title: MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress.
abstract: Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. Death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly up-regulated miR-15a/16 levels in lung epithelial cells, broncho-alveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species (ROS). Functionally, miR-15a/16 inhibitors induced caspase 3-mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and down-regulated Bcl-2 expression. Consistently, cleaved caspase 8 and 9 were highly induced in the miR-15a/16 deficient cells, after hyperoxia. Using airway epithelial cell specific, miR-15a/16-/-mice, we found that Bcl-2 significantly reduced in lung epithelial cellsin vivoafter hyperoxia. In contrast, caspase 3, 8 and Bcl-2 associated death promoter (BAD) were highly elevated in the miR-15a/16-/-epithelial cellsin vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion ofmiR-15a/16in macrophages also prohibited apoptosis, opposite to what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency result in lung epithelial cell apoptosis in response to hyperoxia,viamodulating both intrinsic and extrinsic apoptosis pathways.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Pulmonary Center, Boston University Medical Campus, Boston, MA, USA 02118.|Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Pulmonary Center, Boston University Medical Campus, Boston, MA, USA 02118.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Pulmonary Center, Boston University Medical Campus, Boston, MA, USA 02118.
authors.forename: Hyung-Geun
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Pulmonary Center, Boston University Medical Campus, Boston, MA, USA 02118.
authors.forename: Heedoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Haspel
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, PA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of Respiratory Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, PR China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Pulmonary Center, Boston University Medical Campus, Boston, MA, USA 02118.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
keywords: Apoptose; cell biology; cell death; pulmonary; reactive oxygen species