Abstract
BackgroundChronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. Cigarette smoking induces neutrophil elastase (NE) and contributes to COPD, but the detailed mechanisms involved are not fully established. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema.MethodsHuman bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cells were treated with NE. The PlGF promoter activity was examined by luciferase activity assay, while PlGF expression and secretion were evaluated by RT-PCR, Western blotting, and ELISA. Both cell lines were treated with PlGF to evaluate its effects and the downstream signaling pathways leading to LE cell apoptosis. PlGF knockout and wild-type mice were instilled with NE to determine the roles of PlGF and its downstream molecules in NE-promoted mice pulmonary apoptosis and emphysema phenotype.ResultsThe transcriptional factor, early growth response gene-1, was involved in the NE-promoted PlGF promoter activity, and the expression and secretion of PlGF mRNA and protein in LE cells. PlGF-induced LE cell apoptosis and NE-induced mice pulmonary apoptosis and emphysema were mediated by the downstream c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)δ signaling pathways.ConclusionThe NE-PlGF-JNK/PKCδ pathway contributes to the pathogenesis of LE cell apoptosis and emphysema. PlGF and its downstream signaling molecules may be potential therapeutic targets for COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0106-1) contains supplementary material, which is available to authorized users.
Highlights
Chronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide
neutrophil elastase (NE) increased placenta growth factor (PlGF) promoter activity by Early growth response gene (Egr)-1 in lung epithelial (LE) Cells The results revealed that treatment with 100–300 mU/ml NE for 24 h significantly increased PlGF promoter activity dose-dependently in human bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cell (AEC II) (Figure 1A)
Treatment with 300 mU/ml NE did not alter the expression of mental-regulatory transcription factor (MTF)-1 and hypoxia inducible factor (HIF)-1α (Figure 1B)
Summary
Chronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema. Chronic pulmonary obstructive disease (COPD) is predicted to become the fourth leading cause of death worldwide by 2030 [1,2]. The protease-anti-protease imbalance is triggered by the infiltration of inflammatory cells like neutrophils, macrophages, and CD8+ T lymphocytes [7,8,9,10,11]. The interaction promotes protease-anti-protease imbalance and destroys the pulmonary parenchyma with alveolar space dilatation, i.e. emphysema, which is a major component of COPD [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
