Prevention of elastase-induced emphysema in placenta growth factor knock-out mice

Cheng, Shih Lung; Wang, Hao-Chien; Yu, Chong‐Jen; Tsao, Po‐Nien; Carmeliet, Peter; Cheng, Shi

doi:10.1186/1465-9921-10-115

Cited by 28 publications

(25 citation statements)

References 27 publications

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“…Enforced overexpression of PlGF in lungs of mice causes emphysema due to type II pneumocyte death (Tsao et al 2004), but PlGF deficiency protects mice against elastase-induced pulmonary emphysema (Cheng et al 2009). These phenotypes suggest a role of PlGF in the inflammatory process during emphysema, even though the precise role and mechanism of PlGF in pulmonary homeostasis remain to be unraveled.…”

Section: Pulmonary Emphysemamentioning

confidence: 99%

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Dewerchin¹,

Carmeliet²

2012

Cold Spring Harbor Perspectives in Medicine

196

176

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Section: Pulmonary Emphysemamentioning

confidence: 99%

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Dewerchin¹,

Carmeliet²

2012

Cold Spring Harbor Perspectives in Medicine

196

176

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“…8 Many tissues and organs, including the villous trophoblast and heart, express PlGF, and endothelial cells express PlGF during vascular development. [9][10][11][12][13] Moreover, the placental trophoblast is the main source of PlGF during pregnancy, and its expression is significantly upregulated at an early gestational age after implantation. 9 PlGF knockout mice do not have defects in vascular development and show normal embryogenesis.…”

mentioning

confidence: 99%

Gestational Loss and Growth Restriction by Angiogenic Defects in Placental Growth Factor Transgenic Mice

Kang

Park

Kim

et al. 2014

ATVB

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Objective-Angiogenesis is an important biological process during development, reproduction, and in immune responses.Placental growth factor (PlGF) is a member of vascular endothelial growth factor that is critical for angiogenesis and vasculogenesis. We generated transgenic mice overexpressing PlGF in specifically T cells using the human CD2-promoter to investigate the effects of PlGF overexpression. Approach and Results-Transgenic mice were difficult to obtain owing to high lethality; for this reason, we investigated why gestational loss occurred in these transgenic mice. Here, we report that placenta detachment and inhibition of angiogenesis occurred in PlGF transgenic mice during the gestational period. Moreover, even when transgenic mice were born, their growth was restricted. Conclusions-Conclusively, PlGF overexpression prevents angiogenesis by inhibiting Braf, extracellular signal-regulated kinase activation, and downregulation of HIF-1α in the mouse placenta. Furthermore, it affected regulatory T cells, which are important for maintenance of pregnancy. (Arterioscler Thromb Vasc Biol. 2014;34:2276-2282.)

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“…We also demonstrated that, compared with WT mice, Pgf knockout mice were shown to have lower levels of emphysema after the PPE administration challenge, indicating that PGF is involved in PPE-induced emphysema. 40 In this study, we demonstrated that elastase can cause LE cell autophagy through upregulation of PGF and PGF-activated MAPK8 and MAPK14 signaling pathways. In addition to COPD, the upregulation of PGF has been associated with multiple human diseases in adults.…”

Section: Downloaded By [University Of Saskatchewan Library] At 15:39 mentioning

confidence: 64%

Elastase induces lung epithelial cell autophagy through placental growth factor

et al. 2014

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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 β) 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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Prevention of elastase-induced emphysema in placenta growth factor knock-out mice

Cited by 28 publications

References 27 publications

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Gestational Loss and Growth Restriction by Angiogenic Defects in Placental Growth Factor Transgenic Mice

Elastase induces lung epithelial cell autophagy through placental growth factor

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