title: Effects of phosphoinositide 3-kinase on protease-induced acute and chronic lung inflammation, remodeling, and emphysema in rats.
abstract: BACKGROUND
  Phosphoinositide 3-kinase (PI3K) plays an important role in tissue inflammatory reactions and fibrotic processes. The objective of this study was to evaluate the potential mechanism and therapeutic effects of PI3K inhibitor on pancreatic elastase (PE)-induced acute and chronic lung inflammation, edema, and injury.
  
  
  METHODS
  Rats were terminated at 7 or 28 days after an intratracheal challenge with PE and intranasal instillation with a PI3K inhibitor, SHBM1009. Alterations of airway epithelial cells and myofibroblasts were studied in vitro.
  
  
  METHODS
  Lung inflammation, edema, and injury; emphysema; and tissue remodeling were measured after PE instillation with or without treatment with PI3K inhibitor and budesonide. Cellular biologic functions were monitored.
  
  
  RESULTS
  SHBM1009 could prevent PE-induced acute lung inflammation, edema, and injury, and chronic lung inflammation, remodeling, and emphysema. Different patterns of inhibitory effects of SHBM1009 and BEZ235, a dual PI3K/mechanistic target of rapamycin inhibitor, on PE-challenged epithelial cells were observed. PE per se reduced epithelial cell proliferation and stability through the inhibition of cell division rather than promoting cell death, in dose- and time-dependent patterns. Effects of PI3K inhibitors on cells were associated with the severity of PE challenges.
  
  
  CONCLUSIONS
  PI3K plays a critical role in the development of acute and chronic lung injury, including the process of tissue remodeling and emphysema. PI3K inhibitors could be new therapeutic alternatives for chronic lung diseases.
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Fang
authors.affiliation: Biomedical Research Center, Fudan University, Shanghai, China.
authors.forename: Ka
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Respiratory Diseases, Wenzhou Medical College and The First Hospital, Wenzhou, China.
authors.forename: Chengshui
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Biomedical Research Center, Fudan University, Shanghai, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China; Biomedical Research Center, Fudan University, Shanghai, China.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Wang
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
authors.affiliation: Department of Pulmonary Medicine, Fudan University, Shanghai, China; Biomedical Research Center, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: xiangdong.wang@clintransmed.org.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000208:Acute Disease; D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D019819:Budesonide / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004646:Emphysema / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010196:Pancreatic Elastase / Q000009:adverse effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011014:Pneumonia / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D019819:Budesonide; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010196:Pancreatic Elastase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C531198:dactolisib