Doi Kent, Okamoto Koji, Negishi Kousuke, Suzuki Yoshifumi, Nakao Akihide, Fujita Toshiro, Toda Akiko, Yokomizo Takehiko, Kita Yoshihiro, Kihara Yasuyuki, Ishii Satoshi, Shimizu Takao, Noiri Eisei
Department of Nephrology and Endocrinology, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.
Am J Pathol. 2006 May;168(5):1413-24. doi: 10.2353/ajpath.2006.050634.
Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation 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 PAF 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 PAF pathway might be therapeutic to kidney injury from inflammatory cells.
血小板活化因子（PAF）是一种具有多种生物活性的强效脂质介质，通过募集白细胞在炎症中发挥重要作用。在本研究中，我们使用血小板活化因子受体（PAFR）缺陷小鼠来阐明PAF在叶酸给药诱导的炎症性肾损伤中的作用。PAFR缺陷小鼠的肾功能障碍和病理表现显著改善，如伴有中性粒细胞浸润的急性肾小管损伤、用4-羟基-2-己烯醛抗体观察到的脂质过氧化（第2天），以及伴有单核细胞趋化蛋白-1和肿瘤坏死因子-α在肾脏中表达的巨噬细胞浸润相关的间质纤维化（第14天）。使用单克隆抗体（RB6-8C5）清除中性粒细胞可减轻急性肾小管损伤，表明中性粒细胞对急性期损伤有作用。急性期后开始用PAF拮抗剂（WEB2086）治疗时，巨噬细胞浸润也减少。使用博伊登小室进行的体外趋化试验表明，PAF对巨噬细胞具有很强的趋化活性。这些结果表明，PAF通过在急性期激活中性粒细胞和在慢性间质纤维化中激活巨噬细胞参与叶酸诱导的肾损伤的发病机制。抑制PAF途径可能对炎症细胞引起的肾损伤具有治疗作用。
