目的:研究低氧性肺动脉高压大鼠对实验性红细胞增多的适应。方法:健康SD大鼠28只,体重200～250 g,随机分为4组:常氧对照组（N）、单纯低氧组（H）、低氧+低剂量人重组促红细胞生成素（rEPO） 600 u/kg（H+E1）组、低氧+高剂量rEPO 1200 u/kg（H+E2）组,每组7只大鼠。除常氧对照组外各低氧组大鼠均缺氧21 d,每日8 h。其中后两组每周腹部皮下注射不同剂量的rEPO三次。取血样测定红细胞数、全血粘度及红细胞变形指数；颈外静脉插管测定平均肺动脉压力；光镜观察反映肺动脉重构程度的形态学参数肺小动脉管壁厚度百分比、肺非肌性小动脉肌化程度。结果:①随着rEPO注射剂量的增加,红细胞、全血粘度有不同程度的增高；②全血粘度增高的同时红细胞变形指数也相应地增加；③随着rEPO剂量的增加,平均肺动脉压力逐渐增高,但是肺血管重构程度反而有所缓解。结论:实验性红细胞增多通过改变红细胞变形性和缓解肺血管重构程度来阻遏低氧性肺动脉高压的进一步发展。
ObjectiveTo investigate the effect of azithromycin on chronic obstructive pulmonary disease (COPD) vascular remodeling and its possible mechanism.MethodsEighteen male SD rats were randomly divided into normal control group (group A), model group (group B) and azithromycin intervention group (group C). In group B and group C, the COPD model was established by passive smoking and intratracheal injection of lipopolysaccharide. On the fifteenth day, group C was intragastricly administrated with azithromycin (50 mg/kg) one hour prior to smoking, while group A and group B were given equal amount of normal saline. All the rats were killed 6 weeks later. Hematoxylin-eosin staining was used to observe lung tissue pathological changes and victoria blue + Van Gieson staining was used to observe the pulmonary artery morphology changes. The serum osteopontin (OPN) was determined with ELISA. The protein expression of OPN was measured with immunohistochemistry and OPN mRNA was detected by RT-PCR.ResultsCompared with group A, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling in groups B and C was more serious, but these changes in group C were lighter than those in group B. The serum OPN content, lung tissue OPN protein and OPN mRNA expression in groups B and C were higher than those in group A, while these parameters in group C were lower than those in group B. The content of serum OPN, the expression of OPN protein and OPN mRNA in lung tissue were positively correlated with the degree of pulmonary vascular inflammation and vascular remodeling.ConclusionAzithromycin can alleviate the pulmonary vascular inflammation and pulmonary vascular remodeling in COPD rats, and its mechanism may be related to inhibiting the expression of OPN.
Pulmonary hypertension is a disease characterized by pulmonary artery pressure increased, with or without small artery pathological change, which ultimately leads to right heart failure or even death. Pulmonary hypertension seriously threatens to human health, however, the pathogenesis of pulmonary hypertension is unclear. Previous studies have found that bone morphogenetic protein (BMP) signaling system played an important role in the progress of pulmonary hypertension. In the current review, we describe the mechanism of BMP4 in the development of pulmonary hypertension.
ObjectiveTo explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients.MethodsSystemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored.ResultsThe hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes.ConclusionSystemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.
Pulmonary hypertension is a kind of progressive pulmonary vascular diseases in which there is excessive vasoconstriction and abnormal pulmonary vascular remodeling, and then a gradual increase in pulmonary arterial pressure, and it eventually leads to right ventricular failure and even death. The pathogenesis of pulmonary hypertension is still uncertain, but some studies suggest that Hippo pathway or some components of the Hippo pathway may be involved in the progress of pulmonary hypertension. In this review, we describe the mechanism of the Hippo pathway or some components of the Hippo pathway in the progress of pulmonary hypertension.