title: Central role of cellular senescence in TSLP-induced airway remodeling in asthma.
abstract: BACKGROUND
  Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma.
  
  
  OBJECTIVE
  To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo.
  
  
  METHODS
  Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma.
  
  
  RESULTS
  Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance.
  
  
  CONCLUSIONS
  TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling.
authors.affiliation: Department of Respiratory, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Wu
authors.forename: Fangzheng
authors.initials: F
authors.lastname: Dong
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Junfei
authors.initials: J
authors.lastname: Wang
authors.forename: Jiping
authors.initials: J
authors.lastname: Zhao
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Yang
authors.forename: Wenbin
authors.initials: W
authors.lastname: Gong
authors.forename: Rutao
authors.initials: R
authors.lastname: Cui
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
mesh_terms: D000293:Adolescent; D000328:Adult; D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C498762:CRLF2 protein, human; D007136:Immunoglobulins; D011725:Pyridines; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C410591:Tslpr protein, mouse; D020032:Tyrphostins; C519885:WP1066