Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

H-H Hou,F-Z Yang,S-L Cheng,C-J Yu,H-T Liu,H-C Wang

doi:10.1038/cddis.2013.329

Abstract

Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease–antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.

Highlights

Emphysema is a major component of COPD and is characterized by destruction and enlargement of the alveolar region through chronic inflammation, oxidative stress and protease–antiprotease imbalance.[2,3] the factors and pathogenic mechanisms that cause COPD are not fully understood.[4]
The results of reverse transcriptional (RT)-PCR and western blot demonstrated that 60 mU/ml porcine pancreatic elastase (PPE) upregulated the expressions of placenta growth factor (PlGF) mRNA and protein in the MLE-15 cells (Figures 1c and d)
The data of chromatin immunoprecipitation assay showed that the exposure to 60 mU/ml PPE for 1 h would promote the association of early growth response-1 (Egr-1) protein and PlGF promoter region (Figure 1f)

Summary

Introduction

Emphysema is a major component of COPD and is characterized by destruction and enlargement of the alveolar region through chronic inflammation, oxidative stress and protease–antiprotease imbalance.[2,3] the factors and pathogenic mechanisms that cause COPD are not fully understood.[4] Apoptosis of lung epithelial (LE) cells is one of the potential factors involved in the pathogenesis of COPD.[5] Tsao et al.[6] demonstrated that exogenous placenta growth factor (PlGF) induced LE cell apoptosis and inhibited cellular proliferation, and that the transgenic mice with over-expressed PlGF developed emphysema phenotype, suggesting that PlGF has an important role in the pathogenesis of emphysema. Cigarette smoke, a major factor related to COPD, has been found to increase PlGF expression in rat lungs.[11] ablation of PlGF has been found to protect mice from porcine pancreatic elastase (PPE)-induced emphysema.[12] the detailed mechanisms underlining PlGF-induced LE cell apoptosis and the pathogenesis of emphysema remain to be elucidated.

Methods

Results

Conclusion