Role of toll-like receptor 4 in endotoxin-induced acute renal failure
Role of toll-like receptor 4 in endotoxin-induced acute renal failure
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DOI：
10.4049/jimmunol.172.4.2629
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发表时间：
2004-02-15
影响因子：
4.4
通讯作者：
Quigg, RJ
中科院分区：
文献类型：
--
作者：
Cunningham, PN;Wang, Y;Quigg, RJ
Toll样受体4（TLR 4）存在于单核细胞和其他细胞类型上，并介导炎症事件，例如暴露于LPS后TNF的释放。C3 H/HeJ小鼠对LPS诱导的死亡具有抗性，这是由于TLR 4中天然存在的突变。因此，我们假设LPS诱导的急性肾功能衰竭（ARF）需要由LPS作用于肾外TLR 4触发的全身TNF释放。我们用0.25mg LPS注射C3 H/HeJ小鼠和C3 H/HeOuJ对照，并在6小时后处死它们以分析血尿素氮（BUN）和肾组织（每组n = 8）。与C3 H/HeOuJ对照相比，C3 H/HeJ小鼠对LPS诱导的ARF完全耐受（6小时BUN为32.3 +/- 1.1 vs 61.7 +/- 5.6 mg/dl）。C3 H/HeJ小鼠在2 h时未向循环中释放TNF（0.00 vs 1.24 +/- 0.16 ng/ml），肾中性粒细胞浸润较少（6.4 +/- 1.0 vs 11.4 +/- 1.3个中性粒细胞/高倍视野），肾细胞凋亡较少，如通过DNA梯状评估。移植研究表明，野生型肾的C3 H/HeJ受体（n = 9）免受LPS诱导的ARF，而野生型C3 H/HeJ肾受体（n = 11）发生了严重的LPS诱导的ARF（24小时BUN 44.0 +/- 4.1 vs 112.1 +/- 20.0 mg/dl）。这些实验支持我们的假设，LPS作用于肾外TLR 4，从而导致全身TNF释放和随后的ARF。肾中性粒细胞浸润和肾细胞凋亡是内毒素血症导致功能性ARF的潜在机制。
Toll-like receptor 4 (TLR4) is present on monocytes and other cell types, and mediates inflammatory events such as the release of TNF after exposure to LPS. C3H/HeJ mice are resistant to LPS-induced mortality, due to a naturally occurring mutation in TLR4. We therefore hypothesized that LPS-induced acute renal failure (ARF) requires systemic TNF release triggered by LPS acting on extrarenal TLR4. We injected C3H/HeJ mice and C3H/HeOuJ controls with 0.25 mg of LPS, and sacrificed them 6 h later for analysis of blood urea nitrogen (BUN) and kidney tissue (n = 8 per group). In contrast to C3H/HeOuJ controls, C3H/HeJ mice were completely resistant to LPS-induced ARF (6-h BUN of 32.3 +/- 1.1 vs 61.7 +/- 5.6 mg/dl). C3H/HeJ mice released no TNF into the circulation at 2 h (0.00 vs 1.24 +/- 0.16 ng/ml), had less renal neutrophil infiltration (6.4 +/- 1.0 vs 11.4 +/- 1.3 neutrophils per high power field), and less renal apoptosis, as assessed by DNA laddering. Transplant studies showed that C3H/HeJ recipients of wild-type kidneys (n = 9) were protected from LPS-induced ARF, while wild-type recipients of C3H/HeJ kidneys (n = 11) developed severe LPS-induced ARF (24-h BUN 44.0 +/- 4.1 vs 112.1 +/- 20.0 mg/dl). These experiments support our hypothesis that LPS acts on extrarenal TLR4, thereby leading to systemic TNF release and subsequent ARF. Renal neutrophil infiltration and renal cell apoptosis are potential mechanisms by which endotoxemia leads to functional ARF.