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Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor
- Source :
- Cell Death & Disease
- Publication Year :
- 2013
- Publisher :
- Nature Publishing Group, 2013.
-
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.
- Subjects :
- Cancer Research
MAP Kinase Signaling System
p38 mitogen-activated protein kinases
Immunology
Sus scrofa
Inflammation
Biology
Pregnancy Proteins
p38 Mitogen-Activated Protein Kinases
Cellular and Molecular Neuroscience
Mice
Downregulation and upregulation
medicine
Animals
Humans
chronic pulmonary obstructive disease
Pancreatic elastase
Lung
Pancreas
Emphysema
Pancreatic Elastase
Kinase
Elastase
apoptosis
JNK Mitogen-Activated Protein Kinases
placenta growth factor
Epithelial Cells
Cell Biology
respiratory tract diseases
Enzyme Activation
Mice, Inbred C57BL
medicine.anatomical_structure
Apoptosis
Cancer research
Original Article
medicine.symptom
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 4
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....87b7c2d8bd7bde0125a6d9f849bd985c