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

Departments of Medical Genetics, Pediatrics, Pathology, Medical Research Administration, Obstetrics and Gynecology, and Internal Medicine, National Taiwan University Hospital; Department of Physiology, College of Medicine, National Taiwan University; and Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China

Correspondence and requests for reprints should be addressed to Fon-Jou Hsieh, M.D., Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. E-mail: fjhsieh{at}ha.mc.ntu.edu.tw

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.

Key Words: placenta growth factor • pulmonary emphysema • transgenic mice

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