Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice
Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice
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DOI：
10.2353/ajpath.2006.050634
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发表时间：
2006-05-01
影响因子：
6
通讯作者：
Noiri, E
中科院分区：
文献类型：
--
作者：
Doi, K;Okamoto, K;Noiri, E
血小板活化因子（PAF）是一种具有多种生物活性的脂质介质，通过募集白细胞在炎症反应中发挥重要作用。在这项研究中，我们使用血小板活化因子受体（PAFR）缺陷小鼠阐明PAF在叶酸诱导的炎症性肾损伤中的作用。PAFR缺陷小鼠显示肾功能不全和病理学发现显著改善，如急性肾小管损伤伴中性粒细胞浸润、用4-羟基-2-己烯醛抗体观察到的脂质过氧化（第2天）和间质纤维化伴巨噬细胞浸润（与肾脏中单核细胞趋化蛋白-1和肿瘤坏死因子-α的表达相关）（第14天）。使用单克隆抗体（RB 6 - 8 C5）通过中性粒细胞耗竭来减弱急性肾小管损伤，证明中性粒细胞对急性期损伤的贡献。当在急性期后开始用PAT拮抗剂（WEB 2086）治疗时，巨噬细胞浸润也减少。Boyden小室体外趋化实验表明PAF对巨噬细胞具有较强的趋化活性。这些结果表明PAF通过激活急性期中性粒细胞和慢性间质纤维化中的巨噬细胞参与叶酸诱导的肾损伤的发病机制。抑制PAT通路可能对炎症细胞引起的肾损伤有治疗作用。
Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflamination by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAT antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAT pathway might be therapeutic to kidney injury from inflammatory cells.