title: Preventive and therapeutic effects of phosphoinositide 3-kinase inhibitors on acute lung injury.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine, The First Hospital, Wenzhou Medical College, Zhejiang, China.
authors.forename: Chengshui
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Fang
authors.affiliation: Intensive Care Unit, Daping Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yaoli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, The First Hospital, Wenzhou Medical College, Zhejiang, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Diane
authors.initials: D
authors.lastname: Wang
authors.affiliation: Biomedical Center, Lund University, Lund, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: xiangdong.wang@telia.com.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002867:Chromones; D007191:Indazoles; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one