title: Activation of c-Src tyrosine kinase mediated the degradation of occludin in ventilator-induced lung injury.
abstract: BACKGROUND
  Ventilator-induced lung injury (VILI) is characterized by increased alveolar permeability, pulmonary edema. The tyrosine kinase, c-Src, is involved in VILI but its role has not been fully elucidated. This study examined the relationship between c-Src activation and occludin levels in VILI both in vitro and in vivo.
  
  
  METHODS
  For the in vivo study, Wistar rats were randomly divided into five groups: control (group C); normal tidal volume (group M); normal tidal volume + c-Src inhibitor (PP2) (group M + P); high tidal volume (group H); and high tidal volume + c-Src inhibitor (PP2) (group H + P). Rats in all groups but group C underwent mechanical ventilation for 4 h. For the in vitro study, MLE-12 cells pretreated with PP2 and siRNA underwent cyclic stretching at 8% or 20% for 0, 1, 2 and 4 h. The expressions of occludin, c-Src, and p-c-Src were analyzed by western blotting, hematoxylin and eosin (HE) staining, and immunofluorescence.
  
  
  RESULTS
  For the in vivo study, rats in group H showed decreased occludin expression and activated c-Src compared with group C. HE staining and lung injury score showed more severe lung injury and alveolar edema in group H compared with group M and group C. Group H + P had less pulmonary edema induced by the high tidal volume ventilation. For the in vitro study, occludin expression decreased and c-Src activation increased as indicated by the phosphorylation of c-Src over time. Consistently, PP2 could restore occludin levels.
  
  
  CONCLUSIONS
  Mechanical ventilation can activate c-Src by phosphorylation and increase the degradation of occludin. c-Src inhibitor can ameliorate barrier function and lung injury by up-regulating occludin.
authors.affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. feishi_xin@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. xinruoziming@163.com.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. changpinggu@163.com.
authors.forename: Changping
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Jinan Fifth People's Hospital, Ji'nan, Shandong, China. haven7@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. wyldgf@163.com.
authors.forename: Yuelan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D040542:Mechanotransduction, Cellular; D051379:Mice; D062793:Occludin / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D011654:Pulmonary Edema / Q000201:enzymology; D034622:RNA Interference; D017208:Rats, Wistar; D013997:Time Factors; D014162:Transfection; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology* / Q000503:physiopathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D047428:Protein Kinase Inhibitors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases