PlGF mediates neutrophil elastase-induced airway epithelial cell apoptosis and emphysema

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.

Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice†

“…Later stages in HPS development in our study were characterized by pulmonary neutrophil infiltration and elevated levels of NE in BALF. Other studies have described a role for elastase and PlGF in inducing AT2 cell death during pulmonary emphysema, and a recent report demonstrated AT2 cell dysfunction after CBDL in rats . In line with this, we have shown that αPlGF attenuates the AT2 cell proinflammatory and caspase 3/7 response to LPS in vitro .…”

Cigarette smoke extract induces placental growth factor release from human bronchial epithelial cells via ROS/MAPK(ERK-1/2)/Egr-1 axis

“…For example, one study found that PlGF levels significantly elevate in serum and BALF of COPD patients and negatively relate with forced expiratory volume in 1 sec 13. In a separate study from the same group, it was discussed that the neutrophil’s elastic protease (pig pancreas) could increase the expression of PlGF and induce lung epithelial cell apoptosis 27. However, neither study addressed whether CS could directly stimulate PlGF overproduction in human airway epithelial cells.…”

“…A conserved Egr-1 binding site is found near the PlGF promoters of mouse and human genomes 32–34. Hou et al27 reported that neutrophil elastase induced PlGF expression through promoting Egr-1 transcriptional activity. Our results demonstrate that CSE can induce Egr-1 expression, nuclear translocation and transcriptional activity in 16-HBE cells.…”

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

“…In addition, the JNK inhibitor, SP600125, partly prevented bleomycin-induced hydroxyproline and a smooth muscle actin levels in the lung tissue of rats, and thalidomide, an immunomodulatory drug able to suppress the generation of TNF-a, prevented the induction of JNK phosphorylation and hydroxyproline and a smooth muscle actin levels even more (34). Furthermore, neutrophil elastase-instilled mice showed emphysema and lung epithelial cell apoptosis, which was JNK and protein kinase C signaling dependent (35).…”