Objective To study the intervention effect of ginkgo biloba extract（GBE） on airway and vascular remodeling in rat model of chronic obstructive pulmonary disease(COPD).Methods Forty wistar rats were randomly divided into group A，B，C and D.The rat model of COPD were established by intratracheally injection of lipopolysaccharide and exposure to cigarette smoke in groups B，C and D.Groups C and D were given intraperitoneally injection with 40 mg/kg GBE respectively from day1 to day14 and day29 to day42.Forty-three days later，the rats were sacrificed for lung pathological examination.Results Group B，C and D all showed pathological changes characteristic of COPD to different extent.The average area and standard number of alveoli showed significant difference between each groups（all Plt;0.01）.The structure of bronchiole walls in group C and D show mild changes.The ratio of bronchial smooth muscle thickness to bronchial wall thickness and bronchial wall area to bronchial area of group C and D showed significant difference when compared with group A and B（all Plt;0.01）.The vascular smooth muscle cell of group C and D had mild hyperplasia and the vascular wall had slightly thickened.The ratio of vascular smooth muscle thickness to vascular wall thickness and vascular wall area to vascular area in group C and D showed significant difference when compared with group A and B（all Plt;0.01）.Conclusion GBE has inhibitory effects on airway and vascular remodeling in rats model of COPD.
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 study the local vascular remodeling, inflammatory response, and their correlations following acute spinal cord injury (SCI) with different grades, and to assess the histological changes in SCI rats.MethodsOne hundred and sixteen adult female Sprague Dawley rats were randomly divided into 4 groups (n=29). The rats in sham group were received laminectomy only. A standard MASCIS spinal cord compactor was applied with drop height of 12.5, 25.0, or 50.0 mm to establish the mild, moderate, or severe SCI model, respectively. Quantitative rat endothelial cell antigen 1 (RECA1) and CD68 positive areas and the correlations were studied by double immunofluorescent (DIF) staining at 12 hours, 24 hours, 3 days, 7 days, and 28 days following SCI. Moreover, qualitative neurofilament-H (NF-H) and glial fibrillary acidic protein (GFAP) positive glial cells were studied by DIF staining at 28 days. ELISA was used to detect the levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 in spinal cord homogenates at 12 hours, 24 hours, and 3 days, and the correlations between TNF-α, IL-1β, or IL-6 levels and microvascular density (RECA1) were accordingly studied. Moreover, the neural tissue integrity and neuron damage were assessed by HE staining at 12 hours, 24 hours, 3 days, 7 days, and 28 days, and Nissl’s staining at 28 days following SCI, respectively.ResultsDIF staining revealed that the ratio of RECA1 positive area was the highest in moderate group, higher in mild and severe groups, and the lowest in sham group with significant differences between groups (P<0.05). The ratio of CD68 positive area was the highest in severe group, higher in moderate and mild groups, and the lowest in sham group with significant differences between groups (P<0.05), except the comparisons between mild and moderate groups at 24 hours and 28 days after SCI (P>0.05). There was no significant correlation between the RECA1 and CD68 expressions in sham group at different time points (P>0.05). At 12 and 24 hours after SCI, the RECA1 and CD68 expressions in mild and moderate groups showed significant positive correlations (P<0.05), while no significant correlation was found in severe group (P>0.05). No significant correlations between the RECA1 and CD68 expressions was shown in all SCI groups at 3 days and in severe group at 7 days (P>0.05), while the negative correlations were shown in mild and moderate groups at 7 days, and in all SCI groups at 28 days (P<0.05). In mild, moderate, and severe groups, the axons became disrupted, shorter and thicker rods-like, or even merged blocks with increased injury, while the astrocytes decreased in number, unorganized and condensed in appearance. ELISA studies showed that TNF-α, IL-1β, and IL-6 levels in sham group were significantly lower than those in other 3 groups at different time points (P>0.05). The differences in TNF-α, IL-1β, and IL-6 levels between SCI groups at different time points were sinificant (P<0.05), except IL-1β levels between the mild and moderate groups at 12 hours (P>0.05). Three inflammatory factors were all significantly correlated with the microvascular density grades (P<0.05). Histological analysis indicated that the damage to spinal cord tissue structure correlated with the extent of SCI. In severe group, local hemorrhage, edema, and infiltration of inflammatory cells were found the most drastic, the grey/white matter boundary was disappeared concurrently with the formation of cavity and shortage of normal neurons.ConclusionIn the acute stage following mild or moderate SCI, progressively aggravated injury result in higher microvessel density and increased inflammation. However, at the SCI region, the relation between microvessel density and inflammation inverse with time in the different grades of SCI. Accordingly, the destruction of neural structures positively relate to the grades of SCI and severity of inflammation.
The dynamic coupling of stent degradation and vessel remodeling can influence not only the structural morphology and material property of stent and vessel, but also the development of in-stent restenosis. The research achievements of biomechanical modelling and analysis of stent degradation and vessel remodeling were reviewed; several noteworthy research perspectives were addressed, a stent-vessel coupling model was developed based on stent damage function and vessel growth function, and then concepts of matching ratio and risk factor were established so as to evaluate the treatment effect of stent intervention, which may lay the scientific foundation for the structure design, mechanical analysis and clinical application of biodegradable stent.
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.
ObjectiveTo investigate the effect of ADAM33 gene silencing in VSMCs on the proliferation and lumen formation of airway vascular endothelial cells (VECs) in a co-culture system and the possible regulatory mechanism. MethodsThe Human aortic smooth muscle cells (HASMCs) and human pulmonary microvascular endothelial cells (HPMECs) were used to construct a cell co-culture system. ADAM33 gene expression was silenced by lentivirus transfection technique, and the subjects were divided into endothelial cell blank group, co-culture group, co-culture +shRNA negative control group, and co-culture + ADAM33-SHRNA group. The expressions of sADAM33, VEGFA,VEGER2, ang-1 and ang-2 in co-culture system were detected by ELISA. The proliferation and lumen formation of HPMECs were observed by CCK-8 and Transwell experiments. The protein expression of Tie2, PI3K, Akt, and mTOR key molecules in Tie2/PI3K/Akt/mTOR signaling pathway and the phosphorylation levels of AKT and mTOR were detected by Western-blotting method. Results① Compared with the co-culture group (0.851±0.036) and the co-culture + shRNA negative control group (0.828±0.047), the OD value of the co-culture + ADAM33shRNA group (0.699±0.038) was significantly decreased (P<0.05). ② Compared with the co-culture group (159.169±15.740) and the co-culture +shRNA negative control group (157.357±21.612), the tube length of the co-culture +ADAM33shRNA group (120.812±2.791) was also significantly decreased (P<0.05). ③ After ADAM33 gene expression of HASMCs was silted in co-culture system, the expression levels of VEGFA, VEGFR2, ang-1 and ang-2 were significantly decreased (P<0.05), while the expression levels of Tie2, PI3K, P-Akt and P-mtor were decreased (P<0.05). ConclusionsSilencing the expression of the ADAM33 gene could reduce the release of sADAM33 from the membrane of the airway VSMCs, regulate the proliferation and lumen formation of airway VECs by reducing the expression of VEGF/VEGFR and inhibiting the activities of the Tie2/PI3K/Akt/mTOR signaling pathways,and then participate in airway vascular remodeling in asthma.
Aortic aneurysm and dissection are critical cardiovascular diseases that threaten human life and health seriously. No pharmacological treatment can effectively prevent disease progression. The imbalance of aortic wall cells and non-cellular components leads to structural or functional degeneration of the aorta, which is a prerequisite for disease occurrence. As the important non-cellular component, extracellular matrix (ECM) is crucial to maintain the aortic structure, function, and homeostasis. Abnormal production of elastin and collagen, destruction of cross-linking between elastic fibers and collagen fibers, and the imbalance of metalloproteinase and inhibitors leads to excessive degradation of ECM proteins, all of which have destroyed the structure and function of aorta. It will provide more ideas for disease prevention and treatment by learning ECM proteins and their metabolic mechanism. Here, we focus on the ECM proteins that have been reported to be involved in aortic aneurysm and dissection, and discuss the regulatory mechanism of metalloproteinase and inhibitors.