title: Involvement of the MAPK and PI3K pathways in chitinase 3-like 1-regulated hyperoxia-induced airway epithelial cell death.
abstract: BACKGROUND
  Exposure to 100% oxygen causes hyperoxic acute lung injury characterized by cell death and injury of alveolar epithelial cells. Recently, the role of chitinase 3-like 1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CHI3L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood.
  
  
  OBJECTIVE
  In this study, we demonstrate the role of CHI3L1, along with the MAPK and PI3K signaling pathways, in hyperoxia-exposed airway epithelial cells.
  
  
  METHODS
  The human airway epithelial cell line, BEAS-2B, was exposed to >95% oxygen (hyperoxia) for up to 72h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CHI3L1 in hyperoxia-induced apoptosis. Activation of the MAPK and PI3K pathways was also investigated to determine the role of these signaling cascades in this process.
  
  
  RESULTS
  Hyperoxia exposure increased CHI3L1 expression and apoptosis in a time-dependent manner. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Finally, phosphorylation of ERK1/2, p38, and Akt were affected by CHI3L1 knockdown.
  
  
  CONCLUSIONS
  This study indicates that CHI3L1 is involved in hyperoxia-induced cell death, suggesting that CHI3L1 may be one of several cell death regulators influencing the MAPK and PI3K pathways during oxidative stress in human airway epithelial cells.
authors.affiliation: Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi Na
authors.initials: MN
authors.lastname: Kim
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Hong
authors.forename: Won Il
authors.initials: WI
authors.lastname: Heo
authors.forename: Kyung Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Kyu Earn
authors.initials: KE
authors.lastname: Kim
authors.forename: Myung Hyun
authors.initials: MH
authors.lastname: Sohn
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D000071451:Chitinase-3-Like Protein 1; D055785:Gene Knockdown Techniques; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D019869:Phosphatidylinositol 3-Kinases; D010100:Oxygen