Endothelium-derived toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs
Endothelium-derived toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs
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DOI：
10.1172/jci200316510
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发表时间：
2003-04-01
影响因子：
15.9
通讯作者：
Kubes, P
中科院分区：
文献类型：
--
作者：
Andonegui, G;Bonder, CS;Kubes, P
中性粒细胞进入肺部的快速和选择性积累被认为是导致败血症相关死亡的肺衰竭的基础。在这项研究中，我们通过建立嵌合小鼠（在TLR4（+/+）和TLR4（-/-）小鼠之间转移骨髓）来研究中性粒细胞TLR4在lps诱导的肺中性粒细胞募集中是否重要。在接受TLR4（-/-）骨髓的TLR4（+/+）小鼠中，移植后6周，所有循环白细胞和常驻巨噬细胞（这些小鼠被称为白细胞TLR4(-/-)）中都没有TLR4，这些细胞对LPS完全没有反应。在接受TLR4（+/+）骨髓的TLR4（-/-）小鼠中，内皮细胞而非白细胞缺乏TLR4（内皮TLR4(-/-)）。令人惊讶的是，系统性LPS （0.5 mg/kg）在头4小时内诱导白细胞tlr4（-/-）小鼠肺中中性粒细胞的隔离急剧增加。同时，循环白细胞的数量减少了90%。相比之下，内皮细胞TLR4（-/-）小鼠肺中中性粒细胞的隔离几乎没有增加，这表明内皮细胞而不是白细胞TLR4起重要作用。体外显微镜观察肌外周微循环显示，lps处理的内皮细胞TLR4（-/-）小鼠白细胞与内皮细胞的相互作用比lps处理的白细胞TLR4（-/-）小鼠多30倍。这与EndothefumTLR4（-/-）小鼠肺中较少的白细胞隔离一致。总之，我们的数据挑战了LPS直接激活中性粒细胞在肺中捕获的观点，并表明其作用远比之前认为的内皮细胞重要。
The rapid and selective accumulation of neutrophils into the lungs is thought to underlie the pulmonary failure that leads to sepsis-related death. In this study we investigated whether neutrophil TLR4 is important in LPS-induced pulmonary neutrophil recruitment by creating chimeric mice (transferring bone marrow between TLR4(+/+) and TLR4(-/-) mice). In TLR4(+/+) mice receiving TLR4(-/-) bone marrow, 6 weeks after transplant TLR4 was absent in all circulating leukocytes as well as in resident macrophages (these mice were termed Leukocyte TLR4(-/-)), and these cells were completely nonresponsive to LPS. In TLR4(-/-) mice receiving TLR4(+/+) bone marrow, endothelial cells but not leukocytes were deficient in TLR4 (EndotheliumTLR4(-/-)). Surprisingly, systemic LPS (0.5 mg/kg) induced a dramatic increase in neutrophil sequestration into the lungs of LeukocyteTLR4(-/-) mice over the first 4 hours. Concomitantly, numbers of circulating leukocytes decreased by 90%. By contrast, Endothefum TLR4(-/-) mice showed very little increase in neutrophil sequestration in the lungs, suggesting that endothelium rather than leukocyte TLR4 was important. Intravital microscopy of peripheral microcirculation in the cremaster muscle revealed about 30-fold more leukocyte-endothelial cell interactions in LPS-treated Endothelium TLR4(-/-) mice than in LPS-treated LeukocyteTLR4(-/-) mice. This is consistent with less sequestration of leukocytes into the lungs of EndothefumTLR4(-/-) mice. In conclusion, our data challenge the view that LPS directly activates neutrophils to trap in lungs and suggest a far more important role than previously appreciated for the endothelial cells.