Shanghai JianGong Hospital

Shanghai, China

Shanghai JianGong Hospital

Shanghai, China

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Fang Y.,Shanghai JiaoTong University | Gao F.,Shanghai Jiangong Hospital | Hao J.,Shanghai JiaoTong University | Liu Z.,Shanghai JiaoTong University
American Journal of Translational Research | Year: 2017

In this study, we aimed to identify potential microRNA (miRNA) regulators of angiotensin-converting enzyme 2 (ACE2) and to explore their roles in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The expression of predicted miRNA regulators of ACE2 was examined in LPS-exposed pulmonary microvascular endothelial cells (PMVECs). Gain- and loss-of-function studies were performed to determine the functions of candidate miRNAs in LPS-induced PMVEC apoptosis and inflammatory response. The roles of the miRNAs in LPS-induced lung inflammation and permeability were investigated in a mouse model. Notably, LPS (1 μg/mL) significantly induced the expression of miR-1246 in PMVECs. ACE2 was validated as a target gene of miR-1246. Silencing of miR-1246 prevented LPS-induced inhibition of ACE2, which was accompanied by reduced apoptosis and production of IL-1β and TNF-α. In contrast, ectopic expression of miR-1246 triggered apoptosis in PMVECs and promoted IL-1β and TNF-α release. MiR-1246-mediated apoptosis of PMVECs was impaired by overexpression of ACE2. Depletion of miR-1246 attenuated lung inflammation, neutrophil infiltration, and vascular permeability and restored pulmonary expression of ACE2 in LPS-exposed mice. Taken together, miR-1246 meditates LPS-induced pulmonary endothelial cell apoptosis in vitro and ALI in mouse models, which are, at least partially, ascribed to repression of ACE2. © 2017, E-Century Publishing Corporation. All rights reserved.


Bao H.,Fudan University | Gao F.,Shanghai JianGong Hospital | Xie G.,Shanghai JiaoTong University | Liu Z.,Shanghai JiaoTong University
Cellular Physiology and Biochemistry | Year: 2015

Background/Aims: Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI). The effects of ACE2 in ALI have been shown to not only result from its antagonizing hydrolyzing angiotensin II (AngII), which is responsible for reduction in the vascular tension and pulmonary accumulation of inflammatory cells, but also result from a role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells (PECs). Nevertheless, the underlying mechanisms of the role of ACE2 on PEC apoptosis are not completely understood. Methods: Here, we used a bleomycin-induced mouse model for ALI that has been published in our previous studies. We analyzed the mRNA and protein levels of an anti-apoptotic protein Bcl-2 in the ALI-mice that have been treated w/o ACE2. We analyzed miR-4262 levels in the mouse lung in these mice. Bcl-2-targeting miRNAs were predicted using bioinformatics algorithms and a luciferase reporter assay was applied to examine the effects of miR-4262 on the Bcl-2 protein translation upon their binding to 3'-UTR of Bcl-2 mRNA. Adeno-associated viruses carrying either miR-4262 mimics or antisense were injected into ALI-mice without ACE2, and their effects on the apoptosis in mouse lung cells were analyzed by Western blot. Results: ACE2 inhibited the ALI-induced apoptosis of pulmonary cells in vivo partially through upregulation of Bcl-2 protein, but not Bcl-2 mRNA. ACE2 appeared to significantly suppress the upregulation of miR-4262 in mouse lung after ALI. MiR-4262 was found to target 3'-UTR of Bcl-2 mRNA to inhibit its protein translation in PECs. In vivo administration of antisense of miR-4262 decreased apoptosis of pulmonary cells and severity of the ALI in mice. Conclusion: ACE2-induced suppression of miR-4262 partially contribute to the inhibition of the PEC apoptosis after ALI through Bcl-2. MiR-4262 may be a novel promising treatment target for ALI and ARDS. © 2015 S. Karger AG, Basel.


Gao F.,Shanghai JianGong Hospital | Li Q.,Jiangsu University | Hou L.,Shanghai JiaoTong University | Li Z.,Fudan University | And 2 more authors.
Experimental Lung Research | Year: 2014

Background: Acute lung injury (ALI) is a high incidence disease with no effective therapeutic method (mortality rate > 40%). The aim of this study was to find a new and effective therapeutic method for ALI. Methods: After the isolation of human umbilical cord mesenchymal stem cells (HUMSCs) from cesarean fetus, we transfected the HUMSCs with Lenti-ACE2 (angiotensin-converting enzyme 2) viral particles. Then we evaluated the therapeutic effect of HUMSCs harboring ACE2 on ALI, which induced by bleomycin (BLM) in rat model. Results: Our results showed that HUMSCs harboring ACE2 could attenuate ALI degree through reducing pulmonary inflammatory infiltration and degree of vascular permeability, repressing the mRNA level of pro-inflammatory cytokines, activating the mRNA level of anti-inflammatory cytokines and ACE2. Besides, results also demonstrated that HUMSCs harboring ACE2 gene had higher therapeutic effects to ALI than the single factor of HUMSCs or ACE2. Conclusions: This research provided clues for the development of effective therapeutic methods to ALI using stem cell transplantation and gene therapy. © 2014 Informa Healthcare USA, Inc.


Liu Z.,Shanghai JiaoTong University | Gao F.,Shanghai JianGong Hospital | Hou L.,Shanghai JiaoTong University | Qian Y.,Shanghai JiaoTong University | Tian R.,Shanghai JiaoTong University
Lung | Year: 2013

Purpose: Acute lung injury (ALI) is characterized by impairment in gas exchange and/or lung mechanics that leads to hypoxemia with the presence of diffuse pulmonary infiltrate. Assessments of lung injury play important roles in the development of rational medical countermeasures. The purpose of this study is to investigate the molecular mechanisms of phosgene-induced lung injury. Methods: We downloaded the gene expression profile of lung tissue from mice exposed to air or phosgene from gene expression omnibus database and identified differentially expressed genes (DEGs) in ALI. Furthermore, we constructed a protein-protein interaction (PPI) network and identified network clusters. Results: In total, 582 DEGs were found and 4 network clusters were identified in the constructed PPI network. Gene set enrichment analysis found that DEGs were mainly involved in mitochondrion organization and biogenesis, mRNA metabolic process, negative regulation of transferase activity or catalytic activity, and coenzyme metabolic process. Pathways of spliceosome, glutathione metabolism, and cell cycle were dysregulated in phosgene-induced ALI. Besides, we identified four genes, including F3, Meis1, Pvf, and Cdc6 in network clusters, which may be used as biomarkers of phosgene-induced ALI. Conclusions: Our results revealed biological processes and pathways involved in phosgene-induced ALI and may expand understandings of phosgene-induced ALI. However, further experiments are needed to confirm our findings. © 2013 Springer Science+Business Media New York.


Ji Y.,Shanghai JiaoTong University | Gao F.,Shanghai JianGong Hospital | Sun B.,Shanghai JiaoTong University | Hao J.,Shanghai JiaoTong University | Liu Z.,Shanghai JiaoTong University
Cellular Physiology and Biochemistry | Year: 2015

Background/Aims: Angiotensin converting enzyme 2 (ACE2) has an established role in suppressing the severity of acute lung injury (ALI), especially when it was applied together with transplantation of human umbilical cord mesenchymal stem cells (uMSCs). Although the effects of ACE2 in ALI are believed to mainly result from its role in hydrolyzing angiotensin II (AngII), which subsequently reduces the vascular tension and subsequent pulmonary accumulation of inflammatory cells, we and others have recently reported a possible role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells. However, the underlying mechanisms remain undetermined. Methods: Here, we analyzed the alteration in lung injury severity in ALI after ACE2, by histology and inflammatory cytokine levels. We analyzed apoptosis-associated proteins in lung after ALI, as well as in cultured endothelial cells treated with nitric oxide (NO). We overexpressed SMAD7 to inhibit SMAD2 signaling in cultured endothelial cells and examined its effects on NO-induced cell apoptosis. Results: ACE2 alleviated severity of lung injury after ALI. ACE2 significantly decreased the ALI-induced apoptosis of pulmonary cells in vivo, and ACE2 protected endothelial cells against NO-induced apoptosis in vitro. NO induced phosphorylation of a key factor of transforming growth factor β (TGF β) receptor signaling, SMAD2, which could be dose-dependently inhibited by ACE2. Inhibition of SMAD2 phosphorylation through expression of its inhibitor SMAD7 significantly inhibited NO-induced cell apoptosis, without need for ACE2. Conclusion: Our data suggest that ACE2-mediated AngII degradation may inhibit AngII-mediated SMAD2-phophorylation, possibly through a TGFβ-independent manner, which subsequently suppresses the ALI-induced cell death. Our results thus reveal a novel molecular pathway that controls the pathogenesis of ALI. © 2015 S. Karger AG, Basel.


Min F.,Shanghai JiaoTong University | Gao F.,Shanghai Jiangong Hospital | Li Q.,Jiangsu University | Liu Z.,Shanghai JiaoTong University
Molecular Medicine Reports | Year: 2015

The aim of the present study was to evaluate the therapeutic effects of human umbilical cord mesenchymal stem cells (uMSCs) in the presence of angiotensin-converting enzyme 2 gene (ACE2; ACE2-uMSCs) on bleomycin (BLM)-induced lung injury and pulmonary fibrosis in mice. A total of 100 male C57BL/6 mice were divided at random into five groups (n=20) as follows: Control group, BLM group, ACE2 group, uMSC group and ACE2-uMSC group. At 7, 14 and 28 days post-treatment, the following parameters were evaluated in lung tissue: Oxidation indexes [malondialedehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and oxidized glutathione (GSSG)]; fibrosis factors [tumor necrosis factor (TNF)-β, interferon (IFN)-γ and transforming growth factor (TGF)-β]; inflammatory cytokines [Interleukin (IL)-1, IL-2, IL-6 and IL-10]; ACE2 gene expression; hydroxyproline and collagen type 1 messenger RNA (mRNA) concentration; as well as matrix metalloproteinase (MMPs; 2 and 9) and tissue inhibitor of metalloproteinase (TIMP)1-4 expression. ACE2-uMSC injection following bleomycin pretreatment significantly alleviated lung injury in mice. In addition, treatment with ACE2-uMSCs demonstrated a stronger therapeutic effect than ACE2- or uMSC treatment alone, indicated by decreased expression of MDA, GSSG, TNF-α, IFN-γ, TGF-β, IL-1, IL-2, IL-6, collagen type 1 mRNA, MMPs and TIMPs as well as hydroxyproline concentration, and upregulation of SOD, GSH and ACE2 and IL-10. In conclusion, the results of the present study demonstrated that ACE2 and uMSCs had a synergistic therapeutic effect on bleomycin-induced acute lung injury.


Zhang X.,Shanghai JiaoTong University | Gao F.,Shanghai Jiangong Hospital | Yan Y.,Shanghai JiaoTong University | Ruan Z.,Shanghai JiaoTong University | Liu Z.,Shanghai JiaoTong University
Cell Biochemistry and Function | Year: 2015

Acute lung ischemia-reperfusion injury (ALIRI) is a serious disease that seriously affects human's life. In this study, we aimed to explore a more effective treatment method by combining human umbilical cord mesenchymal stem cells (HUMSCs) and angiotensin-converting enzyme 2 (ACE2) for ALIRI. Fifty rats were firstly divided into five groups, namely sham surgery group (sham) and four model groups (model, ACE2, HUMSCs and HUMSCs+ACE2) that were reperfused with 0.1ml physiological saline (PS), 0.1ml PS containing 1×106 lentiviral-ACE2/HUMSCs/ACE2+UMSCs, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and western blot assays were then conducted to detect the messenger RNA (mRNA) and protein levels of inflammatory cytokines [intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), tumour necrosis factor α (TNF-α), nuclear factor κB (NF-κB), platelet-derived growth factor (PDGF) and angiotensin II (Ang II)], antioxidant proteins [NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1)], DNA damage and apoptotic indicators [BCL2-associated X (Bax), cleaved caspase-3 (C-Csp 3), cleaved-poly(ADP-ribose) polymerase (C-PARP), Y-H2AX], anti-apoptotic indicator (Bcl-2) and smooth muscle cell proliferation indicator [connexin 43 (Cx43)]. According to the qRT-PCR and western results, the mRNA and protein expression levels of ICAM-1, VCAM-1, TNF-α, NF-κB, PDGF, Bax, C-Csp 3, C-PARP and Y-H2AX were significantly higher in model group than those in sham group and they were significantly reduced by HUMSCs or ACE2 treatment (P<0.05). On the contrary, Bcl-2 showed an opposite expression trend with the previous proteins. The mRNA and protein levels of NQO1 and HO-1 were sequentially increased in sham, model, ACE2, HUMSCs and HUMSCs+ACE2 groups. Besides, HUMSCs combined with ACE2 exhibited a better inhibition effect on ALIRI than HUMSCs or ACE2 alone (P<0.05). In summary, HUMSCs combined with ACE2 was demonstrated to have the best therapeutic effect on ALIRI through anti-inflammation, oxidative stress and anti-apoptotic processes. © 2015 John Wiley & Sons, Ltd.


PubMed | Shanghai Putuo District Center Hospital, Shanghai Jiangong Hospital, Tongji University and People's Care
Type: Journal Article | Journal: Journal of physiotherapy | Year: 2014

Does the use of an oscillating positive expiratory pressure (PEP) device reduce postoperative pulmonary complications in thoracic and upper abdominal surgical patients?A multi-centre, parallel-group, randomised controlled trial with intention-to-treat analysis, blinding of some outcomes, and concealed allocation.A total of 203 adults after thoracic or upper abdominal surgery with general anaesthesia.Participants in the experimental group used an oscillating PEP device, thrice daily for 5 postoperative days. Both the experimental and control groups received standard medical postoperative management and early mobilisation.Fever, days of antibiotic therapy, length of hospital stay, white blood cell count, and possible adverse events were recorded for 28 days or until hospital discharge.The 99 participants in the experimental group and 104 in the control group were well matched at baseline and there was no loss to follow-up. Fever affected a significantly lower percentage of the experimental group (22%) than the control group (42%), with a RR of 0.56 (95% CI 0.36 to 0.87, NNT 6). Similarly, length of hospital stay was significantly shorter in the experimental group, at 10.7 days (SD 8.1), than in the control group, at 13.3 days (SD 11.1); the mean difference was 2.6 days (95% CI 0.4 to 4.8). The groups did not differ significantly in the need for antibiotic therapy, white blood cell count or total expense of treatment.In adults undergoing thoracic and upper abdominal surgery, postoperative use of an oscillating PEP device resulted in fewer cases of fever and shorter hospital stay. However, antibiotic therapy and total hospital expenses were not significantly reduced by this intervention.NCT00816881.


PubMed | Tongji University and Shanghai Jiangong Hospital
Type: Journal Article | Journal: World journal of emergency medicine | Year: 2015

Noninvasive monitoring of intra-abdominal pressure (IAP) by measuring abdominal wall tension (AWT) was effective and feasible in previous postmortem and animal studies. This study aimed to investigate the feasibility of the AWT method for noninvasively monitoring IAP in the intensive care unit (ICU).In this prospective study, we observed patients with detained urethral catheters in the ICU of Shanghai Tenth Peoples Hospital between April 2011 and March 2013. The correlation between AWT and urinary bladder pressure (UBP) was analyzed by linear regression analysis. The effects of respiratory and body position on AWT were evaluated using the paired samples t test, whereas the effects of gender and body mass index (BMI) on baseline AWT (IAP<12 mmHg) were assessed using one-way analysis of variance.A total of 51 patients were studied. A significant linear correlation was observed between AWT and UBP (R=0.986, P<0.01); the regression equation was Y=-1.369+9.57X (P<0.01). There were significant differences among the different respiratory phases and body positions (P<0.01). However, gender and BMI had no significant effects on baseline AWT (P=0.457 and 0.313, respectively).There was a significant linear correlation between AWT and UBP and respiratory phase, whereas body position had significant effects on AWT but gender and BMI did not. Therefore, AWT could serve as a simple, rapid, accurate, and important method to monitor IAP in critically ill patients.


PubMed | Shanghai JianGong Hospital
Type: Journal Article | Journal: Experimental lung research | Year: 2014

Acute lung injury (ALI) is a high incidence disease with no effective therapeutic method (mortality rate > 40%). The aim of this study was to find a new and effective therapeutic method for ALI.After the isolation of human umbilical cord mesenchymal stem cells (HUMSCs) from cesarean fetus, we transfected the HUMSCs with Lenti-ACE2 (angiotensin-converting enzyme 2) viral particles. Then we evaluated the therapeutic effect of HUMSCs harboring ACE2 on ALI, which induced by bleomycin (BLM) in rat model.Our results showed that HUMSCs harboring ACE2 could attenuate ALI degree through reducing pulmonary inflammatory infiltration and degree of vascular permeability, repressing the mRNA level of pro-inflammatory cytokines, activating the mRNA level of anti-inflammatory cytokines and ACE2. Besides, results also demonstrated that HUMSCs harboring ACE2 gene had higher therapeutic effects to ALI than the single factor of HUMSCs or ACE2.This research provided clues for the development of effective therapeutic methods to ALI using stem cell transplantation and gene therapy.

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