Preventive and Therapeutic Effects of Phosphoinositide 3-Kinase Inhibitors on Acute Lung Injury
Preventive and Therapeutic Effects of Phosphoinositide 3-Kinase Inhibitors on Acute Lung Injury
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DOI：
10.1378/chest.10-3060
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发表时间：
2011-08-01
期刊：
影响因子：
9.6
通讯作者：
Wang, Xiangdong
中科院分区：
文献类型：
--
作者：
Chen, Chengshui;Fang, Xiaocong;Wang, Xiangdong
背景：磷脂酰肌醇3-激酶（PI 3 Ks）参与许多生物学反应。最近的临床前研究表明，PI 3 K的主导信号通路可能在急性肺损伤的发展中发挥重要作用，但其机制尚不清楚。方法：CD-1小鼠鼻内或灌胃给予不同的PI 3 K抑制剂，每天1次，连续3天，然后在4 h和24 h内注入脂多糖。测定SHBM 1009对脂多糖诱导的毛细血管通透性、白细胞分布和活化以及上皮细胞功能的影响。结果：与全身给药相比，局部给药能更有效地预防内毒素性肺损伤。PI 3 K抑制剂的预防作用最有可能因化学性质、靶向部位和药代动力学而变化。结论：PI 3 K可能是肺损伤的治疗靶点，局部应用PI 3 K抑制剂可能是治疗肺损伤的最佳途径之一。胸部2011; 140（2）：391-400
Background: Phosphoinositide 3-kinases (PI3Ks) are involved in a number of biologic responses. Recent preclinical studies demonstrated that the PI3K-dominant signal pathway could play an important role in the development of acute lung injury, although the mechanism remains unclear.Methods: CD-1 mice were administered different PI3K inhibitors either intranasally or intragastrically once a day for 3 days before intratracheal instillation of lipopolysaccharide at 4 h and 24 h. Effects of SHBM1009 on lipopolysaccharide-induced capillary permeability, leukocyte distribution and activation, and epithelial cell function were measured. Therapeutic effects of SHBM1009 on pancreatic elastase-induced lung injury were evaluated in rats.Results: The data demonstrated that the local delivery of PI3K inhibitors played more effective roles in the prevention of endotoxin-induced lung injury than the systemic delivery. The preventive effects of PI3K inhibitors varied most likely because of chemical properties, targeting sites, and pharmacokinetics. The local PI3K inhibitors prevented both endotoxin- and elastase-induced lung injury in mice and rats, possibly through directly inhibiting or inactivating the function of airway epithelial cells, which could not produce chemoattractant factors to activate neutrophils and macrophages.Conclusions: PI3K may be a therapeutic target for lung injury, and local delivery of PI3K inhibitors may be one of the optimal approaches for the therapy. CHEST 2011; 140(2):391-400