An inhaled phosphodiesterase 4 inhibitor E6005 suppresses pulmonary inflammation in mice
An inhaled phosphodiesterase 4 inhibitor E6005 suppresses pulmonary inflammation in mice
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吸入式磷酸二酯酶 4 抑制剂 E6005 可抑制小鼠肺部炎症
DOI：
10.1016/j.ejphar.2015.10.013
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发表时间：
2015
期刊：
影响因子：
5
通讯作者：
Inoue H
中科院分区：
文献类型：
--
作者：
Kubota S;Watanabe M;Shirato M;Okuno T;Higashimoto I;Machida K;Yokomizo T;Inoue H
慢性阻塞性肺疾病(COPD)是一种进展性肺部疾病，具有显著的发病率和死亡率。虽然已经开发了几种口服磷酸二酯酶4(PDE4)抑制剂来治疗COPD，但由于副作用，包括恶心和呕吐，它们的使用受到了限制。我们假设，吸入干粉PDE4抑制剂将使全身吸收降至最低，并使局部抑制PDE4能够抑制肺部炎症。通过气管内注射脂多糖诱导小鼠中性粒细胞肺炎症。用一种新的干粉PDE4抑制剂E6005(4-[({3-[6，7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino)甲酯)苯甲酸酯对小鼠进行气管内治疗。评价药物动力学、细胞形态、细胞因子、趋化因子和脂质介质水平以及肺组织学改变。小鼠气管内注射E6005可导致肺部高浓度的该化合物。组织学分析显示，E6005处理的小鼠肺组织炎症减轻，这与BALF中中性粒细胞、促炎细胞因子、趋化因子和半胱氨酸白三烯水平的降低有关。因此，气管内给药E6005有效地抑制了中性粒细胞肺部炎症，这表明新型吸入干粉PDE4抑制剂是治疗COPD的传统口服制剂的替代方案。
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease associated with significant morbidity and mortality. Although several oral phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of COPD, their use has been restricted because of side effects including nausea and emesis. We hypothesized that delivery of a dry powdered PDE4 inhibitor by inhalation would minimize systemic absorption and enable local PDE4 inhibition to suppress inflammation within the lung. Neutrophilic pulmonary inflammation was induced in mice by intratracheal administration of lipopolysaccharide. Mice were treated intratracheally with a new dry powder PDE4 inhibitor, E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino) carbonyl] benzoate). The pharmacokinetics, cell profiles and levels of cytokines, chemokines, and lipid mediators in bronchoalveolar lavage fluid (BALF), and lung histology were assessed. Intratracheal administration of E6005 to mice resulted in high concentrations of the compound in the lungs. Histological analysis of E6005-treated mice demonstrated reduced inflammation of lung tissue that correlated with a decrease in BALF levels of neutrophils, proinflammatory cytokines, chemokines, and cysteinyl leukotrienes. Thus, intratracheal administration of E6005 effectively suppresses neutrophilic pulmonary inflammation, suggesting that the new inhaled dry powder PDE4 inhibitor represents an alternative to the conventional oral formulation for treating COPD.