Am80, a Retinoic Acid Receptor Agonist, Ameliorates Murine Vasculitis Through the Suppression of Neutrophil Migration and Activation
Am80, a Retinoic Acid Receptor Agonist, Ameliorates Murine Vasculitis Through the Suppression of Neutrophil Migration and Activation
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DOI：
10.1002/art.37784
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发表时间：
2013-02-01
影响因子：
--
通讯作者：
Nanki, Toshihiro
中科院分区：
文献类型：
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作者：
Miyabe, Chie;Miyabe, Yoshishige;Nanki, Toshihiro
目标。血管炎的特点是白细胞浸润血管壁，并对壁结构造成破坏性损害。类维甲酸是一种与维甲酸受体结合并发挥类似维生素A的生物活性的化合物，包括对细胞增殖和分化的调节作用。本研究研究了合成类维甲酸Am80对白色念珠菌水溶性部分（CAWS）诱导的小鼠血管炎模型的治疗作用。腹腔注射CAWS诱导BALB/c小鼠血管炎。通过注射抗中性粒细胞抗体阳性血清来减少中性粒细胞。Am80每天口服一次。对血管炎进行组织学评价。定量标记的过继转移细胞的迁移。通过细胞迁移分析评估趋化性。流式细胞术检测MAPKs的活性氧（ROS）产生和磷酸化水平。采用酶联免疫吸附法测定弹性蛋白酶的浓度。CAWS引起冠状动脉和主动脉根部血管炎，伴有大量中性粒细胞浸润。中性粒细胞耗竭可减少caws诱导的血管炎。用Am80治疗导致血管炎评分显著降低，并抑制转移的中性粒细胞向血管炎部位的迁移。在体外，Am80抑制fmlp诱导的人外周血中性粒细胞的趋化性。经AM80处理后，受刺激的中性粒细胞ROS生成和弹性蛋白酶释放减少，AM80还能抑制fMLP +脂多糖刺激的中性粒细胞ERK-1/2和p38的磷酸化。Am80显著抑制caws诱导的血管炎。这种作用可能是通过抑制中性粒细胞的迁移和激活来发挥的。
Objective. Vasculitis is characterized by leukocyte infiltration in the vessel walls, with destructive damage to mural structures. Retinoids are compounds that bind to retinoic acid receptors and exert biologic activities similar to those of vitamin A, including modulatory effects on cell proliferation and differentiation. This study was undertaken to examine the therapeutic effects of a synthetic retinoid, Am80, in a murine model of vasculitis induced by Candida albicans water-soluble fraction (CAWS).Methods. Vasculitis was induced in BALB/c mice by intraperitoneal injection of CAWS. Neutrophils were depleted by injection of antineutrophil antibody-positive serum. Am80 was administered orally once daily. Vasculitis was evaluated histologically. Migration of labeled adoptively transferred cells was quantified. Chemotaxis was assessed by cell mobility analysis. Production of reactive oxygen species (ROS) and phosphorylation of MAPKs were measured by flow cytometry. Concentrations of elastase were measured by enzyme-linked immunosorbent assay.Results. Administration of CAWS induced vasculitis in the coronary arteries and aortic root, with abundant neutrophil infiltration. Depletion of neutrophils reduced CAWS-induced vasculitis. Treatment with Am80 led to a significant attenuation of the vasculitis score and inhibition of the migration of transferred neutrophils into the site of vasculitis. In vitro, Am80 suppressed fMLP-induced chemotaxis of human peripheral blood neutrophils. ROS production and elastase release by stimulated neutrophils were reduced by AM80 treatment, and Am80 also inhibited phosphorylation of ERK-1/2 and p38 in neutrophils stimulated with fMLP plus lipopolysaccharide.Conclusion. Am80 significantly suppressed CAWS-induced vasculitis. This effect was presumably exerted via inhibition of neutrophil migration and activation.