lung injury between toll-like receptor 4 （TLR4） mutant mice and wild type mice in a model of lipopolysaccharide （LPS） induced acute lung injury （ALI）, discuss the role of TLR4 in ALI. Methods Different doses of LPS solution （ 1, 5 mg·kg^-1） were injected in vein tail to reproduce ALI model in both TLR4 mutant （TLR4^-/- ） and wild type （WT, TLR4^±/± ） mice. Lung tissues were collected for gross and micrographic histological injury analysis and for assessment of lung edema. Meanwhile, the levels of myeloperoxidase （MPO） in lung tissues in both strains were assessed to evaluate the extent of polymorphological neutrophils （PMN） infiltration. Results The gross and micrographic injury of lung was milder in TLR4 mutant mice than that in wild type mice. The extent of lung edema （W/D） was also reduced compared with wild type mice, especially in 5 mg·kg^-1 group [ （4.08±0.1） vs. （4.55±0.2）, n= 10, t= 12.71, P〈0.01]. With high dosage of LPS, the value of W/D in both mice strains was higher than that in sham operation group （ P 〈 0.01 ）. The extent of PMN infiltration in lung tissues in TLR4 mutant mice was reduced compared with wild type mice. But they were higher than sham operated mice （ P 〈 0.01 ）. Conclusion TLR4 May involve in the development of ALI, by sequestration of PMN into lung tissues.