The Role Of Bone Morphogenetic Protein-2 In Pulmonary Arterial Hypertension Secondary To Chronic Obstructive Pulmonary Disease

Objective: To investigate the apoptosis versus proliferation activities of pulmonary artery smooth muscle cells(PASMCs) and the change of bone morphogenetic protein-2 in pulmonary arterial hypertension(PAH) secondary to chronic obstructive pulmonary disease(COPD) and pulmonary vascular structural remodeling (PVSR).Method:Lung specimens from patients without COPD or PAH(non-COPD group,n=15),COPD patients without PAH(COPD non-PAH group,n=15)and patients with PAH secondary to COPD(COPD and PAH group,n=15)were investigated.The remodeling of pulmonary arteries were observed under microscope and the changes of morphology were analysed by computer-based image analysis system.The proliferation of PASMCs was detected by proliferating cell nuclear antigen (PCNA) with immunohis to chemical technique ,and TUNEL [Terminal deoxynu-cleotidyl transferase (TdT)- mediated deoxyuridine triphosphat(dUTP)-digoxigenin nick end labeling] techniques were used for the detection of the apoptosis of PASMCs ; the distribution of BMP-2 in pulmonary tissues was observed by using streptavidin peroxidase methods(SP), and the morphologic changes of pulmonary arteries and the integrated optical density(IA) of BMP-2 were determined by image analysis.Results: In non-COPD group, the walls of the pulmonary arterioles were thin and the lumens were large. In COPD non-PAH group, the walls were thicker and the lumens were narrower than that of the non-COPD group .In COPD and PAH group, the walls were the thickest and the lumens were the narrowest of the three groups. Both the ratio of the thickness of the wall to the external diameter of the pulmonary arterioles (WT%) and the ratio of the area of the wall to that of the pulmonary arterioles (WA%)were calculated by the computer-based image analysis systym..In the COPD non-PAH group and the COPD and PAH group,the WT% and WA% [(20.45±4.12, 35.35±5.32)%, (28.47±4.67, 50.33±6.47)%] were higher than those of the non-COPD group (15.72±3.02, 24.73±3.32)% (P <0.01) , and the WT% and WA% of the COPD and PAH group were higher than those of the COPD non-PAH group(P<0.01). Both proliferative and apoptotic PASMCs were found in the patients of the three groups. The proliferation indexes (PI) of the COPD non-PAH group and the COPD and PAH group were (18.65±4.82 ) %and (38.37±6.61) % respectively ,both were significantly higher than that of non-COPD group (8.37±2.09)% (P<0.01). while the apoptosis indexes(AI) [(4.49±1.25) %,(3.05±1.34) %] were lower than that of non-COPD group (6.90±1.89) % (P<0.01). The proliferation index (PI) of the COPD non-PAH group was lower than that of the COPD and PAH group while the apoptosis index (Al)was higher than that of the COPD and PAH group (P<0.05). The oxygen tention in arterial blood(PaO₂) of the COPD non-PAH group and the COPD and PAH group were (78.60±5.63 )mmHg and (67.93±4.85 )mmHg respectively ,both were significantly lower than that of non-COPD group(85.93±4.76)mmHg (P<0.01=,the PaO₂ of COPD and PAH group was lower than that of the COPD non-PAH group (P<0.01).The PaO₂ of COPD non-PAH group and the COPD and PAH group was negatively related with the PI(r=-0.519, P=0.003) and with the IA of BMP-2(r=-0.517, P=0.003)while positively related to the AI of the PASMCs (r=0.441, P= 0.015);The distribution of BMP-2 was mainly in the pulmonary arterial walls. In COPD non-PAH group and the COPD and PAH group,the IA of BMP-2 significantly increased(9759±2468, 14063±5261), were higher than those of the non-COPD group(6018±1047,P<0.01),the IA of BMP-2 of the COPD and PAH were higher than those of the COPD non-PAH group (P<0.01).The IA of BMP-2 of COPD non-PAH group and the COPD and PAH showed a positive linear relationship to WT%,WA% and PI respecttively(WT%:r=0.701 P<0.01;WA%:r=0.748 P<0.01;PI: r=0.537, P <0.01); and showed a negative linear relationship to AI( r=-0.428, P=0.019).Conclusion: The imbalance of the increased proliferation and decreased apoptosis of PASMCs may contribute to the pulmonary vascular structural remodeling and pulmonary aterial hypertension in patients of COPD, Chronic hypoxia induced an increased expression of BMP-2. It may play an important role in the pulmonary vascular tructural remodeling. Hypoxia induced an increased expression of BMP-2 and it is one of the main causes of increased proliferation and decreased apoptosis of the PASMCs.