SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung
SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung
复制标题
DOI：
10.1152/ajplung.2000.279.5.l895
复制
发表时间：
2000-11-01
影响因子：
4.9
通讯作者：
Griswold, DE
中科院分区：
文献类型：
--
作者：
Underwood, DC;Osborn, RR;Griswold, DE
第二代p38丝裂原活化蛋白激酶（MAPK）抑制剂SB 239063 [trans-l-（4-羟基环己基）-4-（4-氟苯基）-5-（2-甲氧基嘧啶-4-基）咪唑; IC 50 = 44 nM vs. p38 α]，在代表慢性阻塞性肺疾病（COPD）不同病理学方面的模型中进行评估[气道嗜酸性粒细胞，增强的细胞因子形成和增加的基质金属蛋白酶（MMP）-9活性]和肺纤维化模型。吸入脂多糖（LPS）后48小时通过支气管肺泡灌洗评估的气道中性粒细胞浸润和白细胞介素（IL）-6水平，通过每天两次口服3-30 mg/kg SB 239063剂量依赖性地抑制。此外，SB 239063（30 mg/kg口服）减弱了LPS暴露后6小时评估的IL-6支气管肺泡灌洗液浓度（>90%抑制）和MMP-9活性（64%抑制）。在豚鼠培养的肺泡巨噬细胞中，SB 239063抑制LPS诱导的IL-6产生（IC 50为362 nM）。在博莱霉素诱导的大鼠肺纤维化模型中，SB 239063（2.4或4.8 mg/天，通过渗透泵）治疗显著抑制博莱霉素诱导的右心室肥大（指示继发性肺动脉高压）和肺羟脯氨酸合成增加（指示胶原蛋白合成和纤维化）。因此，SB 239063显示出对一系列通常与COPD和纤维化相关的后遗症的活性，支持p38 MAPK抑制剂如SB 239063在慢性气道疾病中的治疗潜力。
The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl) imidazole; IC50 = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC50 of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.