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Elastase induces lung epithelial cell autophagy through placental growth factor:
a new insight of emphysema pathogenesis
#MMPMID24988221
Hou HH
; Cheng SL
; Chung KP
; Kuo MY
; Yeh CC
; Chang BE
; Lu HH
; Wang HC
; Yu CJ
Autophagy
2014[Sep]; 10
(9
): 1509-21
PMID24988221
show ga
Chronic obstructive pulmonary disease (COPD) is a devastating disease, which is
associated with increasing mortality and morbidity. Therefore, there is a need to
clearly define the COPD pathogenic mechanism and to explore effective therapies.
Previous studies indicated that cigarette smoke (CS) induces autophagy and
apoptosis in lung epithelial (LE) cells. Excessive ELANE/HNE (elastase,
neutrophil elastase), a factor involved in protease-antiprotease imbalance and
the pathogenesis of COPD, causes LE cell apoptosis and upregulates the expression
of several stimulus-responsive genes. However, whether or not elastase induces
autophagy in LE cell remains unknown. The level of PGF (placental growth factor)
is higher in COPD patients than non-COPD controls. We hypothesize that elastase
induces PGF expression and causes autophagy in LE cells. In this study, we
demonstrated that porcine pancreatic elastase (PPE) induced PGF expression and
secretion in LE cells in vitro and in vivo. The activation of MAPK8/JNK1
(mitogen-activated protein kinase 8) and MAPK14/p38alpha MAPK signaling pathways
was involved in the PGF mediated regulation of the TSC (tuberous sclerosis
complex) pathway and autophagy in LE cells. Notably, PGF-induced MAPK8 and MAPK14
signaling pathways mediated the inactivation of MTOR (mechanistic target of
rapamycin), the upregulation of MAP1LC3B/LC3B (microtubule-associated protein 1
light chain 3 ?) and the increase of autophagosome formation in mice.
Furthermore, the PPE-induced autophagy promotes further apoptosis in vitro and in
vivo. In summary, elastase-induced autophagy promotes LE cell apoptosis and
pulmonary emphysema through the upregulation of PGF. PGF and its downstream MAPK8
and MAPK14 signaling pathways are potential therapeutic targets for the treatment
of emphysema and COPD.
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