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Yousefi Zardak M, Keshavarz F, Mahyaei A, Gholami M, Moosavi FS, Abbasloo E, Abdollahi F, Hossein Rezaei M, Madadizadeh E, Soltani N, Bejeshk F, Salehi N, Rostamabadi F, Bagheri F, Jafaraghae M, Ranjbar Zeydabadi M, Baghgoli M, Sepehri G, Bejeshk MA. Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury. Sci Rep 2024; 14:23074. [PMID: 39367100 PMCID: PMC11452703 DOI: 10.1038/s41598-024-73075-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 09/13/2024] [Indexed: 10/06/2024] Open
Abstract
Lung ischemia-reperfusion injury (LIRI) causes oxidative stress, inflammation, and immune system activation. The Nrf2/Keap1/HO-1 pathway is important in cellular defense against these effects. Quercetin, a flavonoid with antioxidant, anti-inflammatory, and anti-cancer properties, has been investigated. Our aim in this study was to investigate the effect of quercetin on preventing lung ischemia-reperfusion injury and the role of the Nrf2/Keap1/HO-1 pathway. Sixty-four male Wistar rats were divided into four distinct groups(n = 16). Sham, lung ischemia-reperfusion (LIR), Saline + LIR, Quercetin + LIR (30 mg/kg i.p for a week before LIR). LIR groups were subjected to 60 min of ischemia (left pulmonary artery, vein, and bronchus) and 120 min of reperfusion. Our assessment encompassed a comprehensive analysis of various factors, including the evaluation of expression Nrf2, Keap1, and Heme Oxygenase-1 (HO-1) levels and NF-κB protein. Furthermore, we examined markers related to inflammation (interleukin-1β and tumor necrosis factor alpha), oxidative stress (malondialdehyde, total oxidant status, superoxide dismutase, glutathione peroxidase, total antioxidant capacity), lung edema (Wet/dry lung weight ratio and total protein concentration), apoptosis (Bax and Bcl2 protein), and histopathological alterations (intra-alveolar edema, alveolar hemorrhage, and neutrophil infiltration). Our results show that ischemia-reperfusion results in heightened inflammation, oxidative stress, apoptosis, lung edema, and histopathological damage. Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.
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Affiliation(s)
- Mohammad Yousefi Zardak
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Keshavarz
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Mahyaei
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Morteza Gholami
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Sadat Moosavi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Abbasloo
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Farzaneh Abdollahi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Hossein Rezaei
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Exercise Physiology, Faculty of Physical Education, Shahid Bahonar University, Kerman, Iran
| | - Elham Madadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Exercise Physiology, Faculty of Physical Education, Shahid Bahonar University, Kerman, Iran
| | - Nasrin Soltani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Bejeshk
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Niyan Salehi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Fahimeh Rostamabadi
- Noncommunicable Diseases Research center, Bam University of Medical Sciences, Bam, Kerman, Iran
| | - Fatemeh Bagheri
- Legal Medicine Research Center, Legal Medicine Organization, Kerman, Iran
| | - Mahla Jafaraghae
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | | | - Meraj Baghgoli
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Sepehri
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran.
- Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Abbas Bejeshk
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran.
- Pulmonary Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
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Ju F, Abbott GW, Li J, Wang Q, Liu T, Liu Q, Hu Z. Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice. Cardiovasc Drugs Ther 2024; 38:279-295. [PMID: 36609949 DOI: 10.1007/s10557-022-07419-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2022] [Indexed: 01/09/2023]
Abstract
OBJECTIVE The SGLT2 inhibitor, canagliflozin, not only reduces glycemia in patients with type 2 diabetes but also exerts cardioprotective effects in individuals without diabetes. However, its potential beneficial effects in cardiac arrest have not been characterized. The purpose of this study was to examine the protective effect of canagliflozin pretreatment on postresuscitation-induced cardiac dysfunction in vivo. METHODS Male C57/BL6 mice were randomized to vehicle (sham and control) or canagliflozin treatment groups. All mice except for the sham-operated mice were subjected to potassium chloride-induced cardiac arrest followed by chest compressions and intravenous epinephrine for resuscitation. Canagliflozin therapy efficacies were evaluated by electrocardiogram, echocardiography, histological analysis, inflammatory response, serum markers of myocardial injury, protein phosphorylation analysis, and immunohistological assessment. RESULTS Canagliflozin-pretreated mice exhibited a higher survival rate (P < 0.05), a shorter return of spontaneous circulation (ROSC) time (P < 0.01) and a higher neurological score (P < 0.01 or P < 0.001) than control mice after resuscitation. Canagliflozin was effective at improving cardiac arrest and resuscitation-associated cardiac dysfunction, indicated by increased left ventricular ejection fraction and fractional shortening (P < 0.001). Canagliflozin reduced serum levels of LDH, CK-MB and α-HBDH, ameliorated systemic inflammatory response, and diminished the incidence of early resuscitation-induced arrhythmia. Notably, canagliflozin promoted phosphorylation of cardiac STAT-3 postresuscitation. Furthermore, pharmacological inhibition of STAT-3 by Ag490 blunted STAT-3 phosphorylation and abolished the cardioprotective actions of canagliflozin. CONCLUSIONS Canagliflozin offered a strong cardioprotective effect against cardiac arrest and resuscitation-induced cardiac dysfunction. This canagliflozin-induced cardioprotection is mediated by the STAT-3-dependent cell-survival signaling pathway.
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Affiliation(s)
- Feng Ju
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Geoffrey W Abbott
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA
| | - Jiaxue Li
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qifeng Wang
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ting Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Quanhua Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Kashiwagi S, Mihara T, Yokoi A, Yokoyama C, Nakajima D, Goto T. Effect of remote ischemic preconditioning on lung function after surgery under general anesthesia: a systematic review and meta-analysis. Sci Rep 2023; 13:17720. [PMID: 37853024 PMCID: PMC10584824 DOI: 10.1038/s41598-023-44833-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
Remote ischemic preconditioning (RIPC) protects organs from ischemia-reperfusion injury. Recent trials showed that RIPC improved gas exchange in patients undergoing lung or cardiac surgery. We performed a systematic search to identify randomized controlled trials involving RIPC in surgery under general anesthesia. The primary outcome was the PaO2/FIO2 (P/F) ratio at 24 h after surgery. Secondary outcomes were A-a DO2, the respiratory index, duration of postoperative mechanical ventilation (MV), incidence of acute respiratory distress syndrome (ARDS), and serum cytokine levels. The analyses included 71 trials comprising 7854 patients. Patients with RIPC showed higher P/F ratio than controls (mean difference [MD] 36.6, 95% confidence interval (CI) 12.8 to 60.4, I2 = 69%). The cause of heterogeneity was not identified by the subgroup analysis. Similarly, A-a DO2 (MD 15.2, 95% CI - 29.7 to - 0.6, I2 = 87%) and respiratory index (MD - 0.17, 95% CI - 0.34 to - 0.01, I2 = 94%) were lower in the RIPC group. Additionally, the RIPC group was weaned from MV earlier (MD - 0.9 h, 95% CI - 1.4 to - 0.4, I2 = 78%). Furthermore, the incidence of ARDS was lower in the RIPC group (relative risk 0.73, 95% CI 0.60 to 0.89, I2 = 0%). Serum TNFα was lower in the RIPC group (SMD - 0.6, 95%CI - 1.0 to - 0.3 I2 = 87%). No significant difference was observed in interleukin-6, 8 and 10. Our meta-analysis suggested that RIPC improved oxygenation after surgery under general anesthesia.Clinical trial number: This study protocol was registered in the University Hospital Medical Information Network (registration number: UMIN000030918), https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035305.
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Affiliation(s)
- Shizuka Kashiwagi
- Department of Anesthesiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
- Department of Anesthesiology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-Ku, Yokohama City, Kanagawa-Ken, 236-0004, Japan.
| | - Takahiro Mihara
- Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Japan
| | - Ayako Yokoi
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chisaki Yokoyama
- Department of Anesthesia, Chiba Children's Hospital, Chiba, Japan
| | - Daisuke Nakajima
- Department of Anesthesiology, Yokohama City University Medical Center, Yokohama City, Japan
| | - Takahisa Goto
- Department of Anesthesiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Gao C, Xu YJ, Meng ZX, Gu S, Zhang L, Zheng L. BMSC-Derived Exosomes Carrying lncRNA-ZFAS1 Alleviate Pulmonary Ischemia/Reperfusion Injury by UPF1-Mediated mRNA Decay of FOXD1. Mol Neurobiol 2023; 60:2379-2396. [PMID: 36652050 DOI: 10.1007/s12035-022-03129-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 11/04/2022] [Indexed: 01/19/2023]
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) exert protective effects against pulmonary ischemia/reperfusion (I/R) injury; however, the potential mechanism involved in their protective ability remains unclear. Thus, this study aimed to explore the function and underlying mechanism of BMSC-derived exosomal lncRNA-ZFAS1 in pulmonary I/R injury. Pulmonary I/R injury models were established in mice and hypoxia/reoxygenation (H/R)-exposed primary mouse lung microvascular endothelial cells (LMECs). Exosomes were extracted from BMSCs. Target molecule expression was assessed by qRT-PCR and Western blotting. Pathological changes in the lungs, pulmonary edema, apoptosis, pro-inflammatory cytokine levels, SOD, MPO activities, and MDA level were measured. The proliferation, apoptosis, and migration of LMECs were detected by CCK-8, EdU staining, flow cytometry, and scratch assay. Dual-luciferase reporter assay, RNA pull-down, RIP, and ChIP assays were performed to validate the molecular interaction. In the mouse model of pulmonary I/R injury, BMSC-Exos treatment relieved lung pathological injury, reduced lung W/D weight ratio, and restrained apoptosis and inflammation, whereas exosomal ZFAS1 silencing abolished these beneficial effects. In addition, the proliferation, migration inhibition, apoptosis, and inflammation in H/R-exposed LMECs were repressed by BMSC-derived exosomal ZFAS1. Mechanistically, ZFAS1 contributed to FOXD1 mRNA decay via interaction with UPF1, thereby leading to Gal-3 inactivation. Furthermore, FOXD1 depletion strengthened the weakened protective effect of ZFAS1-silenced BMSC-Exos on pulmonary I/R injury. ZFAS1 delivered by BMSC-Exos results in FOXD1 mRNA decay and subsequent Gal-3 inactivation via direct interaction with UPF1, thereby attenuating pulmonary I/R injury.
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Affiliation(s)
- Cao Gao
- Departments of Anesthesiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Yan-Jie Xu
- Departments of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Zhi-Xiu Meng
- Departments of Anesthesiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Shuang Gu
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Lei Zhang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Liang Zheng
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China.
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Avtaar Singh SS, Das De S, Al-Adhami A, Singh R, Hopkins PMA, Curry PA. Primary graft dysfunction following lung transplantation: From pathogenesis to future frontiers. World J Transplant 2023; 13:58-85. [PMID: 36968136 PMCID: PMC10037231 DOI: 10.5500/wjt.v13.i3.58] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/11/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.
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Affiliation(s)
- Sanjeet Singh Avtaar Singh
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
| | - Sudeep Das De
- Heart and Lung Transplant Unit, Wythenshawe Hospital, Manchester M23 9NJ, United Kingdom
| | - Ahmed Al-Adhami
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Department of Heart and Lung Transplant, Royal Papworth Hospital, Cambridge CB2 0AY, United Kingdom
| | - Ramesh Singh
- Mechanical Circulatory Support, Inova Health System, Falls Church, VA 22042, United States
| | - Peter MA Hopkins
- Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, QLD 4032, Australia
| | - Philip Alan Curry
- Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Glasgow G81 4DY, United Kingdom
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Wang Q, Ju F, Li J, Liu T, Zuo Y, Abbott GW, Hu Z. Empagliflozin protects against renal ischemia/reperfusion injury in mice. Sci Rep 2022; 12:19323. [PMID: 36369319 PMCID: PMC9652474 DOI: 10.1038/s41598-022-24103-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 11/10/2022] [Indexed: 11/13/2022] Open
Abstract
Renal ischemia/reperfusion (I/R) can induce acute kidney injury. Empagliflozin is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. Despite the established cardioprotective functions of empagliflozin, its protective role in renal I/R is unclear. Here, the present study evaluated the renoprotective effects of empagliflozin in a mouse model of renal I/R injury. Male C57/BL6 mice were allocated to sham-operated, I/R, and empagliflozin groups. Kidney pedicles on both sides were clamped for 45 min and were reperfused for 24 h. Empagliflozin (1 mg/kg) was administered to the mice for 2 days preischemia. The GSK-3β inhibitor SB216763 was administered intravenously at the beginning of reperfusion (0.1 mg/kg). Renal function and histological scores were evaluated. The kidneys were taken for immunohistochemical analysis, western blotting and apoptosis measurements. We found that empagliflozin decreased serum levels of creatinine and urea, reduced the average kidney weight-to-tibia length ratio, attenuated tubular damage, reduced renal proinflammatory cytokine expression and inhibited apoptosis in injured kidneys. Furthermore, empagliflozin increased renal glycogen synthase kinase 3β (GSK-3β) phosphorylation post I/R. Pharmacological inhibition of GSK-3β activity mimicked the renal protective effects offered by empagliflozin. In summary, these results support a protective role of empagliflozin against renal I/R injury.
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Affiliation(s)
- Qifeng Wang
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Feng Ju
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Jiaxue Li
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Ting Liu
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Yunxia Zuo
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Geoffrey W. Abbott
- grid.266093.80000 0001 0668 7243Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA USA
| | - Zhaoyang Hu
- grid.13291.380000 0001 0807 1581Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan China
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Ischemic limb preconditioning-induced anti-arrhythmic effect in reperfusion-induced myocardial injury: is it mediated by the RISK or SAFE pathway? Pflugers Arch 2022; 474:979-991. [PMID: 35695933 DOI: 10.1007/s00424-022-02716-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/04/2022] [Indexed: 02/05/2023]
Abstract
The mechanism for limb ischemic precondition (RLIPC)-induced suppression of reperfusion arrhythmia remains unknown. The purpose of this study was to examine the roles of the pro-survival reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways in this RLIPC-mediated antiarrhythmic activity. Male Sprague Dawley rats were assigned to sham-operated, control, or RLIPC groups. All rats except for the sham rats had 5 min of left main coronary artery occlusion with another 20 min of reperfusion. RLIPC was initiated by four cycles of limb ischemia (5 min) and reperfusion (5 min) on the bilateral femoral arteries. Hearts in every group were taken for protein phosphorylation analysis. RLIPC ameliorated reperfusion-induced arrhythmogenesis and reduced the incidence of sudden cardiac death during the entire 20-min reperfusion period (66.7% of control rats had SCD vs. only 16.7% of RLIPC-treated rats). RLIPC enhances ventricular ERK1/2 phosphorylation after reperfusion. RLIPC-induced antiarrhythmic action and ERK1/2 phosphorylation are abolished in the presence of the ERK1/2 inhibitor U0126. Limb ischemic preconditioning protects the heart against myocardial reperfusion injury-induced lethal arrhythmia. These beneficial effects may involve the activation of ERK1/2 in the RISK signaling pathway.
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Huang D, Chen C, Zuo Y, Du L, Liu T, Abbott GW, Hu Z. Protective effect of remote liver ischemic postconditioning on pulmonary ischemia and reperfusion injury in diabetic and non-diabetic rats. PLoS One 2022; 17:e0268571. [PMID: 35617238 PMCID: PMC9135201 DOI: 10.1371/journal.pone.0268571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 05/03/2022] [Indexed: 11/19/2022] Open
Abstract
Pulmonary ischemia and reperfusion (I/R) injury occurs in many clinical conditions and causes severe damage to the lungs. Diabetes mellitus (DM) predisposes to pulmonary I/R injury. We previously found that remote liver ischemia preconditioning protected lungs against pulmonary I/R injury. The aim of the present study was to investigate whether remote liver ischemic postconditioning (RLIPost) attenuates pulmonary damage induced by I/R injury in non-diabetic or diabetic rats. Male Sprague-Dawley rats were assigned into non-diabetic and diabetic groups. All rats except for the sham were exposed to 45 min of left hilum occlusion followed by 2 h of reperfusion. RLIPost was conducted at the onset of pulmonary reperfusion by four cycles of 5 min of liver ischemia and reperfusion. Lung injury was assessed by the wet/dry weight ratio, pulmonary oxygenation, histopathological changes, apoptosis and the expression of inflammatory cytokines. Reperfusion-associated protein phosphorylation states were determined. RLIPost offered strong pulmonary-protection in both non-diabetic and diabetic rats, as reflected in reduced water content and pulmonary structural damage, recovery of lung function, inhibition of apoptosis and inflammation after ischemia-reperfusion. RLIPost induced the activation of pulmonary STAT-3, a key component in the SAFE pathway, but not activation of the proteins in the RISK pathway, in non-diabetic rats. In contrast, RLIPost-induced pulmonary protection in diabetic lungs was independent of SAFE or RISK pathway activation. These results demonstrate that RLIPost exerts pulmonary protection against I/R-induced lung injury in non-diabetic and diabetic rats. The underlying mechanism for protection may be different in non-diabetic (STAT-3 dependent) versus diabetic (STAT-3 independent) rats.
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Affiliation(s)
- Dou Huang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Changwei Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yunxia Zuo
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lei Du
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ting Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Geoffrey W. Abbott
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, United States of America
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- * E-mail:
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Min SH, Choe SH, Kim WS, Ahn SH, Cho YJ. Effects of ischemic conditioning on head and neck free flap oxygenation: a randomized controlled trial. Sci Rep 2022; 12:8130. [PMID: 35581399 PMCID: PMC9114019 DOI: 10.1038/s41598-022-12374-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/09/2022] [Indexed: 11/09/2022] Open
Abstract
Flap failure after microvascular reconstructive surgery is a rare but devastating complication caused by reperfusion injury and tissue hypoperfusion. Remote ischemic conditioning (RIC) provides protection against ischemia/reperfusion injury and reduces tissue infarction. We hypothesized that RIC would enhance flap oxygenation and exert organ-protective effects during head and neck free flap reconstructive surgery. Adult patients undergoing free flap transfer surgery for head and neck cancer were randomized to receive either RIC or sham-RIC during surgery. RIC consisted of four cycles of 5-min ischemia and 5-min reperfusion applied to the upper or lower extremity. The primary endpoint, tissue oxygen saturation of the flap, was measured by near-infrared spectroscopy on the first postoperative day. Organ-protective effects of RIC were evaluated with infarct size of rat hearts perfused with plasma dialysate from patients received RIC or sham-RIC. Between April 2018 and July 2019, 50 patients were randomized (each n = 25) and 46 were analyzed in the RIC (n = 23) or sham-RIC (n = 23) groups. Tissue oxygen saturation of the flap was similar between the groups (85 ± 12% vs 83 ± 9% in the RIC vs sham-RIC groups; P = 0.471). Myocardial infarct size after treatment of plasma dialysate was significantly reduced in the RIC group (44 ± 7% to 26 ± 6%; P = 0.018) compared to the sham-RIC group (42 ± 6% to 37 ± 7%; P = 0.388). RIC did not improve tissue oxygenation of the transferred free flap in head and neck cancer reconstructive surgery. However, there was evidence of organ-protective effects of RIC in experimental models. Trial registration: Registry number of ClinicalTrials.gov: NCT03474952.
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Affiliation(s)
- Se-Hee Min
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.,Department of Anesthesiology and Pain Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul, 06973, South Korea
| | - Suk Hyung Choe
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Won Shik Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.,Jeil ENT Clinic, 23, Nonhyeon-ro 131-gil, Gangnam-gu, Seoul, 06045, South Korea
| | - Soon-Hyun Ahn
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Youn Joung Cho
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
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10
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Hu Z, Liu Q, Yan Z, Wang Q, Liu J. Protective effect of remote ischemic postconditioning in rat testes after testicular torsion/detorsion. Andrology 2022; 10:973-983. [PMID: 35398995 DOI: 10.1111/andr.13184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/15/2022] [Accepted: 04/03/2022] [Indexed: 02/05/2023]
Affiliation(s)
- Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine National‐Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology Department of Anesthesiology West China Hospital Sichuan University Chengdu Sichuan China
| | - Quanhua Liu
- Laboratory of Anesthesia and Critical Care Medicine National‐Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology Department of Anesthesiology West China Hospital Sichuan University Chengdu Sichuan China
| | - Zhibing Yan
- Laboratory of Anesthesia and Critical Care Medicine National‐Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology Department of Anesthesiology West China Hospital Sichuan University Chengdu Sichuan China
| | - Qifeng Wang
- Laboratory of Anesthesia and Critical Care Medicine National‐Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology Department of Anesthesiology West China Hospital Sichuan University Chengdu Sichuan China
| | - Jin Liu
- Department of Anesthesiology West China Hospital Sichuan University Chengdu Sichuan China
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11
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Huang D, Ju F, Du L, Liu T, Zuo Y, Abbott GW, Hu Z. Empagliflozin Protects against Pulmonary Ischemia/Reperfusion Injury via an Extracellular Signal-Regulated Kinases 1 and 2-Dependent Mechanism. J Pharmacol Exp Ther 2022; 380:230-241. [PMID: 34893552 DOI: 10.1124/jpet.121.000956] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/06/2021] [Indexed: 02/05/2023] Open
Abstract
Ischemia/reperfusion (I/R) injury of the lung can lead to extensive pulmonary damage. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are insulin-independent, oral antihyperglycemic agents used for treating type 2 diabetes mellitus (T2DM). Although their cardioprotective properties have been reported, their potential roles in pulmonary protection in vivo are poorly characterized. Here, we tested a hypothesis that empagliflozin, an SGLT2 inhibitor, can protect lungs in a mouse model of lung I/R injury induced by pulmonary hilum ligation in vivo. We assigned C57/BL6 mice to sham-operated, nonempagliflozin-treated control, or empagliflozin-treated groups. Pulmonary I/R injury was induced by 1-hour left hilum ligation followed by 2-hour reperfusion. Using quantitative polymerase chain reaction (q-PCR) and Western blot analysis, we demonstrate that SGLT2 is highly expressed in mouse kidney but is weakly expressed in mouse lung (n = 5-6 per group, P < 0.01 or P < 0.001). Empagliflozin improved respiratory function, attenuated I/R-induced lung edema, lessened structural damage, inhibited apoptosis, and reduced inflammatory cytokine production and protein concentration in bronchoalveolar lavage (BAL) fluid [P < 0.05 or P < 0.001 versus control group (CON)]. In addition, empagliflozin enhanced phosphorylation of pulmonary extracellular signal-regulated kinases 1 and 2 (ERK1/2) post-I/R injury in vivo (P < 0.001, versus CON, n = 5 per group). We further showed that pharmacological inhibition of ERK1/2 activity reversed these beneficial effects of empagliflozin. In conclusion, we showed that empagliflozin exerts strong lung protective effects against pulmonary I/R injury in vivo, at least in part via the ERK1/2-mediated signaling pathway. SIGNIFICANCE STATEMENT: Pulmonary ischemia-reperfusion (I/R) can exacerbate lung injury. Empagliflozin is a new antidiabetic agent for type 2 diabetes mellitus. This study shows that empagliflozin attenuates lung damage after pulmonary I/R injury in vivo. This protective phenomenon was mediated at least in part via the extracellular signal-regulated kinases 1 and 2-mediated signaling pathway. This opens a new avenue of research for sodium-glucose cotransporter-2 inhibitors in the treatment of reperfusion-induced acute pulmonary injury.
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Affiliation(s)
- Dou Huang
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Feng Ju
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Lei Du
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Ting Liu
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Yunxia Zuo
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Geoffrey W Abbott
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Zhaoyang Hu
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
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12
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Vlastos D, Zeinah M, Ninkovic-Hall G, Vlachos S, Salem A, Asonitis A, Chavan H, Kalampalikis L, Al Shammari A, Alvarez Gallesio JM, Pons A, Andreadou I, Ikonomidis I. The effects of ischaemic conditioning on lung ischaemia-reperfusion injury. Respir Res 2022; 23:351. [PMID: 36527070 PMCID: PMC9756694 DOI: 10.1186/s12931-022-02288-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Ischaemia-reperfusion injury (IRI) encompasses the deleterious effects on cellular function and survival that result from the restoration of organ perfusion. Despite their unique tolerance to ischaemia and hypoxia, afforded by their dual (pulmonary and bronchial) circulation as well as direct oxygen diffusion from the airways, lungs are particularly susceptible to IRI (LIRI). LIRI may be observed in a variety of clinical settings, including lung transplantation, lung resections, cardiopulmonary bypass during cardiac surgery, aortic cross-clamping for abdominal aortic aneurysm repair, as well as tourniquet application for orthopaedic operations. It is a diagnosis of exclusion, manifesting clinically as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Ischaemic conditioning (IC) signifies the original paradigm of treating IRI. It entails the application of short, non-lethal ischemia and reperfusion manoeuvres to an organ, tissue, or arterial territory, which activates mechanisms that reduce IRI. Interestingly, there is accumulating experimental and preliminary clinical evidence that IC may ameliorate LIRI in various pathophysiological contexts. Considering the detrimental effects of LIRI, ranging from ALI following lung resections to primary graft dysfunction (PGD) after lung transplantation, the association of these entities with adverse outcomes, as well as the paucity of protective or therapeutic interventions, IC holds promise as a safe and effective strategy to protect the lung. This article aims to provide a narrative review of the existing experimental and clinical evidence regarding the effects of IC on LIRI and prompt further investigation to refine its clinical application.
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Affiliation(s)
- Dimitrios Vlastos
- grid.415914.c0000 0004 0399 9999Department of Vascular Surgery, Countess of Chester Hospital, Chester, UK ,grid.411449.d0000 0004 0622 4662Second Department of Cardiology, Attikon University Hospital, Athens, Greece ,Present Address: Liverpool, UK
| | - Mohamed Zeinah
- grid.415992.20000 0004 0398 7066Department of Cardiac Surgery, Liverpool Heart and Chest Hospital, Liverpool, UK ,grid.7269.a0000 0004 0621 1570Ain Shams University, Cairo, Egypt
| | - George Ninkovic-Hall
- grid.415970.e0000 0004 0417 2395Department of Vascular Surgery, Royal Liverpool University Hospital, Liverpool, UK
| | - Stefanos Vlachos
- grid.411449.d0000 0004 0622 4662Second Department of Cardiology, Attikon University Hospital, Athens, Greece
| | - Agni Salem
- grid.415992.20000 0004 0398 7066Department of Cardiac Surgery, Liverpool Heart and Chest Hospital, Liverpool, UK
| | - Athanasios Asonitis
- grid.413157.50000 0004 0590 2070Department of Cardiothoracic Surgery, NHS Golden Jubilee National Hospital, Glascow, UK
| | - Hemangi Chavan
- grid.421662.50000 0000 9216 5443Department of Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Lazaros Kalampalikis
- grid.414012.20000 0004 0622 6596Department of Minimally Invasive Cardiac Surgery, Metropolitan General Hospital, Athens, Greece
| | - Abdullah Al Shammari
- grid.421662.50000 0000 9216 5443Department of Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - José María Alvarez Gallesio
- grid.421662.50000 0000 9216 5443Department of Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Aina Pons
- grid.421662.50000 0000 9216 5443Department of Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Ioanna Andreadou
- grid.5216.00000 0001 2155 0800School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Ignatios Ikonomidis
- grid.411449.d0000 0004 0622 4662Second Department of Cardiology, Attikon University Hospital, Athens, Greece
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13
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Yan Z, Du L, Liu Q, Zhou L, Hu Z. Remote limb ischaemic conditioning produces cardioprotection in rats with testicular ischaemia-reperfusion injury. Exp Physiol 2021; 106:2223-2234. [PMID: 34487401 DOI: 10.1113/ep089289] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 08/31/2021] [Indexed: 02/05/2023]
Abstract
NEW FINDINGS What is the central question of this study? Can remote limb ischaemic conditioning produce cardioprotection in rats with testicular ischaemia-reperfusion injury? What is the main finding and its importance? Testicular ischaemia-reperfusion (TI/R)-injured rats were predisposed to myocardial reperfusion-induced atrioventricular block. Remote limb ischaemia preconditioning and postconditioning protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of sudden cardiac death, with a possible role of c-Jun N-terminal kinase inhibition and connexin 43 activation. ABSTRACT Remote ischaemic conditioning can protect hearts against arrhythmia. Testicular ischaemia-reperfusion (TI/R) injury is associated with electrocardiographic abnormalities. We investigated the effect of remote limb ischaemia preconditioning (RIPre) and postconditioning (RIPost) on arrhythmogenesis in TI/R rats, and determined the potential role of c-Jun N-terminal kinase (JNK)/connexin 43 (Cx43) signalling. Rats were randomized to sham-operated, control, TI/R, RIPre and RIPost groups. TI/R rats were more predisposed to myocardial reperfusion-induced atrioventricular block (AVB). RIPre and RIPost reduced the incidence of sudden cardiac death (SCD) or AVB, and duration of ventricular tachyarrhythmias during myocardial reperfusion. RIPre and RIPost decreased myocardial I/R-induced phosphorylation level of JNK, while preserving myocardial Cx43 expression in TI/R rats. Taken together, TI/R rats were predisposed to myocardial reperfusion-induced AVB. RIPre and RIPost protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of SCD by suppressing JNK activation and restoring Cx43 expression.
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Affiliation(s)
- Zhibing Yan
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Du
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Quanhua Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Leng Zhou
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
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14
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Chen J, Li X, Zhao F, Hu Y. HOTAIR/miR-17-5p Axis is Involved in the Propofol-Mediated Cardioprotection Against Ischemia/Reperfusion Injury. Clin Interv Aging 2021; 16:621-632. [PMID: 33883889 PMCID: PMC8055365 DOI: 10.2147/cia.s286429] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/21/2021] [Indexed: 12/11/2022] Open
Abstract
Background Propofol (PPF) ameliorates ischemia/reperfusion (I/R) injury in multiple organs by reducing apoptosis and release of pro-inflammatory cytokines. This study aims to explore the mechanism of PPF in attenuating myocardial ischemia-reperfusion injury (MIRI). Materials and Methods Rat MIRI model was established, and PPF pre-treatment was performed 10 min before I/R. H9c2 cardiomyocytes treated with hypoxia/reoxygenation (H/R) were used to establish an in vitro model. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate HOTAIR and miR-17-5p expression levels. Flow cytometry was employed to detect the apoptosis of H9c2 cells. The interaction between HOTAIR and miR-17-5p was determined by bioinformatics analysis, luciferase reporter gene analysis, and RNA immunoprecipitation experiments. STAT3 and p-STAT3 expressions were detected by Western blot. Results PPF pre-treatment significantly reduced creatine kinase isoenzyme (CK-MB) and serum lactate dehydrogenase (LDH) levels in the serum of the rats with MIRI. PPF pre-treatment remarkably up-regulated HOTAIR expression and down-regulated miR-17-5p expression in both in vivo and in vitro models. HOTAIR adsorbed miR-17-5p to repress the expression of miR-17-5p. PPF pre-treatment markedly inhibited cardiomyocyte apoptosis induced by I/R or H/R. HOTAIR knockdown could partially reverse the protective effects of PPF on MIRI. HOTAIR could activate STAT3 signaling via repressing miR-17-5p expression. Conclusion PPF protects the MIRI by modulating the HOTAIR/miR-17-5p/STAT3 axis.
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Affiliation(s)
- Junyang Chen
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Xuefeng Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Feng Zhao
- Department of Operating Room, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Yubo Hu
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
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15
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Liu X, Chen H, Yan Z, Du L, Huang D, Gao WD, Hu Z. Remote liver ischemic preconditioning attenuates myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats. Sci Rep 2021; 11:1903. [PMID: 33479330 PMCID: PMC7820418 DOI: 10.1038/s41598-021-81422-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 01/06/2021] [Indexed: 02/08/2023] Open
Abstract
Diabetes mellitus (DM) exhibits a higher sensitivity to myocardial ischemia/reperfusion (I/R) injury and may compromise the effectiveness of cardioprotective interventions, including ischemic preconditioning. We previously found that liver ischemic preconditioning (RLIPC) could limit infarct size post I/R in non-diabetic rat hearts and further exerted anti-arrhythmic effects in diabetic or non-diabetic rats after myocardial I/R, however, little is known regarding the effect of RLIPC on infarct-sparing in diabetic hearts. In this study, we evaluated the protective effects of RLIPC on I/R injury in streptozotocin-induced type 1 diabetic rats. Type 1 diabetes mellitus was induced by one-time intraperitoneal injection of streptozotocin in Sprague-Dawley rats. Rats were exposed to 45 min of left anterior descend in (LAD) coronary artery occlusion, followed by 3 h of reperfusion. For liver ischemic preconditioning, four cycles of 5 min of liver I/R stimuli were performed before LAD occlusion. The cardioprotective effect of RLIPC was determined in diabetic rats. Compared to non-RLIPC treated DM rats, RLIPC treatment significantly reduced infarct size and cardiac tissue damage, inhibited apoptosis in diabetic hearts post I/R. RLIPC also improved cardiac functions including LVESP, LVEDP, dp/dtmax, and - dp/dtmax. In addition, RLIPC preserved cardiac morphology by reducing the pathological score post I/R in diabetic hearts. Finally, Westernblotting showed that RLIPC stimulated phosphorylation of ventricular GSK-3β and STAT-5, which are key components of RISK and SAFE signaling pathways. Our study showed that liver ischemic preconditioning retains strong cardioprotective properties in diabetic hearts against myocardial I/R injury via GSK-3β/STAT5 signaling pathway.
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Affiliation(s)
- Xinhao Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hui Chen
- Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhibing Yan
- Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lei Du
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dou Huang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wei Dong Gao
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Zhaoyang Hu
- Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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16
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Incognito AV, Millar PJ, Pyle WG. Remote ischemic conditioning for acute respiratory distress syndrome in COVID-19. Am J Physiol Lung Cell Mol Physiol 2021; 320:L331-L338. [PMID: 33404365 PMCID: PMC7938644 DOI: 10.1152/ajplung.00223.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Acute respiratory distress syndrome and subsequent respiratory failure remains the leading cause of death (>80%) in patients severely impacted by COVID-19. The lack of clinically effective therapies for COVID-19 calls for the consideration of novel adjunct therapeutic approaches. Though novel antiviral treatments and vaccination hold promise in control and prevention of early disease, it is noteworthy that in severe cases of COVID-19, addressing "run-away" inflammatory cascades are likely more relevant for improvement of clinical outcomes. Viral loads may decrease in severe, end-stage coronavirus cases, but a systemically damaging cytokine storm persists and mediates multiple organ injury. Remote ischemic conditioning (RIC) of the limbs has shown potential in recent years to protect the lungs and other organs against pathological conditions similar to that observed in COVID-19. We review the efficacy of RIC in protecting the lungs against acute injury and current points of consideration. The beneficial effects of RIC on lung injury along with other related cardiovascular complications are discussed, as are the limitations presented by sex and aging. This adjunct therapy is highly feasible, noninvasive, and proven to be safe in clinical conditions. If proven effective in clinical trials for acute respiratory distress syndrome and COVID-19, application in the clinical setting could be immediately implemented to improve outcomes.
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Affiliation(s)
- Anthony V Incognito
- Department of Human Health and Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, Ontario, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Philip J Millar
- Department of Human Health and Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, Ontario, Canada.,Toronto General Research Institute, Toronto, Ontario, Canada
| | - W Glen Pyle
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.,IMPART Team Canada Investigator Network, Dalhousie Medicine, Dalhousie University, Saint John, New Brunswick, Canada
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17
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Liu Y, Wang J, Jin X, Xin Z, Wu X, Tong X, Tao Y, Wang D. A novel rat model of ocular hypertension by a single intracameral injection of cross-linked hyaluronic acid hydrogel (Healaflow ® ). Basic Clin Pharmacol Toxicol 2020; 127:361-370. [PMID: 32383327 DOI: 10.1111/bcpt.13430] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/26/2020] [Accepted: 05/03/2020] [Indexed: 12/28/2022]
Abstract
To create a novel animal model of ocular hypertension via the intracameral injection of Healaflow. Unilateral chronic ocular hypertension model of rats was created by the intracameral injection of 3 μL Healaflow. The IOP of subjects was monitored. Dynamic morphological changes were evaluated by fundus imaging, OCT and histological examination. Visual function changes were measured by electroretinography and flash visual-evoked potentials. 24 and 72 hours after injection, the retinal tissue was collected for transcriptome analysis. The expression levels of related genes and proteins were further evaluated by qRT-PCR and Western blotting. The IOP peaked within 1 day after a single intracameral injection of Healaflow and then decreased gradually within 4 weeks. Furthermore, the persistently degenerating retinal ganglion cells occurred within 4 weeks. The visual function of these rats was also impaired. The results of transcriptome analyses, qRT-PCR and Western blotting showed that the expression levels of B2m, Ikzf1 and Stat3 were up-regulated, while the expression levels of Six3 and Prss56 were down-regulated in the retinal tissues. Intracameral injection of Healaflow is an effective approach to induce glaucomatous neurodegeneration in rats. Six3 and Prss56 may be involved in the pathogenesis of progressive glaucomatous damage.
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Affiliation(s)
- Ying Liu
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of Ophthalmology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jichen Wang
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Xin Jin
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhiyuan Xin
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xing Wu
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xu Tong
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ye Tao
- Department of Ophthalmology, Henan Provincial People's Hospital, People's Hospital, Zhengzhou University, Zhengzhou, China
| | - Dajiang Wang
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Yang G, Yang Y, Li Y, Hu Z. Remote liver ischaemic preconditioning protects rat brain against cerebral ischaemia-reperfusion injury by activation of an AKT-dependent pathway. Exp Physiol 2020; 105:852-863. [PMID: 32134522 DOI: 10.1113/ep088394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 03/02/2020] [Indexed: 02/05/2023]
Abstract
NEW FINDINGS What is the central question of this study? Can remote liver ischaemic preconditioning (RLIPC) protect rat brain against cerebral ischaemia-reperfusion injury? What is the main finding and its importance? Pretreatment with RLIPC reduced cerebral infarct volume, improved neurological outcomes and inhibited neuron apoptosis. RLIPC led to increased phosphorylation of AKT, while inhibition of AKT abolished the effects of RLIPC. Our data suggest that liver ischaemic preconditioning exerts a strong neuroprotective effect against cerebral ischaemia-reperfusion injury by activating an AKT-dependent pathway. ABSTRACT Remote limb ischaemic preconditioning has been shown to have beneficial effects in protecting brains against ischaemia-reperfusion (I/R) injury. However, little is known regarding the effect of remote liver ischaemic conditioning (RLIPC). We therefore investigated the effect of RLIPC on brain tissues suffering from I/R injury. Rats were randomly assigned to a sham group, a control group or a RLIPC group. Rats in all groups except for the sham group received middle cerebral artery occlusion (MCAO) for 1 h, followed by 48 h of reperfusion. For the RLIPC rats, four cycles of 5 min of liver ischaemia (portal vein, hepatic arterial and venous trunk occlusion) with 5 min intermittent reperfusion were carried out before cerebral ischaemia. Infarct volume was assessed after 48 h of reperfusion. Blood samples were taken for serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) tests. Morphological changes of cortical tissue and cellular apoptosis were determined. Right cortex tissues were taken for western blotting measurements. Our data demonstrate that RLIPC reduced cerebral I/R injury, decreased the volume of the MCAO-evoked infarct region, decreased serum levels of LDH and CK-MB, and reduced neurological deficits and apoptosis after I/R injury. Moreover, rats receiving RLIPC showed increased cortical AKT phosphorylation, but protein phosphorylation level was unchanged in the survivor activating factor enhancement (SAFE) signalling pathway. Accordingly, inhibition of AKT with wortmannin abolished the neuroprotective action of liver preconditioning. Our study showed for the first time that liver ischaemic preconditioning effectively protects brain against cerebral I/R injury by activating an AKT-dependent pathway.
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Affiliation(s)
- Guang Yang
- Department of Experimental Animal Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Yang
- Lab for Aging Research, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanmei Li
- Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhaoyang Hu
- Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Zhang L, Liu H, Xu K, Ling Z, Huang Y, Hu Q, Lu K, Liu C, Wang Y, Liu N, Zhang X, Xu B, Wu J, Chen S, Zhang G, Chen M. Hypoxia preconditioned renal tubular epithelial cell-derived extracellular vesicles alleviate renal ischaemia-reperfusion injury mediated by the HIF-1α/Rab22 pathway and potentially affected by microRNAs. Int J Biol Sci 2019; 15:1161-1176. [PMID: 31223277 PMCID: PMC6567810 DOI: 10.7150/ijbs.32004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/16/2019] [Indexed: 02/06/2023] Open
Abstract
We previously found that hypoxia induced renal tubular epithelial cells (RTECs) release functional extracellular vesicles (EVs), which mediate the protection of remote ischaemic preconditioning (RIPC) for kidney ischaemia-reperfusion (I/R) injury. We intend to investigate whether the EVs were regulated by hypoxia-inducible factor 1α (HIF-1α) and Rab22 during RIPC. We also attempted to determine the potentially protective cargo of the EVs and reveal their underlying mechanism. Hypoxia preconditioning (HPC) of human kidney 2 (HK2) cells was conducted at 1% oxygen (O2) for different amounts of time to simulate IPC in vitro. EVs were isolated and then quantified. HIF-1α- and Rab22-inhibited HK2 cells were used to investigate the role of the HIF-1α/Rab22 pathway in HPC-induced EV production. Both normoxic and HPC EVs were treated in vivo to assess the protective effect of I/R injury. Moreover, microRNA (miRNA) sequencing analysis and bioinformatics analysis was performed. We revealed that the optimal conditions for simulating IPC in vitro was no more than 12 h under the 1% O2 culture circumstance. HPC enhanced the production of EVs, and the production of EVs was regulated by the HIF-1α/Rab22 pathway during HPC. Moreover, HPC EVs were found to be more effective at attenuating mice renal I/R injury. Furthermore, 16 miRNAs were upregulated in HPC EVs. Functional and pathway analysis indicated that the miRNAs may participate in multiple processes and pathways by binding their targets to influence the biochemical results during RIPC. We demonstrated that HIF-1α/Rab22 pathway mediated RTEC-derived EVs during RIPC. The HPC EVs protected renal I/R injury potentially through differentially expressed miRNAs. Further study is needed to verify the effective EV-miRNAs and their underlying mechanism.
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Affiliation(s)
- Lei Zhang
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Han Liu
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Kai Xu
- Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhixin Ling
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yeqing Huang
- Department of Urology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Qiang Hu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Kai Lu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Chunhui Liu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Yiduo Wang
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Ning Liu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaowen Zhang
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Bin Xu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jianping Wu
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Shuqiu Chen
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Guangyuan Zhang
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Ming Chen
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China.,Institute of Urology, Surgical Research Center, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Pulmonary effects of remote ischemic preconditioning in a porcine model of ventilation-induced lung injury. Respir Physiol Neurobiol 2019; 259:111-118. [DOI: 10.1016/j.resp.2018.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 08/19/2018] [Accepted: 08/29/2018] [Indexed: 12/13/2022]
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