Overexpression of Placenta Growth Factor Contributes to the Pathogenesis of Pulmonary Emphysema

Abstract

To examine the role of placenta growth factor (PlGF) in the pathogenesis of pulmonary emphysema, we generated PlGF-transgenic (TG) mice using a phosphoglycerate kinase promoter. This resulted in constitutive overexpression of PlGF. In these TG mice, pulmonary emphysema, with enlarged air spaces and enhanced pulmonary compliance, first appeared at 6 months of age and became prominent at 12 months. Increased alveolar septal cell apoptosis was noted in their lungs. Fluorescence-activated cell sorter analysis suggests that these apoptotic septal cells are type II pneumocytes. At the same time, the messenger RNA of vascular endothelial growth factor and platelet-endothelial cell adhesion molecule-1, an endothelial cell marker, were downregulated indicating a reduced number of endothelial cells and its survival factor VEGF. In vitro, exogenous PlGF can inhibit the proliferation and promote the cell death of mouse type II pneumocytes. In normal newborn mice, abundant expression of PlGF messenger RNA was detected in the lungs during saccular division but was rapidly downregulated after alveolarization was complete. Thus, a persistently elevated PlGF was detrimental to the developed lung and causes the emphysematous change seen in our TG mice. Our study suggests that PlGF plays an important role in the pathogenesis of pulmonary emphysema via its action on type II pneumocytes.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…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.…”

Pathogenesis of Emphysema: From the Bench to the Bedside

“…Thus, failure of one cell type may result in damage to the other cell types and failure of the overall maintenance program. Tsao and colleagues, in a mouse model of lung over expression of placental-like growth factor, reported pulmonary emphysema starting at 6 months of age, which became prominent at 12 months of age (24). The mice showed increased apoptosis of type II pneumocytes and reduced mRNA of vascular endothelial growth factor and platelet-endothelial cell adhesion molecule-1, indicating a reduced number of endothelial cells.…”

“…The mice showed increased apoptosis of type II pneumocytes and reduced mRNA of vascular endothelial growth factor and platelet-endothelial cell adhesion molecule-1, indicating a reduced number of endothelial cells. The authors speculated that the apoptosis of type II pneumocytes may have resulted in a reduction of endothelial cells (24).…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Augmented apoptosis (39,44,46) and attenuated proliferation (56,57) of alveolar cells were shown to be critical for the maintenance of normal alveolar structure in other animal models of emphysema. Evidence suggests that high levels of Nrp1 may attenuate apoptosis (58).…”