Distinct roles of pattern recognition receptors CD14 and toll-like receptor 4 in acute lung injury
Distinct roles of pattern recognition receptors CD14 and toll-like receptor 4 in acute lung injury
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DOI：
10.1128/iai.73.3.1754-1763.2005
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发表时间：
2005-03-01
影响因子：
3.1
通讯作者：
Worthen, GS
中科院分区：
文献类型：
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作者：
Jeyaseelan, S;Chu, HW;Worthen, GS
脂多糖（LPS）引起的急性肺损伤（ALI）是人类死亡的主要原因之一。ALI的特点是微血管蛋白渗漏、中性粒细胞内流和促炎介质的表达，随后是严重的肺损伤。脂多糖与其受体的结合是导致这些多步骤事件的关键步骤。脂多糖的结合和信号传导涉及CD14和toll样受体4 （TLR4）。然而，CD14和TLR4在ALI诱导中的相对作用及其在体内的治疗潜力尚不清楚。因此，本研究的目的是比较CD14和TLR4在lps诱导的ALI中的作用，以确定在小鼠模型中，哪一个分子是减弱ALI的更关键的靶点。我们的研究结果表明，CD14和TLR4对于低剂量（300杯/毫升）lps诱导的微血管渗漏、NF-kappaB激活、中性粒细胞内流、细胞因子和趋化因子（KC、巨噬细胞炎症蛋白2、肿瘤坏死因子α、白细胞介素6）表达以及随后的肺损伤是必需的。另一方面，当使用10倍剂量的LPS （3mg /ml）时，这些反应仅部分依赖于CD14，而完全依赖于TLR4。不依赖cd14的LPS反应依赖于CD11b。TLR4阻断抗体在低剂量LPS下可以消除微血管渗漏、中性粒细胞积累、细胞因子反应和肺部病理，但在高剂量LPS下只能减弱这些反应。这些数据首次证明了LPS诱导的肺中cd14依赖性和非依赖性（cd11b依赖性）信号通路完全依赖于TLR4，阻断TLR4可能对由革兰氏阴性病原体引起的LPS引起的肺部疾病有益。
Acute lung injury (ALI) induced by lipopollysaccharide (LPS) is a major cause of mortality among humans. ALI is characterized by microvascular protein leakage, neutrophil influx, and expression of proinflammatory mediators, followed by severe lung damage. LPS binding to its receptors is the crucial step in the causation of these multistep events. LPS binding and signaling involves CD14 and Toll-like receptor 4 (TLR4). However, the relative contributions of CD14 and TLR4 in the induction of ALI and their therapeutic potentials are not clear in vivo. Therefore, the aim of the present study was to compare the roles of CD14 and TLR4 in LPS-induced ALI to determine which of these molecules is the more critical target for attenuating ALI in a mouse model. Our results show that CD14 and TLR4 are necessary for low-dose (300-mug/ml) LPS-induced microvascular leakage, NF-kappaB activation, neutrophil influx, cytokine and chemokine (KC, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-6) expression, and subsequent lung damage. On the other hand, when a 10-fold-higher dose of LPS (3 mg/ml) was used, these responses were only partially dependent on CD14 and they were totally dependent on TLR4. The CD14-independent LPS response was dependent on CD11b. A TLR4 blocking antibody abolished microvascular leakage, neutrophil accumulation, cytokine responses, and lung pathology with a low dose of LPS but only attenuated the responses with a high dose of LPS. These data are the first to demonstrate that LPS-induced CD14-depdendent and -independent (CD11b-dependent) signaling pathways in the lung are entirely dependent on TLR4 and that blocking TLR4 might be beneficial in lung diseases caused by LPS from gram-negative pathogens.