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Preventive and Therapeutic Effects of Phosphoinositide 3-Kinase Inhibitors on Acute Lung Injury

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Author

  • Chengshui Chen
  • Xiaocong Fang
  • Yaoli Wang
  • Yuping Li
  • Diane Wang
  • Xia Zhao
  • Chunxue Bai
  • Xiangdong Wang

Summary, in English

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

Department/s

Publishing year

2011

Language

English

Pages

391-400

Publication/Series

Chest

Volume

140

Issue

2

Document type

Journal article

Publisher

American College of Chest Physicians

Topic

  • Respiratory Medicine and Allergy

Status

Published

ISBN/ISSN/Other

  • ISSN: 1931-3543