Zhao-Hua Zhang

Implantation of Mesenchymal Stem Cells Improves Right Ventricular Impairments Caused by Experimental Pulmonary Hypertension

Introduction:Pulmonary hypertension (PH) is a rapidly progressive and fatal disease. In recent years, despite drug treatment made significant progress, the prognosis of patients with advanced PH remains extremely poor. The authors implanted bone marrow-derived mesenchymal stem cells (BMSCs) intravenously into the PH model rats and observed the effect of MSCs on right ventricular (RV) impairments. Methods:BMSCs were isolated, cultured from bone marrow of rats and stained with the cross-linkable membrane dye in vitro. One week after, a PH model was induced by subcutaneous injection of monocrotaline, the animals were randomly divided into 4 groups (n = 20 in each group): I, control; II, MSCs implantation; III, PH and IV, PH + MSCs implantation. Two weeks after MSCs implantation, the authors observed the MSC survival and transformation by immunofluorescence microscopy. On the other hand, RV hypertrophy and the elevation of systolic pressure were detected by echocardiography. Result:Three weeks after monocrotaline injection, RV systolic pressure, mean right ventricular pressure and mean pulmonary arterial pressure were significantly elevated in group III than in group I and II (P < 0.05) but significantly lower in group IV than in group III (P < 0.05). These results showed that implantation of MSCs could improve RV impairments caused by experimental PH. Histochemical results confirmed that transplanted MSCs were still alive after 2 weeks and part of the cells could differentiate into pulmonary vascular endothelial cells. Conclusion:Intravenous implantation of MSCs could significantly reduce or even reverse the progression of MCT-induced PH, improve cardiac function and hemodynamics.

Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism.

UNLABELLED Pulmonary arterial hypertension (PAH) is characterized by functional and structural changes in the pulmonary vasculature, and despite the drug treatment that made significant progress, the prognosis of patients with advanced PH remains extremely poor. In the present study, we investigated the early effect of bone marrow mesenchymal stem cells (BMSCs) on experimental high blood flow-induced PAH model rats and discussed the mechanism. BMSCs were isolated, cultured from bone marrow of Sprague-Dawley (SD) rat. The animal model of PAH was created by surgical methods to produce a left-to-right shunt. Following the successful establishment of the PAH model, rats were randomly assigned to three groups (n=20 in each group): sham group (control), PAH group, and BMSC group (received a sublingual vein injection of 1-5 × 10(6) BMSCs). Two weeks after the administration, BMSCs significantly reduced the vascular remodeling, improved the hemodynamic data, and deceased the right ventricle weight ratio to left ventricular plus septal weight (RV/LV+S) (P<0.05). Real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry analysis results indicated that the inflammation factors such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were reduced (P<0.05); the expression of matrix metallo proteinase-9 (MMP-9) was lower (P<0.05); vascular endothelial growth factor (VEGF) was higher in BMSC group than those in PAH group (P<0.05). CONCLUSION Sublingual vein injection of BMSCs for 2 weeks, significantly improved the lung and heart injury caused by left-to-right shunt-induced PAH; decreased pulmonary vascular remodeling and inflammation; and enhanced angiogenesis.

Effect of bone marrow mesenchymal stem cells on experimental pulmonary arterial hypertension

The aim of the present study was to investigate the effect of bone marrow mesenchymal stem cell (BMSC) transp1antation on lung and heart damage in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). The animals were randomly divided into 3 groups: control, PAH and BMSC implantation groups. Structural changes in the pulmonary vascular wall, such as the pulmonary artery lumen area (VA) and vascular area (TAA) were measured by hematoxylin and eosin (H&E) staining, and the hemodynamics were detected by echocardiography. Two weeks post-operation, our results demonstrated that sublingual vein injection of BMSCs significantly attenuated the pulmonary vascular structural and hemodynamic changes caused by pulmonary arterial hypertension. The mechanism may be executed via paracrine effects.

Mesenchymal stem cells in combination with erythropoietin repair hyperoxia-induced alveoli dysplasia injury in neonatal mice via inhibition of TGF-β1 signaling.

The aim of the present study is to investigate the protection effects of bone marrow mesenchymal stem cells (MSCs) in combination with EPO against hyperoxia-induced bronchopulmonary dysplasia (BPD) injury in neonatal mice. BPD model was prepared by continuous high oxygen exposure, 1×106 bone marrow MSCs and 5000U/kg recombinant human erythropoietin (EPO) were injected respectively. Results showed that administration of MSCs, EPO especially MSCs+EPO significant attenuated hyperoxia-induced lung damage with a decrease of fibrosis, radical alveolar counts and inhibition of the occurrence of epithelial-mesenchymal transition (EMT). Furthermore, MSCs+EPO co-treatment more significantly suppressed the levels of transforming growth factor-β1(TGF-β1) than MSCs or EPO alone. Collectively, these results suggested that MSCs, EPO in particular MSCs+EPO co-treatment could promote lung repair in hyperoxia-induced alveoli dysplasia injury via inhibition of TGF-β1 signaling pathway to further suppress EMT process and may be a promising therapeutic strategy.

The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension

The aim of the present study was to investigate the effects of PS-341 on vascular remodeling in an experimental rat model of high blood flow-induced pulmonary arterial hypertension (PAH), as well as to elucidate its mechanisms of action. We established the PAH model by a surgical method that implanted a left-to-right shunt. Three days post-surgery, the animals were randomly assigned to 3 groups (n=15 in each group): sham-operated (control), shunt (model) and PS-341 (treated) groups. Eight weeks post-surgery, hemodynamic parameters were significantly improved in the PS-341 group compared with the shunt group (P<0.05). Immunohistochemical analysis indicated that the expression levels of ubiquitin and nuclear factor-κB (NF-κB) p65 were significantly higher in the shunt group compared with the sham-operated group (P<0.05). Semi-quantitative western blot analysis further confirmed that the levels of ubiquitin and NF-κB p65 were decreased, while those of IκB-α (an inhibitor of NF-κB) were significantly increased in the PS-341 group compared with the shunt group (P<0.05). In conclusion, PS-341 attenuates high blood flow-induced pulmonary artery remodeling in rats via inhibition of the NF-κB pathway.

Characterization of the expression of macrophage inflammatory protein‐1α (MIP‐1α) and C‐C chemokine receptor 5 (CCR5) after kainic acid‐induced status epilepticus (SE) in juvenile rats

X. B. Zhu, Y. B. Wang, O. Chen, D. Q. Zhang, Z. H. Zhang, A. H. Cao, S. Y. Huang and R. P. Sun (2012) Neuropathology and Applied Neurobiology38, 602–616

Baicalin attenuates monocrotaline-induced pulmonary hypertension through bone morphogenetic protein signaling pathway

Baicalin, a flavonoid compound extracted from roots of Scutellaria baicalensis Georgi (huang qin), it has been shown to effectively attenuates pulmonary hypertension (PH), however, the potential mechanism remains unexplored. In this study, we investigated the potential mechanism of baicalin on monocrotaline (MCT)-induced PH in rats. The results showed that baicalin attenuated lung damage in PH rat model through inhibiting the pulmonary arterial smooth muscle cell proliferation and induction of cells apoptosis. Furthermore, we demonstrated that baicalin inhibition the expression of nuclear factor-κB (NF-κB) p65 and bone morphogenetic protein (BMP) antagonists gremlin-1, but increased the expression of inhibitor of NF-κB (I-κBα), BMPR2, BMP-4, BMP-9 and Smad1/5/8. Additionally, baicalin suppression endothelial-to-mesenchymal transition in PH lung tissue. Collectively, we confirmed that baicalin via inhibition of NF-κB signaling to further activation of BMP signaling to have a therapeutic effect on PH and providing a promising therapeutic strategy for PH.Baicalin, a flavonoid compound extracted from roots of Scutellaria baicalensis Georgi (huang qin), it has been shown to effectively attenuates pulmonary hypertension (PH), however, the potential mechanism remains unexplored. In this study, we investigated the potential mechanism of baicalin on monocrotaline (MCT)-induced PH in rats. The results showed that baicalin attenuated lung damage in PH rat model through inhibiting the pulmonary arterial smooth muscle cell proliferation and induction of cells apoptosis. Furthermore, we demonstrated that baicalin inhibition the expression of nuclear factor-κB (NF-κB) p65 and bone morphogenetic protein (BMP) antagonists gremlin-1, but increased the expression of inhibitor of NF-κB (I-κBα), BMPR2, BMP-4, BMP-9 and Smad1/5/8. Additionally, baicalin suppression endothelial-to-mesenchymal transition in PH lung tissue. Collectively, we confirmed that baicalin via inhibition of NF-κB signaling to further activation of BMP signaling to have a therapeutic effect on PH and providing a promising therapeutic strategy for PH.

Timing of erythropoietin modified mesenchymal stromal cell transplantation for the treatment of experimental bronchopulmonary dysplasia

The aim of this study is to optimize the timing of erythropoietin gene modified mesenchymal stem cells (EPO‐MSCs) transplantation for bronchopulmonary dysplasia (BPD). Three weeks post‐operation, the results indicated that the damage of airway structure and apoptosis were significantly decreased, the proliferation was increased in three EPO‐MSCs transplantation groups as compared with BPD mice. Moreover, the inflammation cytokines were improvement in early EPO‐MSCs injection mice than in BPD mice, but there was no significant difference between late injection and BPD groups. Furthermore, the protein expression ratio of p‐p38/p38MAPK was down‐regulation in early mice but not in late transplantation mice. Our findings suggest that EPO‐MSCs maybe attenuate BPD injury in early than in late administration by inhibiting inflammation response through down‐regulation of the p38MAPK signalling pathway.

Baicalin attenuates myocardial ischemia-reperfusion injury through Akt/NF-κB pathway: LUAN et al.

Baicalin can attenuate myocardial ischemia‐reperfusion (I/R) on damage. However, the mechanisms are still not fully understood. The study aimed to investigate the antiapoptosis and anti‐inflammatory effects of baicalin on myocardial I/R‐induced injury.