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 (CH13L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CH13L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CH13L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CH13L1 in this process are poorly understood. Purpose: In this study, we demonstrate the role of CH13L1, along with the MAPK and P13K signaling pathways, in hyperoxia-exposed airway epithelial cells. Method: The human airway epithelial cell line, BEAS-2B, was exposed to > 95% oxygen (hyperoxia) for up to 72 h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CH13L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CH13L1 in hyperoxia-induced apoptosis. Activation of the MAPK and P13K pathways was also investigated to determine the role of these signaling cascades in this process. Results: Hyperoxia exposure increased CH13L1 expression and apoptosis in a time-dependent manner. CH13L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CH13L1 overexpression promoted cell death after hyperoxia exposure. Finally, phosphorylation of ERK1/2, p38, and Akt were affected by CH13L1 knockdown. Conclusion: This study indicates that CH13L1 is involved in hyperoxia-induced cell death, suggesting that CH13L1 may be one of several cell death regulators influencing the MAPK and P13K pathways during oxidative stress in human airway epithelial cells. (C) 2012 Elsevier Inc. All rights reserved.