SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence

作     者：Underwood, DC Osborn, RR Kotzer, CJ Adams, JL Lee, JC Webb, EF Carpenter, DC Bochnowicz, S Thomas, HC Hay, DWP Griswold, DE 

作者机构：SmithKline Beecham Pharmaceut Dept Pulm Pharmacol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Med Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Bone Biol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Safety Assessment King Of Prussia PA 19406 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第293卷第1期

页      面：281-288页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

主　　题：投药 吸入 细胞凋亡/药物作用 印迹法 蛋白质 支气管肺泡灌洗液/细胞学 支气管收缩/药物作用 细胞因子类/生物合成 酶抑制剂/药理学 嗜酸粒细胞增多/化学诱导 嗜酸粒细胞增多/病理学 咪唑类/药理学 白三烯D4/投药和剂量 白三烯D4/药理学 脂多糖类/药理学 小鼠 近交BALBC 丝裂原激活蛋白激酶类 单核细胞/药物作用 单核细胞/代谢 吞噬作用/药物作用 体积描记术 全身 嘧啶类/药理学 呼吸系统/药物作用 呼吸系统/病理学 肿瘤坏死因子α/生物合成 p38丝裂原活化蛋白激酶类 动物 豚鼠 人类 小鼠 

摘      要：The anti-inflammatory/antiallergic activity of a novel second-generation p38 mitogen-activated protein kinase inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl methoxypyridimidin-4-yl)imidazole], was investigated in vivo and in vitro. SB 239063 had an IC50 of 44 nM for inhibition of recombinant purified human p38 alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis factor-alpha production (IC50 values = 0.12 and 0.35 mu M, respectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysaccharide-induced tumor necrosis factor-a production by SB 239063 (ED50 = 5.8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolition (similar to 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosinophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage (BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western analysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced (similar to 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotriene D-4 inhalation, reduced by 60% the persistent airway eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by SB 239063 (1-10 mu M) in the presence of interleukin-5. These results indicate that SE 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SE 239063, for the treatment of asthma and other inflammatory disorders.