Increased expression of placenta growth factor in chronic obstructive pulmonary disease

• Main Authors: Shih-Lung Cheng, 鄭世隆
• Other Authors: 楊泮池
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/26911163931554035264

博士 === 臺灣大學 === 臨床醫學研究所 === 98 === Vascular endothelial growth factor (VEGF) and its receptor may play an important role in the pathogenesis of emphysema. But the effect of another angiogenic factor, placenta growth factor (PlGF), to chronic obstructive pulmonary disease (COPD) is unknown. The purpose of this study was to elucidate the role of VEGF and PlGF in patients with chronic obstructive pulmonary disease (COPD). At first, we measure the levels of VEGF and PlGF in sera and BAL fluids of COPD patients. We then studied the regulation of PlGF and VEGF in cultured bronchial epithelial cells after exposure to various pro-inflammatory cytokines, as well as the effects of 14 days exposure to heightened PlGF on bronchial epithelial cells. Thirdly, the animal model for emphysema was established and aimed to test this hypothesis by determining whether emphysema could be prevented in mice whose PlGF had been knocked out. It further aimed to elucidate the role of PlGF in the pathogenesis of emphysema. We measured the levels of VEGF and PlGF in serum from patients with COPD (n=184), smokers (n=212), nonsmokers (n=159), and in bronchoalveolar lavage (BAL) fluid from another group (COPD n=20, controls n=18). In vitro cell culture experiments were performed to investigate the effect of PlGF on VEGF. Besides, pulmonary emphysema was induced in PlGF knock-out (KO) and wild type (WT) mice by intra-tracheal instillation of porcine pancreatic elastase (PPE). A group of KO mice was then treated with exogenous PlGF and WT mice with neutralizing anti-VEGFR1 antibody. Tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), and VEGF were quantified. Apoptosis measurement and immuno-histochemical staining for VEGF R1 and R2 were performed in emphysematous lung tissues. The serum levels of PlGF were significantly higher in COPD than in controls (27.1 (SE, 7.4) pg/ml vs. 12.3 (SE, 5.1) pg/ml in smokers and 10.8 (SE, 6.3) pg/ml in nonsmokers, p=0.005). The levels of PlGF in BAL fluids were also significantly higher in COPD than in controls (45.7 (SE, 12.3) pg/ml vs. 23.9 (SE, 7.6) pg/ml, p=0.005), associated with an increase of all measured cytokines, like tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8). In COPD patients, the levels of PlGF correlated inversely with forced expiratory volume in one second (FEV1) (in serum, r=-0.59, p=0.002; and in BAL fluids, r=-0.51, p=0.001). While the levels of VEGF in serum were the same between COPD and controls, the levels in BAL fluids were significantly lower in COPD than in controls (127.5 (SE, 30.1) pg/ml vs. 237.8 (SE, 36.1) pg/ml, p=0.002). In cultured bronchial epithelial cells, proinflammatory cytokines induced an increase in the protein expression of both PlGF and VEGF. Continuous concomitant treatment with PlGF, TNF-α and IL-8 stimulation reduced VEGF expression and induced cell death. This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11). After 4 weeks of PPE instillation, lung airspaces enlarged more significantly in WT than in KO mice. The levels of TNF-α and MMP-9, but not VEGF, increased in the lungs of WT compared with those of KO mice. There was also increased in apoptosis of alveolar septal cells in WT mice. Instillation of exogenous PlGF in KO mice restored the emphysematous changes. The expression of both VEGF R1 and R2 decreased in the emphysematous lungs. In this study including clinical data, in vitro cell culture results, and animal model, implying that PlGF contributes to the pathogenesis of emphysema.