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.