title: Protective role of p120-catenin in maintaining the integrity of adherens and tight junctions in ventilator-induced lung injury.
abstract: BACKGROUND
  Ventilator-induced lung injury (VILI) is one of the most common complications for patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Although p120 is an important protein in the regulation of cell junctions, further mechanisms should be explored for prevention and treatment of VILI.
  
  
  METHODS
  Mouse lung epithelial cells (MLE-12), which were transfected with p120 small interfering (si)RNA, p120 cDNA, wild-type E-cadherin juxtamembrane domain or a K83R mutant juxtamembrane domain (K83R-JMD), were subjected to 20% cyclic stretches for 2 or 4 h. Furthermore, MLE-12 cells and mice, which were pretreated with the c-Src inhibitor PP2 or RhoA inhibitor Y27632, underwent 20% cyclic stretches or mechanical stretching, respectively. Moreover, wild-type C57BL/6 mice were transfected with p120 siRNA-liposome complexes before mechanical ventilation. Cell lysates and lung tissues were then analyzed to detect lung injury.
  
  
  RESULTS
  cyclic stretches of 20% actived c-Src, which induced degradation of E-cadherin, p120 and occludin. However, loss of p120 increased the degradation and endocytosis of E-cadherin. Immunoprecipitation and Immunofluorescence results showed a decrease in the association between p120 and E-cadherin, while gap formation increased in p120 siRNA and K83R-JMD groups after 20% cyclic stretches. Loss of p120 also reduced the occludin level and decreased the association of occludin and ZO-1 by enhancing RhoA activity. However, the altered levels of occludin and E-cadherin were reversed by PP2 or Y27632 treatments compared with the cyclic stretch group. Consistently, the expression, redistribution and disassociation of junction proteins were all restored in the p120 overexpression group after 20% cyclic stretches. Moreover, the role of p120 in VILI was confirmed by increased wet/dry weigh ratio and enhanced production of cytokines (tumor necrosis factor-α and interleukin-six) in p120-depleted mice under mechanical ventilation.
  
  
  CONCLUSIONS
  p120 protected against VILI by regulating both adherens and tight junctions. p120 inhibited E-cadherin endocytosis by increasing the association between p120 and juxtamembrane domain of E-cadherin. Furthermore, p120 reduced the degradation of occludin by inhibiting RhoA activity. These findings illustrated further mechanisms of p120 in the prevention of VILI, especially for patients with ALI or ARDS.
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, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. liumengjie31@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. 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. ngbaise@163.com.
authors.forename: Dong
authors.initials: D
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: D022005:Adherens Junctions / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D051177:Catenins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism*; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000473:pathology; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse