LSC Abstract – The specific upregulation of placenta growth factor (PlGF) by matrix metalloproteinase (MMP)-12 in the pathogenesis of COPD

Abstract

Due to the increasing population of smoking and aging, chronic pulmonary obstructive disease (COPD) is predicted to be the fourth leading cause of death worldwide in 2030. Therefore, it is urgent to development novel efficient therapeutic strategy to promote the regular medical care for COPD. Cigarette smoke-mediated protease-antiprotease imbalance is a major pathogenic factor for COPD and is resulted from large pulmonary infiltration of neutrophil and macrophage to chronic inflammatory region which release excesses neutrophil elastase (NE) and matrix metalloproteinase (MMP) respectively. Our previous study indicated placenta growth factor (PlGF) and PlGF-triggered downstream signaling pathways mediate NE-induced lung epithelial cell apoptosis, a potential pathogenic mechanism for emphysema and COPD. However, the relationship between MMP and PlGF remains elusive. The upregulation and hypersecretion of MMP-2, MMP-9 and MMP-12 have been reported in COPD. In this study, we discover only MMP-12 (300mU/ml) upregulates PlGF expression in BEAS-2B cells. Therefore, we hypothesize that there may be a conserved mechanisms involved in elastase (NE and MMP-12)-induced PlGF expression rather than collagenase (MMP-2 and MMP-9). In addition, the results of TUNEL assay and H & E stain proved only MMP-12 (intratracheal instillation with 400mU/ml MMP-12 weekly for one month) triggers pulmonary epithelial cell apoptosis and pulmonary emphysema in B6 mice. Given these findings, we suggest that both human COPD-associated elastases, NE and MMP-12, share a conserved mechanism that through PlGF upregulation and PlGF-mediate pathogenic processes, lead to emphysema and COPD.