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Prem PN, Swaminathan H, Kurian GA. The temporal relationship between mitochondrial quality and renal tissue recovery following ischemia-reperfusion injury. Heliyon 2025; 11:e41634. [PMID: 39866419 PMCID: PMC11758212 DOI: 10.1016/j.heliyon.2025.e41634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 01/28/2025] Open
Abstract
Background Growing evidence indicates that disruptions in mitochondrial quality management contribute to the development of acute kidney injury (AKI), incomplete or maladaptive kidney repair, and chronic kidney disease. However, the temporal dynamics of mitochondrial quality control alterations in relation to renal injury and its recovery remain poorly understood and are addressed in this manuscript. Method ology: Male Wistar rats (n = 60) were subjected to varying durations of ischemia and reperfusion. Ischemia was instigated by clamping both renal arteries and for reperfusion, the clamps were removed to restore the blood flow. Renal injury, physiological function, mitochondrial assessment, and cellular mediators were analyzed. Results Prolonging ischemia duration reduces bioenergetic function while disrupting the balance of mitochondrial fusion, fission, and mitophagy at the gene expression level while maintaining intact mitochondrial copy number. However, reperfusing a kidney after 45 min of ischemia with varying reperfusion times exacerbates mitochondrial dysfunction and significantly decreases mitochondrial copy number. These declines are particularly evident at 24 h of reperfusion, with some parameters improving by 7 days of reperfusion. Despite these improvements, 7 days of reperfusion did not correlate with renal injury indicators (CrCl- 0.46 ± 0.01, BUN-86.29 ± 4.9, Cr-1.75 ± 0.16) following 45 min of ischemia. Conversely, 15 min of ischemia followed by 7 days of reperfusion restored mitochondrial quality and renal function (CrCl- 7.33 ± 0.59, BUN-43.6 ± 3.16, Cr-0.93 ± 0.14). Conclusion The above findings emphasize that mitochondrial quality control alters with the extent of ischemia and subsequent reperfusion time, impacting not only mitochondrial copy number but also the resilience of mitochondria during tissue repair.
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Affiliation(s)
- Priyanka N. Prem
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
- Vascular Biology Lab, Anusandhan Kendra-1, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
| | - Harish Swaminathan
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
- Vascular Biology Lab, Anusandhan Kendra-1, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
| | - Gino A. Kurian
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
- Vascular Biology Lab, Anusandhan Kendra-1, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
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Bathrinarayanan PV, Hallam SM, Grover LM, Vigolo D, Simmons MJH. Microfluidics as a Powerful Tool to Investigate Microvascular Dysfunction in Trauma Conditions: A Review of the State-of-the-Art. Adv Biol (Weinh) 2024; 8:e2400037. [PMID: 39031943 DOI: 10.1002/adbi.202400037] [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: 01/21/2024] [Revised: 04/18/2024] [Indexed: 07/22/2024]
Abstract
Skeletal muscle trauma such as fracture or crush injury can result in a life-threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo-fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro-muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ-on-chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state-of-the-art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective.
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Affiliation(s)
- P Vasanthi Bathrinarayanan
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B152TT, UK
- Healthcare Technologies Institute, School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - S M Hallam
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B152TT, UK
| | - L M Grover
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B152TT, UK
- Healthcare Technologies Institute, School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - D Vigolo
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B152TT, UK
- The University of Sydney, School of Biomedical Engineering, Sydney, NSW, 2006, Australia
- The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia
| | - M J H Simmons
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B152TT, UK
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Zhou M, Jia X, Liu H, Xue Y, Wang Y, Li Z, Wu Y, Rui Y. Bibliometric analysis of skeletal muscle ischemia/reperfusion (I/R) research from 1986 to 2022. Heliyon 2024; 10:e37492. [PMID: 39309867 PMCID: PMC11416534 DOI: 10.1016/j.heliyon.2024.e37492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 08/10/2024] [Accepted: 09/04/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Tissue damage due to ischemia and reperfusion is a critical medical problem worldwide. Studies in this field have made remarkable advances in understanding the pathogenesis of ischemia/reperfusion (I/R) injury and its treatment with new and known drugs. However, no bibliometric analysis exists in this area of research. Methods Research articles and reviews related to skeletal muscle I/R from 1986 to 2022 were retrieved from the Web of Science Core Collection. Bibliometric analysis was performed using Microsoft Excel 2019, VOSviewer (version 1.6.19), Bibliometrix (R-Tool for R-Studio), and CiteSpace (version 6.1.R5). Results A total of 3682 research articles and reviews from 2846 institutions in 83 countries were considered in this study. Most studies were conducted in the USA. Hobson RW (UMDNJ-New Jersey Medical School) had the highest publication, and Korthuis RJ (Louisiana State University) had the highest co-citations. Our analysis showed that, though the Journal of Surgical Research was most favored, the Journal of Biological Chemistry had the highest number of co-citations. The pathophysiology, interventions, and molecular mechanisms of skeletal muscle I/R injury emerged as the primary research areas, with "apoptosis," "signaling pathway," and "oxidative stress" as the main keywords of research hotspots. Conclusions This study provides a thorough overview of research trends and focal points in skeletal muscle I/R injury by applying bibliometric and visualization techniques. The insights gained from our findings offer a profound understanding of the evolving landscape of skeletal muscle I/R injury research, thereby functioning as a valuable reference and roadmap for future investigations.
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Affiliation(s)
| | | | | | - Yuan Xue
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, 214000, China
| | - Yapeng Wang
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, 214000, China
| | - Zeqing Li
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, 214000, China
| | - Yongwei Wu
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, 214000, China
| | - Yongjun Rui
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, 214000, China
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Zollet V, Arenas Hoyos I, Hirsiger S, Brahim BB, Petrucci MF, Casoni D, Wang J, Spirig R, Nettelbeck K, Garcia L, Fuest L, Vögelin E, Constantinescu M, Rieben R. Neutrophil extracellular traps and citrullinated fibrinogen contribute to injury in a porcine model of limb ischemia and reperfusion. Front Immunol 2024; 15:1436926. [PMID: 39315100 PMCID: PMC11416929 DOI: 10.3389/fimmu.2024.1436926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Background Ischemia/reperfusion injury (IRI) is a complex pathological process, triggered by the restoration of blood flow following an interrupted blood supply. While restoring the blood flow is the only option to salvage the ischemic tissue, reperfusion after a prolonged period of ischemia initiates IRI, triggering a cascade of inflammatory responses ultimately leading to neutrophil recruitment to the inflamed tissue, where they release neutrophil extracellular traps (NETs). NETs are web-like structures of decondensed chromatin and neutrophilic proteins, including peptidyl-arginine deiminase 2 and 4 (PAD2, PAD4), that, once outside, can citrullinate plasma proteins, irreversibly changing their conformation and potentially their function. While the involvement of NETs in IRI is known mainly from rodent models, we aimed to determine the effect of NET formation and especially PADs-mediated extracellular protein citrullination in a porcine model of limb IRI. Methods We conducted our study on amputated pig forelimbs exposed to 1 h or 9 h of ischemia and then reperfused in vivo for 12 h. Limb weight, edema formation, compartmental pressure were measured, and skeletal muscle was analyzed by immunofluorescence (TUNEL assay and dystrophin staining) to evaluate tissue damage. Fibrin tissue deposition, complement deposition and NETs were investigated by immunofluorescence. Citrullinated plasma proteins were immunoprecipitated and citrullinated fibrinogen was identified in the plasma by Western blot and in the tissue by immunofluorescence and Western blot. Results Our data consolidate the involvement of NETs in a porcine model of limb IRI, correlating their contribution to damage extension with the duration of the ischemic time. We found a massive infiltration of NETs in the group subjected to 9 h ischemia compared to the 1 h and citrullinated fibrinogen levels, in plasma and tissue, were higher in 9 h ischemia group. We propose fibrinogen citrullination as one of the mechanisms contributing to the worsening of IRI. NETs and protein citrullination represent a potential therapeutic target, but approaches are still a matter of debate. Here we introduce the idea of therapeutic approaches against citrullination to specifically inhibit PADs extracellularly, avoiding the downstream effects of hypercitrullination and keeping PADs' and NETs' intracellular regulatory functions.
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Affiliation(s)
- Valentina Zollet
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Isabel Arenas Hoyos
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
- Department of Plastic and Hand Surgery, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Stefanie Hirsiger
- Department of Plastic and Hand Surgery, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Bilal Ben Brahim
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Maria Francesca Petrucci
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Daniela Casoni
- Experimental Surgery Facility, Experimental Animal Center, University of Bern, Bern, Switzerland
| | - Junhua Wang
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Rolf Spirig
- Commonwealth Serum Laboratories (CSL) Behring, Research, Commonwealth Serum Laboratories (CSL) Behring Biologics Research Center, Bern, Switzerland
| | - Kay Nettelbeck
- Experimental Surgery Facility, Experimental Animal Center, University of Bern, Bern, Switzerland
| | - Luisana Garcia
- Experimental Surgery Facility, Experimental Animal Center, University of Bern, Bern, Switzerland
| | - Lena Fuest
- Department of Plastic and Hand Surgery, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Esther Vögelin
- Department of Plastic and Hand Surgery, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Mihai Constantinescu
- Department of Plastic and Hand Surgery, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Robert Rieben
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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Costa D, Ielapi N, Perri P, Minici R, Faga T, Michael A, Bracale UM, Andreucci M, Serra R. Molecular Insight into Acute Limb Ischemia. Biomolecules 2024; 14:838. [PMID: 39062551 PMCID: PMC11274792 DOI: 10.3390/biom14070838] [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: 06/18/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Acute limb ischemia (ALI) is defined as a sudden reduction in blood flow to a limb, resulting in cessation of blood flow and, therefore, cessation of the delivery of nutrients and oxygen to the tissues of the lower limb. Despite optimal treatment to restore blood flow to ischemic tissues, some patients may suffer from ischemia/reperfusion (I/R) syndrome, the most severe complication after a revascularization procedure used to restore blood flow. There are multiple molecular and cellular factors that are involved in each phase of ALI. This review focuses firstly on molecular and cellular factors of arterial thrombosis, highlighting the role of atherosclerotic plaques, smooth muscle cells (SMCs), and cytokine which may alter key components of the extracellular matrix (ECM). Then, molecular and cellular factors of arterial embolism will be discussed, highlighting the importance of thrombi composition. Molecular and cellular factors of ischemia/reperfusion syndrome are analyzed in depth, highlighting several important mechanisms related to tissue damage, such as inflammation, apoptosis, autophagy, necrosis, and necroptosis. Furthermore, local and general complications of ALI are discussed in the context of molecular alterations. Ultimately, the role of novel biomarkers and targeted therapies is discussed.
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Affiliation(s)
- Davide Costa
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- Interuniversity Center of Phlebolymphology (CIFL), "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Nicola Ielapi
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- Interuniversity Center of Phlebolymphology (CIFL), "Magna Graecia" University, 88100 Catanzaro, Italy
- Department of Public Health and Infectious Disease, "Sapienza" University of Rome, 00185 Rome, Italy
| | - Paolo Perri
- Department of Vascular and Endovascular Surgery, Annunziata Hospital, 1 Via Migliori, 87100 Cosenza, Italy
| | - Roberto Minici
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Teresa Faga
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Ashour Michael
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | | | - Michele Andreucci
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- Interuniversity Center of Phlebolymphology (CIFL), "Magna Graecia" University, 88100 Catanzaro, Italy
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Ren Y, Toyoshima Y, Vrieze A, Freedman B, Alizad A, Zhao C. In Vivo Ultrasound Shear Wave Elastography Assessment of Acute Compartment Syndrome in a Turkey Model. ULTRASOUND IN MEDICINE & BIOLOGY 2024; 50:571-579. [PMID: 38281889 DOI: 10.1016/j.ultrasmedbio.2023.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/08/2023] [Accepted: 12/22/2023] [Indexed: 01/30/2024]
Abstract
OBJECTIVE The aim of the work described here was to evaluate the objectivity and reproducibility of non-invasive intra-compartment pressure (ICP) measurement using ultrasound shear wave elastography (SWE) in a turkey model in vivo and to determine the biological and histologic changes in acute compartment syndrome (ACS). METHODS Twenty-four turkeys were randomly divided into four groups based on the duration and fasciotomy of ACS created by infusion of up to 50 mm Hg in the tibialis muscle: group 1, ACS 2 h; group 2, ACS 4 h; group 3, ACS 2 h + fasciotomy 2 h; group 4, ACS 4 h + fasciotomy 2 h. For each turkey, the contralateral limb was considered the control. Time-synchronized measures of SWE and ICP from each leg were collected. Then turkeys were euthanized for histology and quantitative reverse transcription polymerase chain reaction (qRT-PCR) examination. RESULTS All models created reproducible increases in ICP and SWE, which had a strong linear relationship (r = 0.802, p < 0.0001) during phase 1. SWE remained stable (50.86 ± 9.64 kPa) when ICP remained at 50.28 ± 2.17 mm Hg in phase 2. After fasciotomy, SWE declined stepwise and then normalized (r = 0.737, p < 0.0001). Histologically, the myofiber diameter of group 2 (82.31 ± 22.92 μm) and group 4 (90.90 ± 20.48 μm) decreased significantly (p < 0.01) compared with that of the control group (103.1 ± 20.39 μm); the interstitial space of all groups increased significantly (p < 0.01). Multifocal muscle damage revealed neutrophilic infiltration, degeneration, hemorrhage and necrosis, especially in group 4. Quantitative RT-PCR verified that interleukin-6 and heparin-binding EGF-like growth factor were significantly increased in group 4. CONCLUSION SWE provided sensitive measurements correlating to ICP in a clinically relevant ACS animal model. Once ACS time was exceeded, progression to irreversible necrosis continued spontaneously, even after fasciotomy. SWE may help surgeons in the early detection, monitoring, prognosis and decision making on fasciotomy for ACS.
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Affiliation(s)
- Ye Ren
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yoichi Toyoshima
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Alyssa Vrieze
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Brett Freedman
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Azra Alizad
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Chunfeng Zhao
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
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Immunomodulatory effects of β-defensin 2 on macrophages induced immuno-upregulation and their antitumor function in breast cancer. BMC Immunol 2022; 23:53. [PMID: 36324077 PMCID: PMC9632142 DOI: 10.1186/s12865-022-00527-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 09/27/2022] [Indexed: 11/05/2022] Open
Abstract
Background Macrophages are mononuclear CD34+ antigen-presenting cells of defense mechanism and play dual roles in tumor burden. The immunomodulatory and their antitumor function of β-defensin 2 is still unclear, despite the accumulating evidence of the response in infection. So, the aim of present study is to elucidate the role of β-defensin 2 on the level of ROS, cytokines, chemokine expression in macrophages and antitumor function in breast cancer. Method Swiss albino mice were used to harvest PEC macrophages and C127i breast cancer cells line for tumor model was used in this study. Macrophages were harvested and characterized by flow-cytometry using F4/80 and CD11c antibodies. MTT was performed to estimate cytotoxicity and dose optimization of β-defensin 2. Oxidative stress was analyzed by H2O2 and NO estimation followed by iNOS quantified by q-PCR. Cytokines and chemokines estimation was done using q-PCR. Co-culture experiment was performed to study anti-tumor function using PI for cell cycle, Annexin –V and CFSE analysis for cell proliferation. Results PEC harvested macrophages were characterized by flow-cytometry using F4/80 and CD11c antibodies with the purity of 8% pure population of macrophages. It was found that 99% of cells viable at the maximum dose of 100 ng/ml of β-defensin 2 in MTT. Levels of NO and H2O2 were found to be decreased in β-defensin 2 as compared to control. Expression of cytokines of IFN-γ, IL-1α, TNF-α, TGF-βwas found to be increased while IL-3 was decreased in β-defensin 2 group as compared to control. Levels of chemokines CXCL-1, CXCL-5 and CCL5 increased in treated macrophages while CCL24 and CXCL-15 expression decreased. Adhesion receptor (CD32) and fusion receptor (CD204) were decreased in the β-defensin 2 group as compared to control. Anti-tumor experiment was performed using co-culture experiment apoptosis (Annexin-V) was induced, cell cycle arrest in phage and cell proliferation of C127i cells was decreased. Conclusion This is the first report of β-defensin 2 modulates macrophage immunomodulatory and their antitumor function in breast cancer. β-defensin 2 as a new therapeutic target for immunotherapy as an adjuvant in vaccines.
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Deng P, Qiu S, Liao F, Jiang Y, Zheng C, Zhu Q. Contusion concomitant with ischemia injury aggravates skeletal muscle necrosis and hinders muscle functional recovery. Exp Biol Med (Maywood) 2022; 247:1577-1590. [PMID: 35775612 PMCID: PMC9554171 DOI: 10.1177/15353702221102376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Contusion concomitant with ischemia injury to skeletal muscles is common in civilian and battlefield trauma. Despite their clinical importance, few experimental studies on these injuries are reported. The present study established a rat skeletal muscle contusion concomitant with ischemia injury model to identify skeletal muscle alterations compared with contusion injury or ischemia injury. Macroscopic and microscopic morphological evaluation showed that contusion concomitant with ischemia injury aggravated muscle edema and hematoxylin-eosin (HE) injury score at 24 h postinjury. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels, together with gastrocnemius muscle (GM) tumor necrosis factor-alpha (TNF-α) content elevated at 24 h postinjury too. During the 28-day follow-up, electrophysiological and contractile impairment was more severe in the contusion concomitant with ischemia injury group. In addition, contusion concomitant with ischemia injury decreased the percentage of larger (600-3000 μm2) fibers and increased the fibrotic area and collagen I proportion in the GM. Smaller proportions of Pax7+ and MyoD+ satellite cells (SCs) were observed in the contusion concomitant with ischemia injury group at 7 days postinjury. In conclusion, contusion concomitant with ischemia injury to skeletal muscle not only aggravates early muscle fiber necrosis but also hinders muscle functional recovery by impairing SC differentiation and exacerbating fibrosis during skeletal muscle repair.
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Affiliation(s)
- Peijun Deng
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China
| | - Shuai Qiu
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China
| | - Fawei Liao
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China
| | - Yifei Jiang
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China
| | - Canbin Zheng
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China
| | - Qingtang Zhu
- Department of Microsurgery, Orthopedic Trauma and Hand Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China,Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou 510080, China,Guangdong Provincial Peripheral Nerve Tissue Engineering and Technology Research Center, Guangzhou 510080, China,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, China,Qingtang Zhu.
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Resolution of Inflammation after Skeletal Muscle Ischemia-Reperfusion Injury: A Focus on the Lipid Mediators Lipoxins, Resolvins, Protectins and Maresins. Antioxidants (Basel) 2022; 11:antiox11061213. [PMID: 35740110 PMCID: PMC9220296 DOI: 10.3390/antiox11061213] [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: 04/19/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/01/2023] Open
Abstract
Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.
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10
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Frisby DM, Tu H, Qian J, Zhang D, Barksdale AN, Wadman MC, Cooper JS, Li YL. Hyperbaric oxygen therapy does not alleviate tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles. Injury 2022; 53:368-375. [PMID: 34876256 DOI: 10.1016/j.injury.2021.11.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/20/2021] [Indexed: 02/02/2023]
Abstract
During tourniquet application, blood flow is restricted to a limb to stop excessive limb hemorrhage in a trauma setting and to create a bloodless operating field in the surgical setting. During tourniquet-related ischemia, aerobic respiration stops, and ATP is depleted, and during subsequent reperfusion, there is an increase in reactive oxygen species (ROS) production and other endogenous substances, which leads to acute ischemia-reperfusion (IR) injuries, including tissue necrosis and skeletal muscle contractile dysfunction. Hyperbaric oxygen (HBO) therapy can increase the arterial oxygen tension in the tissues of patients with general hypoxia/anoxia, including carbon monoxide poisoning, circulatory arrest, and cerebral and myocardial ischemia. Here, we studied the protective effects of HBO pretreatment with 100% oxygen at 2.5 ATA against tourniquet/IR injury in mice. After one hour of HBO therapy with 100% oxygen at 2.5 ATA was administered to C57/BL6 mice, a rubber band was placed at the hip joint of the unilateral hindlimb to induce 3 h of ischemia and then released for 48 h of reperfusion. We analyzed gastrocnemius muscle morphology and contractile function and measured the levels of ATP and ROS accumulation in the muscles. HBO pretreatment did not improve tourniquet/IR-injured gastrocnemius muscle morphology and muscle contraction. Tourniquet/IR mice with HBO pretreatment showed no increase in ATP levels in IR tissues, but they did have a decreased amount of ROS accumulation in the muscles, compared to IR mice with no HBO pretreatment. These data suggest that one hour of HBO pretreatment with 100% oxygen at 2.5 ATA increases the antioxidant response to lower ROS accumulation but does not increase ATP levels in IR muscles and improve tourniquet/IR-injured muscle morphology and contractile function.
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Affiliation(s)
- Devin M Frisby
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Huiyin Tu
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Junliang Qian
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Dongze Zhang
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Aaron N Barksdale
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael C Wadman
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jeffrey S Cooper
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Yu-Long Li
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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11
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Vakhitov D, Mella M, Hakovirta H, Suominen V, Oksala N, Saarinen E, Romsi P. Prognostic Risk Factors for the Development of Compartment Syndrome in Acute Lower Limb Ischemia Patients Treated with Catheter-Directed Thrombolysis. Ann Vasc Surg 2022; 84:305-313. [PMID: 35108554 DOI: 10.1016/j.avsg.2022.01.008] [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: 07/27/2021] [Revised: 12/13/2021] [Accepted: 01/05/2022] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To determine predisposing factors that may lead to the development of compartment syndrome (CS) in patients with acute lower limb ischemia (ALLI) managed with intra-arterial catheter-directed thrombolysis (CDT). METHODS This is a retrospective study of patients admitted between 01/2002 and 12/2015 to three university hospitals in Tampere, Turku, and Oulu, Finland, with acute or acute-on-chronic lower limb ischemia (Rutherford I-IIb). Patients managed with CDT and aspiration thrombectomies (AT) as an adjunct to CDT were included in the study. Multivariable binary logistic regression models were used to detect possible risk factors for the development of CS and its impact on the limb salvage and survival. Amputation-free survival (AFS) rates of CS and non-CS patients were compared using Kaplan-Meier survival analysis. The length of hospitalization was calculated and compared between the CS and non-CS groups. RESULTS A total of 292 CDTs with or without ATs were performed on patients with a mean age of 71 years (standard deviation 13 years), 151 (51.7%) being male. Altogether, 12/292 (4.1%) treatment-related CS cases were registered. Renal insufficiency (odds ratio [OR] 4.27, P = .07) was associated with an increased risk of CS. All CS cases were managed with fasciotomies. Treatment with fasciotomy was associated with a prolonged hospitalization of a median of 7 days versus the 4 days for non-CS patients, P < .001. During the median follow-up of 51 months (interquartile range 72 months), 152/292 (52.1%) patients died and 51/292 (17.5%) underwent major amputations. CS was not associated with an increased risk of mortality, but it was associated with a higher risk of major amputation (OR 3.87, P = .027). The AFS rates of patients with or without CS did not significantly differ from each other in the long term. CONCLUSION CS after CDT for the treatment of ALLI is uncommon. Renal insufficiency is associated with an increased risk of CS. Fasciotomy prolongs the hospitalization. Patients with CS are exposed to an increased risk of major amputation.
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Affiliation(s)
- D Vakhitov
- Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital, PSHP. PL2000, 33521, Tampere, Finland.
| | - M Mella
- Department of Vascular Surgery, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
| | - H Hakovirta
- Department of Vascular Surgery, Turku University Hospital, Kiinamyllynkatu 4-8, 20521, Turku, Finland
| | - V Suominen
- Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital, PSHP. PL2000, 33521, Tampere, Finland
| | - N Oksala
- Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital, PSHP. PL2000, 33521, Tampere, Finland; Department of Surgery, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34,33520 Tampere, Finland; Finnish Cardiovascular Research Center Tampere, Arvo Ylpön katu 34, 33520 Tampere, Finland
| | - E Saarinen
- Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital, PSHP. PL2000, 33521, Tampere, Finland
| | - P Romsi
- Department of Vascular Surgery, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
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12
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Sheets K, Overbey J, Ksajikian A, Bovid K, Kenter K, Li Y. The pathophysiology and treatment of musculoskeletal fibrosis. J Cell Biochem 2022; 123:843-851. [DOI: 10.1002/jcb.30217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/20/2021] [Accepted: 01/07/2022] [Indexed: 12/19/2022]
Affiliation(s)
- Kelsey Sheets
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Juliana Overbey
- BioMedical Engineering, Department of Orthopaedic Surgery, WMed, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Andre Ksajikian
- BioMedical Engineering, Department of Orthopaedic Surgery, WMed, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Karen Bovid
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Keith Kenter
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Yong Li
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
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13
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Kubo Y, Ikeya M, Sugiyama S, Takachu R, Tanaka M, Sugiura T, Kobori K, Kobori M. Association between Preoperative Long-Chain Polyunsaturated Fatty Acids and Oxidative Stress Immediately after Total Knee Arthroplasty: A Pilot Study. Nutrients 2021; 13:nu13062093. [PMID: 34205251 PMCID: PMC8235381 DOI: 10.3390/nu13062093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/16/2022] Open
Abstract
Quadriceps muscle atrophy following total knee arthroplasty (TKA) can be caused by tourniquet-induced ischemia–reperfusion (IR) injury, which is often accompanied by oxidative stress and inflammatory responses. n-3 long-chain polyunsaturated fatty acids (LCPUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert antioxidant and anti-inflammatory effects against IR injury, whereas n-6 LCPUFAs, particularly arachidonic acid (AA), exhibit pro-inflammatory effects and promote IR injury. This study aimed to examine whether preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio are associated with oxidative stress immediately after TKA. Fourteen eligible patients with knee osteoarthritis scheduled for unilateral TKA participated in this study. The levels of serum EPA, DHA, and AA were measured immediately before surgery. Derivatives of reactive oxygen metabolites (d-ROMs) were used as biomarkers for oxidative stress. The preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio were found to be significantly negatively correlated with the serum d-ROM levels at 96 h after surgery, and the rate of increase in serum d-ROM levels between baseline and 96 h postoperatively. This study suggested the preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio can be negatively associated with oxidative stress immediately after TKA.
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Affiliation(s)
- Yusuke Kubo
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
- Correspondence:
| | - Masae Ikeya
- Department of Health and Nutrition Sciences, Tokoha University, 1230, Miyakodachou, Kita-ku, Hamamatsu 431-2102, Japan;
| | - Shuhei Sugiyama
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
| | - Rie Takachu
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
| | - Maki Tanaka
- Rehabilitation Sciences, Seirei Christopher University, 3453 Mikataharachou, Kita-ku, Hamamatsu 433-8558, Japan;
| | - Takeshi Sugiura
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
| | - Kaori Kobori
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
| | - Makoto Kobori
- Department of Rehabilitation, Kobori Orthopedic Clinic, 548-2 Nearaichou, Kita-ku, Hamamatsu 433-8108, Japan; (S.S.); (R.T.); (T.S.); (K.K.); (M.K.)
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14
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Wallner C, Drysch M, Becerikli M, Schmidt SV, Hahn S, Wagner JM, Reinkemeier F, Dadras M, Sogorski A, von Glinski M, Lehnhardt M, Behr B. Deficiency of myostatin protects skeletal muscle cells from ischemia reperfusion injury. Sci Rep 2021; 11:12572. [PMID: 34131275 PMCID: PMC8206371 DOI: 10.1038/s41598-021-92159-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/26/2021] [Indexed: 02/05/2023] Open
Abstract
Ischemia reperfusion (IR) injury plays a pivotal role in many diseases and leads to collateral damage during surgical interventions. While most studies focus on alleviating its severity in the context of brain, liver, kidney, and cardiac tissue, research as regards to skeletal muscle has not been conducted to the same extent. In the past, myostatin (MSTN), primarily known for supressing muscle growth, has been implicated in inflammatory circuits, and research provided promising results for cardiac IR injury mitigation by inhibiting MSTN cell surface receptor ACVR2B. This generated the question if interrupting MSTN signaling could temper IR injury in skeletal muscle. Examining human specimens from free myocutaneous flap transfer demonstrated increased MSTN signaling and tissue damage in terms of apoptotic activity, cell death, tissue edema, and lipid peroxidation. In subsequent in vivo MstnLn/Ln IR injury models, we identified potential mechanisms linking MSTN deficiency to protective effects, among others, inhibition of p38 MAPK signaling and SERCA2a modulation. Furthermore, transcriptional profiling revealed a putative involvement of NK cells. Collectively, this work establishes a protective role of MSTN deficiency in skeletal muscle IR injury.
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Affiliation(s)
- Christoph Wallner
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Marius Drysch
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Mustafa Becerikli
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Sonja Verena Schmidt
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Stephan Hahn
- grid.5570.70000 0004 0490 981XDepartment of Molecular Gastrointestinal Oncology, Ruhr University Bochum, Universitätsstraße 150, 44780 Bochum, Germany
| | - Johannes Maximilian Wagner
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Felix Reinkemeier
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Mehran Dadras
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Alexander Sogorski
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Maxi von Glinski
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Marcus Lehnhardt
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Björn Behr
- grid.412471.50000 0004 0551 2937Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
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15
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Carleton MM, Sefton MV. Promoting endogenous repair of skeletal muscle using regenerative biomaterials. J Biomed Mater Res A 2021; 109:2720-2739. [PMID: 34041836 DOI: 10.1002/jbm.a.37239] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 02/06/2023]
Abstract
Skeletal muscles normally have a remarkable ability to repair themselves; however, large muscle injuries and several myopathies diminish this ability leading to permanent loss of function. No clinical therapy yet exists that reliably restores muscle integrity and function following severe injury. Consequently, numerous tissue engineering techniques, both acellular and with cells, are being investigated to enhance muscle regeneration. Biomaterials are an essential part of these techniques as they can present physical and biochemical signals that augment the repair process. Successful tissue engineering strategies require regenerative biomaterials that either actively promote endogenous muscle repair or create an environment supportive of regeneration. This review will discuss several acellular biomaterial strategies for skeletal muscle regeneration with a focus on those under investigation in vivo. This includes materials that release bioactive molecules, biomimetic materials and immunomodulatory materials.
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Affiliation(s)
- Miranda M Carleton
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Michael V Sefton
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.,Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
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16
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Liu Y, Wang M, Wang D, Fay WP, Korthuis RJ, Sowa G. Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1. Am J Physiol Heart Circ Physiol 2021; 320:H1185-H1198. [PMID: 33416452 PMCID: PMC8362680 DOI: 10.1152/ajpheart.00682.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 01/13/2023]
Abstract
Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2-deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2-deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2-deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.NEW & NOTEWORTHY The role of caveolin-2 in regulating ischemia/reperfusion (I/R) tissue injury and the mechanisms underlying its effects are unknown. This study uses caveolin-2-deficient mouse and small intestinal I/R injury models to examine the role of caveolin-2 in the leukocyte-dependent reperfusion injury. We demonstrate for the first time that caveolin-2 plays a protective role from the I/R-induced leukocyte-dependent reperfusion injury by reducing PAI-1 protein levels in intestinal tissue and leukocyte-endothelial adhesive interactions in postcapillary venules.
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Affiliation(s)
- Yajun Liu
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Meifang Wang
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Derek Wang
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - William P Fay
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- Department of Medicine, University of Missouri, Columbia, Missouri
| | - Ronald J Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- The Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Grzegorz Sowa
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
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17
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Gong C, Zhou X, Lai S, Wang L, Liu J. Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8838524. [PMID: 33299883 PMCID: PMC7710414 DOI: 10.1155/2020/8838524] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/30/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Ischemia-reperfusion injury (IRI) elicits tissue injury involved in a wide range of pathologies. Multiple studies have demonstrated that noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), participate in the pathological development of IRI, and they may act as biomarkers, therapeutic targets, or prognostic indicators. Nonetheless, the specific molecular mechanisms of ncRNAs in IRI have not been completely elucidated. Regulatory networks among lncRNAs/circRNAs, miRNAs, and mRNAs have been the focus of attention in recent years. Studies on the underlying molecular mechanisms have contributed to the discovery of therapeutic targets or strategies in IRI. In this review, we comprehensively summarize the current research on the lncRNA/circRNA-miRNA-mRNA axes and highlight the important role of these axes in IRI.
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Affiliation(s)
- Chengwu Gong
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xueliang Zhou
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Songqing Lai
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Lijun Wang
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Jichun Liu
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
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18
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Mechanisms underlying performance impairments following prolonged static stretching without a comprehensive warm-up. Eur J Appl Physiol 2020; 121:67-94. [PMID: 33175242 DOI: 10.1007/s00421-020-04538-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/21/2020] [Indexed: 01/28/2023]
Abstract
Whereas a variety of pre-exercise activities have been incorporated as part of a "warm-up" prior to work, combat, and athletic activities for millennia, the inclusion of static stretching (SS) within a warm-up has lost favor in the last 25 years. Research emphasized the possibility of SS-induced impairments in subsequent performance following prolonged stretching without proper dynamic warm-up activities. Proposed mechanisms underlying stretch-induced deficits include both neural (i.e., decreased voluntary activation, persistent inward current effects on motoneuron excitability) and morphological (i.e., changes in the force-length relationship, decreased Ca2+ sensitivity, alterations in parallel elastic component) factors. Psychological influences such as a mental energy deficit and nocebo effects could also adversely affect performance. However, significant practical limitations exist within published studies, e.g., long-stretching durations, stretching exercises with little task specificity, lack of warm-up before/after stretching, testing performed immediately after stretch completion, and risk of investigator and participant bias. Recent research indicates that appropriate durations of static stretching performed within a full warm-up (i.e., aerobic activities before and task-specific dynamic stretching and intense physical activities after SS) have trivial effects on subsequent performance with some evidence of improved force output at longer muscle lengths. For conditions in which muscular force production is compromised by stretching, knowledge of the underlying mechanisms would aid development of mitigation strategies. However, these mechanisms are yet to be perfectly defined. More information is needed to better understand both the warm-up components and mechanisms that contribute to performance enhancements or impairments when SS is incorporated within a pre-activity warm-up.
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19
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Rytter N, Carter H, Piil P, Sørensen H, Ehlers T, Holmegaard F, Tuxen C, Jones H, Thijssen D, Gliemann L, Hellsten Y. Ischemic Preconditioning Improves Microvascular Endothelial Function in Remote Vasculature by Enhanced Prostacyclin Production. J Am Heart Assoc 2020; 9:e016017. [PMID: 32750305 PMCID: PMC7792245 DOI: 10.1161/jaha.120.016017] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects. METHODS AND RESULTS A total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand-grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (P<0.05) the remote vasodilator response to intra-arterial acetylcholine in the leg at 5 and 90 minutes after application. The enhanced response was associated with a 6-fold increase (P<0.05) in femoral venous plasma prostacyclin levels and with a transient increase (P<0.05) in arterial plasma levels of brain-derived neurotrophic factor and vascular endothelial growth factor. In contrast, hand-grip exercise did not influence remote microvascular function. CONCLUSIONS These findings demonstrate that ischemic preconditioning of the forearm improves remote microvascular endothelial function and suggest that one of the underlying mechanisms is a humoral-mediated potentiation of prostacyclin formation.
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Affiliation(s)
- Nicolai Rytter
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Howard Carter
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Peter Piil
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Henrik Sørensen
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark.,Department of Anesthesia Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen Denmark
| | - Thomas Ehlers
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Frederik Holmegaard
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Christoffer Tuxen
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Helen Jones
- Research Institute for Sport and Exercise Sciences Liverpool John Moores University Liverpool United Kingdom
| | - Dick Thijssen
- Research Institute for Sport and Exercise Sciences Liverpool John Moores University Liverpool United Kingdom.,Department of Physiology Radboud Institute for Health Sciences Nijmegen The Netherlands
| | - Lasse Gliemann
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
| | - Ylva Hellsten
- Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark
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Van Damme N, Van Hecke A, Remue E, Van den Bussche K, Moore Z, Gefen A, Verhaeghe S, Beeckman D. Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review. Wound Repair Regen 2020; 28:242-265. [PMID: 31677314 DOI: 10.1111/wrr.12777] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 09/23/2019] [Accepted: 10/23/2019] [Indexed: 12/13/2022]
Abstract
Deep tissue injuries are pressure ulcers which initiate in the subcutaneous tissues and extend through a bottom-up pathway. Once deep tissue injuries are visual at skin level, serious irreversible tissue damage has already occurred. In pressure ulcer development, inflammation and edema are coupled physiological processes associated with tissue damage arising due to sustained mechanical loading. This study aimed to provide an in-depth overview of the physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues, in the context of pressure ulceration. A scoping review was performed according to the framework by Arksey and O'Malley. The databases MEDLINE, EMBASE, Web of Science, and Scopus, and the reference lists of included studies were searched for in vivo (animal, human), and in vitro studies matching the study objectives (from inception to 28 May 2018). No restrictions for inclusion were applied for study design, setting, participants, and year of publication. A total of 12 studies were included, varying in study design, sample characteristics, amount and duration of mechanical loads that were applied, follow-up time, and assessment methods. Neutrophil infiltration and edema occur in the subcutaneous tissues nearly immediately after the application of load on soft tissues. The amount of neutrophils and edema increase in the first days after the mechanical insult and decrease once healing has been initiated and no supplementary mechanical load was applied. One study indicated that edema may extend up to the level of the dermo-epidermal junction. Further research should focus on how deep tissue inflammation and edema are reflected into unique tissue changes at skin level, and how abnormal inflammatory responses manifest (e.g. when the nervous system is not functioning normally).
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Affiliation(s)
- Nele Van Damme
- Skin Integrity Research Group (SKINT), University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
| | - Ann Van Hecke
- University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
| | - Eline Remue
- University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
- Nursing department, Ghent University Hospital, Ghent, Belgium
| | - Karen Van den Bussche
- Skin Integrity Research Group (SKINT), University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
| | - Zena Moore
- Skin Integrity Research Group (SKINT), University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
- School of Nursing & Midwifery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | - Amit Gefen
- Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel
| | - Sofie Verhaeghe
- University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
- Department of Health Care, VIVES University of Applied Sciences, Roeselare, Belgium
| | - Dimitri Beeckman
- Skin Integrity Research Group (SKINT), University Centre for Nursing and Midwifery, Department of Public Health, Ghent University, Ghent, Belgium
- School of Nursing & Midwifery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
- School of Health Sciences, Örebro University, Örebro, Sweden
- Research Unit of Plastic Surgery, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- School of Nursing and Midwifery, Monash University, Melbourne, Australia
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21
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Loyd BJ, Burrows K, Forster JE, Stackhouse SK, Hogan C, Stevens-Lapsley JE. Reliability and precision of single frequency bioelectrical impedance assessment of lower extremity swelling following total knee arthroplasty. Physiother Theory Pract 2019; 37:197-203. [PMID: 31140887 DOI: 10.1080/09593985.2019.1619886] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Total knee arthroplasty (TKA) is the most common elective orthopedic surgery performed in the United States. Following surgery patients experience significant lower extremity swelling that is related to poor satisfaction with surgery and is hypothesized to contribute to functional decline. However, in practice, precise and reliable methods for measuring lower extremity swelling do not exist. The purpose of this study was to provide reliability and precision parameters of an innovative approach, single frequency bioelectrical impedance assessment (SF-BIA), for measuring post-TKA lower extremity swelling. Swelling in 56 patients (64.3 ± 9.3 years; 29 males) was measured before and after TKA using SF-BIA and circumferential measures (CM). Reliability of the measures was calculated using Intraclass Correlation Coefficients (ICC). Precision of the measures was provided using standard error of the measurement and minimal detectable change (MDC90). Change values between time points for SF-BIA and CM are provided. SF-BIA was found to have greater reliability following surgery compared to CM (ICC = 0.99 vs 0.68). SF-BIA was found to have an MDC90 = 2% following surgery, indicating improved ability to detect minute fluctuations in swelling compared to CM (MDC90 = 6%) following surgery. These results indicate that SF-BIA improves the precision and reliability of swelling measurement compared to CM.
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Affiliation(s)
- Brian J Loyd
- Physical Therapy Program, Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
| | - Kristine Burrows
- Physical Therapy Program, Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
| | - Jeri E Forster
- Physical Therapy Program, Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
| | - Scott K Stackhouse
- Department of Physical Therapy, University of New England , Portland, ME, USA
| | - Craig Hogan
- Department of Orthopedic Surgery, University of Colorado Hospital , Aurora, CO, USA
| | - Jennifer E Stevens-Lapsley
- Physical Therapy Program, Department of Physical Medicine and Rehabilitation, University of Colorado Anschutz Medical Campus , Aurora, CO, USA.,Eastern Colorado Geriatric Research Education and Clinical Center , Aurora, CO, USA
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22
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Compartment syndrome-induced muscle injury is diminished by the neutralization of pro-inflammatory cytokines. OTA Int 2018; 1:e011. [PMID: 33937648 PMCID: PMC7953480 DOI: 10.1097/oi9.0000000000000011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 11/26/2022]
Abstract
Objectives: Compartment syndrome (CS) is one of the most devastating consequences of musculoskeletal trauma. The pathophysiology of CS includes elevation of intracompartmental pressure (ICP), causing damage to the microcirculation, decreased oxygen delivery, tissue anoxia, and cell death. CS is a combined ischemic and inflammatory condition that induces the systemic inflammatory cascade. In complete ischemia, within the first hour of reperfusion, a peak in the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) has been previously reported. The purpose of this study was to examine the suspected systemic inflammatory cytokine/chemokine release in response to CS, and to evaluate the microvascular dysfunction, tissue injury, and inflammatory response following the neutralization of pro-inflammatory cytokines TNF-α and/or interleukin-1 beta (IL-1β). Methods: Twenty-eight male Wistar rats were randomly assigned into 5 groups: Sham (no CS), CS (with isotype control), CS+TNF-α neutralizing antibody (NA), CS+IL-1β NA, CS+Combo (both TNF-α and IL-1β NA). CS was induced by elevation of ICP above 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours; NA were administered just prior to fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy for 45 minutes after fasciotomy. Systemic levels of 24 different cytokines/chemokines were also measured, using the xMAP Luminex technology. Results: Of the 24 cytokines/chemokines sampled, 6 were significantly elevated from their baseline levels, and included the pro-inflammatory cytokines TNF-α, IL-1β, growth-related oncogene/keratinocyte chemoattractant (GRO/KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1α), and the anti-inflammatory cytokine IL-10. CS resulted in a significant decrease in microvascular perfusion, from 75 ± 2% continuously perfused capillaries in the sham to 31 ± 4% in CS (P < .001), a significant increase in tissue injury (0.33 ± 0.4 versus 0.04 ± 0.01 in sham) and leukocyte activation (14 ± 2 adherent leukocytes/1000 μm2 versus 2 ± 1 adherent leukocytes/100 μm2 in sham, P < .001). CS-associated tissue injury was significantly decreased with TNF-α neutralization (P < .05), both when administered alone or in combination with IL-1β (P < .05). Additionally, TNF-α neutralization blocked CS-associated leukocyte activation (P < .05); IL-1β neutralization also diminished leukocyte adhesion (P < .05). Perfusion remained virtually unchanged in CS animals treated with NA (36 ± 4%, 32 ± 3% and 30 ± 2% in CS+TNF-α, CS+IL-1β and CS+Combo groups, respectively). Conclusion: The results of this study indicate that CS induces a systemic inflammation, as evidenced by upregulation of inflammatory cytokines/chemokines in circulation. Neutralization of TNF-α led to a significant reduction in tissue injury; however, it had no effect on the CS-induced microvascular dysfunction. This suggests a distinct role of TNF-α in the pathophysiology of muscle injury in CS.
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23
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Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res 2018; 64:1-55. [PMID: 29229445 PMCID: PMC6404988 DOI: 10.1016/j.preteyeres.2017.11.003] [Citation(s) in RCA: 1111] [Impact Index Per Article: 158.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 11/20/2017] [Accepted: 11/22/2017] [Indexed: 02/07/2023]
Abstract
Optical coherence tomography (OCT) was one of the biggest advances in ophthalmic imaging. Building on that platform, OCT angiography (OCTA) provides depth resolved images of blood flow in the retina and choroid with levels of detail far exceeding that obtained with older forms of imaging. This new modality is challenging because of the need for new equipment and processing techniques, current limitations of imaging capability, and rapid advancements in both imaging and in our understanding of the imaging and applicable pathophysiology of the retina and choroid. These factors lead to a steep learning curve, even for those with a working understanding dye-based ocular angiography. All for a method of imaging that is a little more than 10 years old. This review begins with a historical account of the development of OCTA, and the methods used in OCTA, including signal processing, image generation, and display techniques. This forms the basis to understand what OCTA images show as well as how image artifacts arise. The anatomy and imaging of specific vascular layers of the eye are reviewed. The integration of OCTA in multimodal imaging in the evaluation of retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, and disorders of the optic nerve is presented. OCTA is an exciting, disruptive technology. Its use is rapidly expanding in clinical practice as well as for research into the pathophysiology of diseases of the posterior pole.
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Affiliation(s)
- Richard F Spaide
- Vitreous, Retina, Macula Consultants of New York, New York, NY, United States.
| | - James G Fujimoto
- Department of Electrical Engineering & Computer Science and Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge MA, United States
| | - Nadia K Waheed
- The Department of Ophthalmology, Tufts University School of Medicine, Boston MA, United States
| | - Srinivas R Sadda
- Doheny Eye Institute, University of California - Los Angeles, Los Angeles, CA, United States
| | - Giovanni Staurenghi
- Eye Clinic, Department of Biomedical and Clinical Sciences "Luigi Sacco", Luigi Sacco Hospital, University of Milan, Milan, Italy
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24
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Mandel ER, Dunford EC, Abdifarkosh G, Turnbull PC, Perry CGR, Riddell MC, Haas TL. The superoxide dismutase mimetic tempol does not alleviate glucocorticoid-mediated rarefaction of rat skeletal muscle capillaries. Physiol Rep 2018; 5:e13243. [PMID: 28533261 PMCID: PMC5449555 DOI: 10.14814/phy2.13243] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 03/13/2017] [Accepted: 03/16/2017] [Indexed: 12/17/2022] Open
Abstract
Sustained elevations in circulating glucocorticoids elicit reductions in skeletal muscle microvascular content, but little is known of the underlying mechanisms. We hypothesized that glucocorticoid‐induced oxidative stress contributes to this phenomenon. In rats that were implanted with corticosterone (CORT) or control pellets, CORT caused a significant decrease in muscle glutathione levels and a corresponding increase in protein carbonylation, an irreversible oxidative modification of proteins. Decreased endothelial nitric oxide synthase and increased endothelin‐1 mRNA levels were detected after 9 days of CORT, and blood flow to glycolytic muscles was diminished. Control and CORT rats were treated concurrently with drinking water containing the superoxide dismutase mimetic tempol (172 mg/L) or the α‐1 adrenergic receptor antagonist prazosin (50 mg/L) for 6 or 16 days. Both tempol and prazosin alleviated skeletal muscle protein carbonylation. Tempol failed to prevent CORT‐mediated capillary rarefaction and was ineffective in restoring skeletal muscle blood flow. In contrast, prazosin blocked capillary rarefaction and restored skeletal muscle blood flow to control levels. The failure of tempol to prevent CORT‐induced skeletal muscle microvascular rarefaction does not support a dominant role of superoxide‐induced oxidative stress in this process. Although a decrease in protein carbonylation was observed with prazosin treatment, our data suggest that the maintenance of skeletal muscle microvascular content is related more closely with counteracting the CORT‐mediated influence on skeletal muscle vascular tone.
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Affiliation(s)
- Erin R Mandel
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Emily C Dunford
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Ghoncheh Abdifarkosh
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Patrick C Turnbull
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Christopher G R Perry
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Michael C Riddell
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Tara L Haas
- School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada
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25
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Zhou T, Prather ER, Garrison DE, Zuo L. Interplay between ROS and Antioxidants during Ischemia-Reperfusion Injuries in Cardiac and Skeletal Muscle. Int J Mol Sci 2018; 19:ijms19020417. [PMID: 29385043 PMCID: PMC5855639 DOI: 10.3390/ijms19020417] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 01/14/2018] [Accepted: 01/21/2018] [Indexed: 12/16/2022] Open
Abstract
Ischemia reperfusion (IR), present in myocardial infarction or extremity injuries, is a major clinical issue and leads to substantial tissue damage. Molecular mechanisms underlying IR injury in striated muscles involve the production of reactive oxygen species (ROS). Excessive ROS accumulation results in cellular oxidative stress, mitochondrial dysfunction, and initiation of cell death by activation of the mitochondrial permeability transition pore. Elevated ROS levels can also decrease myofibrillar Ca2+ sensitivity, thereby compromising muscle contractile function. Low levels of ROS can act as signaling molecules involved in the protective pathways of ischemic preconditioning (IPC). By scavenging ROS, antioxidant therapies aim to prevent IR injuries with positive treatment outcomes. Novel therapies such as postconditioning and pharmacological interventions that target IPC pathways hold great potential in attenuating IR injuries. Factors such as aging and diabetes could have a significant impact on the severity of IR injuries. The current paper aims to provide a comprehensive review on the multifaceted roles of ROS in IR injuries, with a focus on cardiac and skeletal muscle, as well as recent advancement in ROS-related therapies.
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Affiliation(s)
- Tingyang Zhou
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
- Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
| | - Evan R Prather
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
| | - Davis E Garrison
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
| | - Li Zuo
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
- Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
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26
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MICROVASCULAR FLOW ABNORMALITIES ASSOCIATED WITH RETINAL VASCULITIS: A Potential of Mechanism of Retinal Injury. Retina 2018; 37:1034-1042. [PMID: 27759582 DOI: 10.1097/iae.0000000000001359] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
PURPOSE To investigate the structural optical coherence tomography and related microvascular flow characteristics in eyes with retinal vasculitis. METHODS Regions involved with perivascular infiltration in eyes with retinal vasculitis, but no evidence of large vessel occlusion were evaluated with optical coherence tomography (OCT), OCT angiography, and fluorescein angiography. RESULTS Ten eyes of 5 patients with a variety of etiologies of retinal vasculitis were evaluated. These patients did not have either cotton wool spots or deeper placoid areas of retinal ischemia. Around large vessels there was perivascular infiltration with leakage and staining seen during fluorescein angiography. Structural OCT showed slight thickening with loss of visualization of normal retinal laminations. OCT angiography showed a lack of flow signal in capillary sized vessels in the same areas. Treatment resulted in a rapid thinning of the affected areas, with the inner and middle layers of the retina becoming thinner than surrounding uninvolved areas. OCT angiography did not show a return of capillary perfusion in these regions. The thickness change in the structural OCT as shown by a heat map had a pattern mimicking the original perivascular infiltration around large retinal vessels. CONCLUSION Capillary level perfusion abnormalities can develop in regions adjacent to large vessel inflammatory infiltrate that result in retinal thinning without the development of usual stigmata of acute microvascular flow obstruction such as cotton wool spots. This suggests that retinal damage may occur in retinal vasculitis that would not be recognized without using OCT-based imaging modalities.
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27
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Bihari A, Cepinskas G, Forbes TL, Potter RF, Lawendy AR. Systemic application of carbon monoxide-releasing molecule 3 protects skeletal muscle from ischemia-reperfusion injury. J Vasc Surg 2017; 66:1864-1871. [DOI: 10.1016/j.jvs.2016.11.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 11/30/2016] [Indexed: 11/28/2022]
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28
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Lee CM, Peng HH, Yang P, Liou JT, Liao CC, Day YJ. C-C Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury. Sci Rep 2017. [PMID: 28623253 PMCID: PMC5473895 DOI: 10.1038/s41598-017-03956-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5-aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI.
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Affiliation(s)
- Chiou-Mei Lee
- Laboratory Animal Center, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Hsin-Hsin Peng
- Center for Molecular and Clinical Immunology, Chang Gung University, Chang Gung, Taiwan.,Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Polung Yang
- Molecular Medicine Research Center, Chang Gung University, Chang Gung, Taiwan
| | - Jiin-Tarng Liou
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chia-Chih Liao
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Yuan-Ji Day
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan. .,Department of Anesthesiology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
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29
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Effects of Postconditioning on Skeletal Muscle Injury and Apoptosis Induced by Partial Ischemia and Reperfusion in Rats. Ann Vasc Surg 2017; 40:285-293. [DOI: 10.1016/j.avsg.2016.10.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/09/2016] [Accepted: 10/17/2016] [Indexed: 11/18/2022]
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30
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Delay C, Paradis S, Charles AL, Thaveau F, Chenesseau B, Zoll J, Chakfe N, Geny B, Lejay A. [Skeletal muscle ischemia-reperfusion and ischemic conditioning pathophysiology-clinical applications for the vascular surgeon]. JOURNAL DE MEDECINE VASCULAIRE 2017; 42:29-38. [PMID: 27989659 DOI: 10.1016/j.jmv.2016.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/15/2016] [Indexed: 06/06/2023]
Abstract
Ischemia-reperfusion, which is characterized by deficient oxygen supply and subsequent restoration of blood flow, can cause irreversible damage to tissue. The vascular surgeon is daily faced with ischemia-reperfusion situations. Indeed, arterial clamping induces ischemia, followed by reperfusion when declamping. Mechanisms underlying ischemia-reperfusion injury are complex and multifactorial. Increases in cellular calcium and reactive oxygen species, initiated during ischemia and then amplified upon reperfusion are thought to be the main mediators of reperfusion injury. Mitochondrial dysfunction also plays an important role. Extensive research has focused on increasing skeletal muscle tolerance to ischemia-reperfusion injury, especially through the use of ischemic conditioning strategies. The purpose of this review is to focus on the cellular responses associated with ischemia-reperfusion, as well as to discuss the effects of ischemic conditioning strategies. This would help the vascular surgeon in daily practice, in order to try to improve surgical outcome in the setting of ischemia-reperfusion.
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Affiliation(s)
- C Delay
- Service de chirurgie vasculaire et transplantation rénale, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg, France
| | - S Paradis
- Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France
| | - A L Charles
- Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France
| | - F Thaveau
- Service de chirurgie vasculaire et transplantation rénale, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg, France
| | - B Chenesseau
- Service de chirurgie vasculaire et transplantation rénale, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg, France
| | - J Zoll
- Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France
| | - N Chakfe
- Service de chirurgie vasculaire et transplantation rénale, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg, France; Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France
| | - B Geny
- Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France
| | - A Lejay
- Service de chirurgie vasculaire et transplantation rénale, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg, France; Unité EA 3072 « Mitochondries, stress oxydant et protection musculaire », université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France.
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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32
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Omer K, Nermin G, Ali A, Mehmet A, Unal D, Sezen KS, Hakan K. [Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine]. Rev Bras Anestesiol 2016; 67:246-250. [PMID: 27842707 DOI: 10.1016/j.bjan.2016.10.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 09/30/2015] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anesthesia on tourniquet-induced ischemia-reperfusion injury. METHODS 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2mg.kg-1 followed by infusion at a rate of 2mg.kg-1.h-1. In the ketamine group, a continuous infusion of ketamine 0.5mg.kg-1.h-1 was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1), at 30minutes (min) of tourniquet ischemia (T2), and 5min after tourniquet deflation (T3) for malondialdehyde (MDA) measurements. RESULTS No differences were noted between the groups in hemodynamic (p>0.05) and demographic data (p>0.05). There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p>0.05). There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95±0.59, 2.31±0.48) and pre-ischemia (1.41±0.38, 1.54±0.45), and ischemia (1.76±0.70, 1.71±0.38) (μmoL-1) periods (p<0.05). CONCLUSIONS Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anesthesia.
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Affiliation(s)
- Karaca Omer
- Ordu State Hospital, Department of Anesthesiology and Reanimation, Ordu, Turquia
| | - Gogus Nermin
- Hitit University School of Medicine, Department of Anesthesiology and Reanimation, Çorum, Turquia
| | - Ahiskalioglu Ali
- Ataturk University School of Medicine, Department of Anesthesiology and Reanimation, Erzurum, Turquia.
| | - Aksoy Mehmet
- Ataturk University School of Medicine, Department of Anesthesiology and Reanimation, Erzurum, Turquia
| | - Dogus Unal
- Ordu State Hospital, Department of Anesthesiology and Reanimation, Ordu, Turquia
| | - Kumas Solak Sezen
- Ordu State Hospital, Department of Anesthesiology and Reanimation, Ordu, Turquia
| | - Kalafat Hakan
- Ordu State Hospital, Department of Biochemistry, Ordu, Turquia
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Rizo-Roca D, Ríos-Kristjánsson JG, Núñez-Espinosa C, Santos-Alves E, Gonçalves IO, Magalhães J, Ascensão A, Pagès T, Viscor G, Torrella JR. Intermittent hypobaric hypoxia combined with aerobic exercise improves muscle morphofunctional recovery after eccentric exercise to exhaustion in trained rats. J Appl Physiol (1985) 2016; 122:580-592. [PMID: 27765844 DOI: 10.1152/japplphysiol.00501.2016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/27/2016] [Accepted: 10/13/2016] [Indexed: 01/07/2023] Open
Abstract
Unaccustomed eccentric exercise leads to muscle morphological and functional alterations, including microvasculature damage, the repair of which is modulated by hypoxia. We present the effects of intermittent hypobaric hypoxia and exercise on recovery from eccentric exercise-induced muscle damage (EEIMD). Soleus muscles from trained rats were excised before (CTRL) and 1, 3, 7, and 14 days after a double session of EEIMD protocol. A recovery treatment consisting of one of the following protocols was applied 1 day after the EEIMD: passive normobaric recovery (PNR), a 4-h daily exposure to passive hypobaric hypoxia at 4,000 m (PHR), or hypobaric hypoxia exposure followed by aerobic exercise (AHR). EEIMD produced an increase in the percentage of abnormal fibers compared with CTRL, and it affected the microvasculature by decreasing capillary density (CD, capillaries per mm2) and the capillary-to-fiber ratio (CF). After 14 days, AHR exhibited CD and CF values similar to those of CTRL animals (789 and 3.30 vs. 746 and 3.06) and significantly higher than PNR (575 and 2.62) and PHR (630 and 2.92). Furthermore, VEGF expression showed a significant 43% increase in AHR when compared with PNR. Moreover, after 14 days, the muscle fibers in AHR had a more oxidative phenotype than the other groups, with significantly smaller cross-sectional areas (AHR, 3,745; PNR, 4,502; and PHR, 4,790 µm2), higher citrate synthase activity (AHR, 14.8; PNR, 13.1; and PHR, 12 µmol·min-1·mg-1) and a significant 27% increment in PGC-1α levels compared with PNR. Our data show that hypoxia combined with exercise attenuates or reverses the morphofunctional alterations induced by EEIMD.NEW & NOTEWORTHY Our study provides new insights into the use of intermittent hypobaric hypoxia combined with exercise as a strategy to recover muscle damage induced by eccentric exercise. We analyzed the effects of hypobaric exposure combined with aerobic exercise on histopathological features of muscle damage, fiber morphofunctionality, capillarization, angiogenesis, and the oxidative capacity of damaged soleus muscle. Most of these parameters were improved after a 2-wk protocol of intermittent hypobaric hypoxia combined with aerobic exercise.
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Affiliation(s)
- D Rizo-Roca
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
| | - J G Ríos-Kristjánsson
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
| | - C Núñez-Espinosa
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
| | - E Santos-Alves
- Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal
| | - I O Gonçalves
- Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal
| | - J Magalhães
- Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal
| | - A Ascensão
- Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal
| | - T Pagès
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
| | - G Viscor
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
| | - J R Torrella
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; and
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Lawendy AR, Bihari A, Sanders DW, Badhwar A, Cepinskas G. Compartment syndrome causes systemic inflammation in a rat. Bone Joint J 2016; 98-B:1132-7. [DOI: 10.1302/0301-620x.98b8.36325] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 04/07/2016] [Indexed: 01/13/2023]
Abstract
Aims Compartment syndrome results from increased intra-compartmental pressure (ICP) causing local tissue ischaemia and cell death, but the systemic effects are not well described. We hypothesised that compartment syndrome would have a profound effect not only on the affected limb, but also on remote organs. Methods Using a rat model of compartment syndrome, its systemic effects on the viability of hepatocytes and on inflammation and circulation were directly visualised using intravital video microscopy. Results We found that hepatocellular injury was significantly higher in the compartment syndrome group (192 PI-labelled cells/10-1 mm3, standard error of the mean (sem) 51) compared with controls (30 PI-labelled cells/10-1 mm3, sem 12, p < 0.01). The number of adherent venular white blood cells was significantly higher for the compartment syndrome group (5 leukocytes/30s/10 000 μm2, sem 1) than controls (0.2 leukocytes/30 s/10 000 μm2, sem 0.2, p < 0.01). Volumetric blood flow was not significantly different between the two groups, although there was an increase in the heterogeneity of perfusion. Conclusions Compartment syndrome can be accompanied by severe systemic inflammation and end organ damage. This study provides evidence of the relationship between compartment syndrome in a limb and systemic inflammation and dysfunction in a remote organ. Cite this article: Bone Joint J 2016; 98-B:1132–7.
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Affiliation(s)
- A-R. Lawendy
- Victoria Hospital, London
Health Sciences Centre, 800 Commissioners Road
East London, Ontario, N6A
4G5, Canada
| | - A. Bihari
- Victoria Hospital, London
Health Sciences Centre, 800 Commissioners Road
East London, Ontario, N6A
4G5, Canada
| | - D. W. Sanders
- Victoria Hospital, London
Health Sciences Centre, 800 Commissioners Road
East London, Ontario, N6A
4G5, Canada
| | - A. Badhwar
- Davol, A Bard Company, Warwick, Rhode
Island, USA
| | - G. Cepinskas
- Victoria Hospital, London
Health Sciences Centre, 800 Commissioners Road
East London, Ontario, N6A
4G5, Canada
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Jennings CL, Dziubla TD, Puleo DA. Combined Effects of Drugs and Plasticizers on the Properties of Drug Delivery Films. J BIOACT COMPAT POL 2016; 31:323-333. [PMID: 27821905 DOI: 10.1177/0883911515627178] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Formation of scar tissue may be reduced or prevented if wounds were locally treated with a combination of molecules tuned to the different healing phases, guiding tissue regeneration along a scar free path. To this end, drug delivery devices made of cellulose acetate phthalate and Pluronic F-127 were loaded with either quercetin or pirfenidone and plasticized with either triethyl citrate (TEC) or tributyl citrate (TBC). Quercetin inhibits oxidative stress, and pirfenidone has been shown to reduce production of pro-inflammatory and fibrogenic molecules. The combined effects of drug and plasticizer on erosion, release, and mechanical properties of the drug delivery films were investigated. TEC-plasticized films containing quercetin released drug at a slower rate than did TBC films. Pirfenidone-loaded films released drug at a faster rate than erosion occurred for both types of plasticizers. Higher plasticizer contents of both TEC and TBC increased the elongation and decreased the elastic modulus. In contrast, increased pirfenidone loading in both TEC and TBC films resulted in a significantly higher modulus, an anti-plasticizer effect. Adding pirfenidone significantly decreased elongation for all film types, but quercetin-loaded samples had significantly greater elongation with increasing drug content. Films containing quercetin elongated more than did pirfenidone-loaded films. Quercetin is over 1.5 times larger than pirfenidone, has water solubility over 12 times lower, and has 6 times more bonding sites than pirfenidone. These differences affected how the two drugs interacted with cellulose acetate phthalate and Pluronic F-127 and thereby determined polymer properties. Drug release, erosion, and mechanical properties of association polymer films can be tailored by the characteristics of the drugs and plasticizers included in the system.
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Affiliation(s)
- Cheryl L Jennings
- Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA
| | - Thomas D Dziubla
- Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY, USA
| | - David A Puleo
- Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA
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LI YUEBING, KANG YUQING, WONG KELVINKL, GHISTA DHANJOON, GU MIAONING. INVESTIGATING EXPRESSION OF AUTOPHAGY-ASSOCIATED PROTEINS LEVEL IN RATS WITH ACUTE LUNG INJURY INDUCED BY REMOTE LIMB ISCHEMIA-REPERFUSION. J MECH MED BIOL 2016. [DOI: 10.1142/s0219519416500196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Objective: To explore the early expression of autophagy-associated proteins in lung tissues in acute lung injury (ALI) induced by remote limb ischemia-reperfusion (LIR) by using rats as our test specimens. Method: A total of 48 adult male Sprague-Dawley (SD) rats with weights in the range of 220–250[Formula: see text]g were designated as LIR models, and divided randomly into two groups of 24 each: Sham group and ischemia-reperfusion (I/R) group. Then, each group was divided into four subgroups at the end of 0, 2, 4, 8[Formula: see text]h of reperfusion, after 3[Formula: see text]h of ischemia. The rats were anesthetized by pentobarbital sodium. The serum lactate dehydrogenases (LDH) were detected with enzyme linked immunosorbent assay (ELISA), and the pathological changes of lung tissues were observed by using immunofluorescence techniques. The expression of Beclin1 protein and Atg5 mRNA in the lung tissues were detected by using reverse transcription polymerase chain reaction (RT-PCR), and analyzed by 2[Formula: see text] method; Microtubules associated protein light chain 3 (LC3) in the lung tissues were detected by Western blot test. Result: The levels of serum LDH in I/R groups were much higher than those in Sham groups ([Formula: see text]), which showed that the rats models of LIR were successful. Immunofluorescence examination demonstrated injuries of lung tissues, thickening of alveolar septum and partial consolidation in I/R groups; however, this damage was not observed significantly in Sham groups. The expression of Beclin1 and Atg5 mRNA, LC3-II and the ratio of LC3-II/GAPDH in lung tissues were very much higher at 4 and 8[Formula: see text]h in IR groups ([Formula: see text] or [Formula: see text]), and were significantly higher at the same time compared with Sham groups ([Formula: see text] or [Formula: see text]). Conclusion: LIR causes ALI to induce increased autophagy and high expression of its relevant proteins; while continuous I/R can also cause autophagy inhibition.
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Affiliation(s)
- YUEBING LI
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, P. R. China
- Southern Hospital of Southern Medical University, Guangzhou 510515, P. R. China
| | - YUQING KANG
- Southern Hospital of Southern Medical University, Guangzhou 510515, P. R. China
| | - KELVIN KL WONG
- Engineering Computational Biology, School of Computer Science and Software Engineering, The University of Western Australia, 35 Stirling Highway, Crawley WA 6000, Australia
| | - DHANJOO N. GHISTA
- Education Committee, Southern Ozarks Alliance for Rural Development, Willow Springs, MO, USA
| | - MIAONING GU
- Southern Hospital of Southern Medical University, Guangzhou 510515, P. R. China
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Mase VJ, Roe JL, Christy RJ, Dubick MA, Walters TJ. Postischemic conditioning does not reduce muscle injury after tourniquet-induced ischemia-reperfusion injury in rats. Am J Emerg Med 2016; 34:2065-2069. [PMID: 27614371 DOI: 10.1016/j.ajem.2016.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/11/2016] [Accepted: 04/13/2016] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND The widespread application of tourniquets has reduced battlefield mortality related to extremity exsanguinations. Tourniquet-induced ischemia-reperfusion injury (I/R) can contribute to muscle loss. Postischemic conditioning (PostC) confers protection against I/R in cardiac muscle and skeletal muscle flaps. The objective of this study was to determine the effect of PostC on extremity muscle viability in an established rat hindlimb tourniquet model. METHODS Rats were randomly assigned to PostC-1, PostC-2, or no conditioning ischemic groups (n = 10 per group). Postischemic conditioning, performed immediately after tourniquet release, consisted of four 15-second cycles (PostC-1) or eight 15-second cycles (PostC-2) of alternating occlusion and perfusion of hindlimbs. Twenty-four hours later, muscles were excised. The primary end points were muscle edema and viability; secondary end points were histologic and markers of oxidative stress. RESULTS Ischemia-reperfusion injury decreased viability in all tourniquet limbs, but viability was not improved in either PostC group. Likewise, I/R resulted in substantial muscle edema that was not reduced by PostC. The predominant histologic feature was necrosis, but no significant differences were found among groups. Markers of oxidative stress were increased similarly among groups after I/R, although myeloperoxidase activity was significantly increased only in the no conditioning ischemic group. A protective effect from PostC was not observed in our model suggesting that PostC was not effective in reducing I/R skeletal muscle injury or any benefits of PostC were not sustained for 24 hours when tissues were assessed. CONCLUSION These negative findings are pertinent as the military investigates different strategies to extend the safe time for tourniquet application.
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Affiliation(s)
- Vincent J Mase
- US Army Institute of Surgical Research (USAISR), Extremity Trauma Research Program, San Antonio, TX 78234-7767.
| | - Janet L Roe
- US Army Institute of Surgical Research (USAISR), Extremity Trauma Research Program, San Antonio, TX 78234-7767.
| | - Robert J Christy
- US Army Institute of Surgical Research (USAISR), Extremity Trauma Research Program, San Antonio, TX 78234-7767.
| | - Michael A Dubick
- US Army Institute of Surgical Research (USAISR), Damage Control Resuscitation Research Program, San Antonio, TX 78234-7767.
| | - Thomas J Walters
- US Army Institute of Surgical Research (USAISR), Extremity Trauma Research Program, San Antonio, TX 78234-7767.
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Paradis S, Charles AL, Meyer A, Lejay A, Scholey JW, Chakfé N, Zoll J, Geny B. Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion. Am J Physiol Cell Physiol 2016; 310:C968-82. [PMID: 27076618 DOI: 10.1152/ajpcell.00356.2015] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.
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Affiliation(s)
- Stéphanie Paradis
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France;
| | - Anne-Laure Charles
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
| | - Alain Meyer
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
| | - Anne Lejay
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France; Department of Vascular Surgery and Kidney Transplantation, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France; and
| | - James W Scholey
- Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Nabil Chakfé
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Vascular Surgery and Kidney Transplantation, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France; and
| | - Joffrey Zoll
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
| | - Bernard Geny
- University of Strasbourg, Fédération de Médecine Translationelle, EA 3072, Strasbourg, France; Department of Physiology and Functional Explorations, Thoracic Pathology Unit, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
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Ergün Y, Üremiş M, Kılınç M, Alıcı T. Antioxidant effect of Legalon(r) SIL in ischemia-reperfusion injury of rat skeletal muscle. Acta Cir Bras 2016; 31:264-70. [DOI: 10.1590/s0102-865020160040000007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 03/12/2016] [Indexed: 12/31/2022] Open
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Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice. Sci Rep 2016; 6:23261. [PMID: 26983498 PMCID: PMC4794653 DOI: 10.1038/srep23261] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 03/02/2016] [Indexed: 11/13/2022] Open
Abstract
Dysesthesia is an unpleasant abnormal sensation, which is often accompanied by peripheral neuropathy or vascular impairment. Here, we examined the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia-like behaviours elicited by transient hindlimb ischemia (15–60 min) by tightly compressing the hindlimb, and reperfusion by releasing the ligature. The paw-withdrawal responses to tactile stimulation were reduced during ischemia and lasted for a while after reperfusion. Hindlimb ischemia/reperfusion elicited spontaneous licking of the ischemic hindpaw that peaked within 10 min. The licking was inhibited by reactive oxygen species (ROS) scavengers, a TRPA1 antagonist, or TRPA1 deficiency, but not by TRPV1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion neurons, the H2O2-evoked TRPA1 response was significantly increased by pretreatment with hypoxia (80 mmHg) for 30 min. This hypoxia-induced TRPA1 sensitisation to H2O2 was inhibited by overexpressing a catalytically-inactive mutant of prolyl hydroxylase (PHD) 2 or in a TRPA1 proline mutant resistant to PHDs. Consistent with these results, a PHD inhibitor increased H2O2-evoked nocifensive behaviours through TRPA1 activation. Our results suggest that transient hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 sensitised by hypoxia through inhibiting PHD-mediated hydroxylation of a proline residue in TRPA1.
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Ozciftci S, Gamli M, Ornek D, Horasanli E, Dikmen B, Canpolat O, Ciraci MZ, Kilci O. An evaluation of the effects of perioperatively administered fluids on ischemia/reperfusion injury. Pak J Med Sci 2016; 31:1349-54. [PMID: 26870095 PMCID: PMC4744280 DOI: 10.12669/pjms.316.7630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objective: To investigate the effects of normal saline (0.9% NaCl) and 6% Hydroxyethyl Starch 130/0.4(HES) solution on Ischemia/Reperfusion (I/R) injury in patients undergoing knee arthroscopy operations with spinal anesthesia using a tourniquet. Methods: The study comprised 48 ASA I-II patients undergoing knee arthroscopy with spinal anesthesia using a tourniquet. The patients were randomised into two groups and after standard monitoring two venous lines were introduced to obtain blood samples and to give intravenous therapy. In the control group (Group A) (n=21) 0.9% NaCl, 10 ml/kg/hours and in the study group (Group B) (n=19) 6% Hydroxyethyl Starch 130/0.4, 10 ml/kg/hours infusion were administered. Spinal anesthesia was applied with 12.5 mg hyperbaric bupivacaine to all patients. The tourniquet was applied and the operation was started when the sensorial block level reached T10 dermatome. Blood xanthine oxidase (XO) and malondialdehyde (MDA) levels as an indicator of ischemia and reperfusion injury were measured in samples before fluid infusion (t1), before tourniquet application (t2), 1 minute before tourniquet release (t3), and at 5 (t4) and 15 (t5) minutes after tourniquet release. Results: No difference was observed between the two groups in respect of demographic parameters, the highest block level, duration before tourniquet application and tourniquet duration (p>0.05). The MDA level after tourniquet application and 15 minutes after tourniquet release was lower in Group B (p<0.05). XO levels were not different (p>0.05). Conclusion: In this study 6% Hydroxyethyl Starch 130/0.4 solution reduced MDA level which is an indicator of lipid peroxidation. 6% Hydroxyethyl Starch 130/0.4 solution may be beneficial for Ischemia/reperfusion injuries.
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Affiliation(s)
- S Ozciftci
- S. Ozciftci, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
| | - M Gamli
- M. Gamli, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
| | - D Ornek
- D. Ornek, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
| | - E Horasanli
- E. Horasanli, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
| | - B Dikmen
- B. Dikmen, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
| | - O Canpolat
- O. Canpolat, Gazi University, Biochemistry Department, Ankara, Turkey
| | - M Z Ciraci
- M.Z. Ciraci, Gazi University, Biochemistry Department, Ankara, Turkey
| | - O Kilci
- O. Kilci, Ankara Numune Training & Research Hospital, Anesthesiology & Reanimation Department, Ankara, Turkey
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Fresh frozen plasma reduces edema in skeletal muscle following combined limb ischemia-reperfusion injury and hemorrhagic shock in rats. J Trauma Acute Care Surg 2016; 79:S110-5. [PMID: 26406422 DOI: 10.1097/ta.0000000000000752] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Exsanguination from extremity vascular injuries is the most common potentially survivable injury on the battlefield. Advances in treatment have dramatically improved survival, increasing the need to address associated morbidities including ischemia-reperfusion injury and extremity compartment syndrome. Despite advances, hemorrhagic shock (HS) requiring fluid resuscitation is common. Plasma-based resuscitation for the treatment of HS has been shown to reduce edema and injury in tissues other than muscle. The objective of this study was to determine if fresh frozen plasma (FFP) resuscitation offered protection in a rat model of combined HS and skeletal muscle ischemia-reperfusion injury. METHODS Anesthetized Sprague-Dawley rats underwent 37.5% arterial hemorrhage, producing HS, followed by 3 hours of tourniquet application. Animals were not resuscitated or resuscitated with either FFP (equal to the shed blood volume) or lactated Ringer's solution (three times shed volume) after 30 minutes of ischemia. They were euthanized 24 hours later, and their muscles were analyzed for edema (wet weight-dry weight). Routine histology was performed on muscle cross-sections stained with hematoxylin and eosin and graded using a semiquantitative grading system. RESULTS All animals developed HS; the mortality rate was 50% in no resuscitation rats. FFP reduced edema by 13% (p = 0.02) compared with lactated Ringer's solution. Pathology scores were not different between treatment groups. CONCLUSION FFP resuscitation reduces edema following muscle injury, decreasing the risk of developing extremity compartment syndrome.
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Wang L, Shan Y, Ye Y, Jin L, Zhuo Q, Xiong X, Zhao X, Lin L, Miao J. COX-2 inhibition attenuates lung injury induced by skeletal muscle ischemia reperfusion in rats. Int Immunopharmacol 2015; 31:116-22. [PMID: 26724476 DOI: 10.1016/j.intimp.2015.12.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 11/30/2015] [Accepted: 12/16/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND Skeletal muscle ischemia reperfusion accounts for high morbidity and mortality, and cyclooxygenase (COX)-2 is implicated in causing muscle damage. Downregulation of aquaporin-1 (AQP-1) transmembrane protein is implicated in skeletal muscle ischemia reperfusion induced remote lung injury. The expression of COX-2 in lung tissue and the effect of COX-2 inhibition on AQP-1 expression and lung injury during skeletal muscle ischemia reperfusion are not known. We investigated the role of COX-2 in lung injury induced by skeletal muscle ischemia reperfusion in rats and evaluated the effects of NS-398, a specific COX-2 inhibitor. METHODS Twenty-four Sprague Dawley rats were randomized into 4 groups: sham group (SM group), sham+NS-398 group (SN group), ischemia reperfusion group (IR group) and ischemia reperfusion+NS-398 group (IN group). Rats in the IR and IN groups were subjected to 3h of bilateral ischemia followed by 6h of reperfusion in hindlimbs, and intravenous NS-398 8 mg/kg was administered in the IN group. In the SM and SN groups, rubber bands were in place without inflation. At the end of reperfusion, myeloperoxidase (MPO) activity, COX-2 and AQP-1 protein expression in lung tissue, PGE2 metabolite (PGEM), tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels in bronchoalveolar lavage (BAL) fluid were assessed. Histological changes in lung and muscle tissues and wet/dry (W/D) ratio were also evaluated. RESULTS MPO activity, COX-2 expression, W/D ratio in lung tissue, and PGEM, TNF-α and IL-1β levels in BAL fluid were significantly increased, while AQP-1 protein expression downregulated in the IR group as compared to that in the SM group (P<0.05). These changes were remarkably mitigated in the IN group (P<0.05). NS-398 treatment also alleviated histological signs of lung and skeletal muscle injury. CONCLUSION COX-2 protein expression was upregulated in lung tissue in response to skeletal muscle ischemia reperfusion. COX-2 inhibition may modulate pulmonary AQP-1 expression and attenuate lung injury.
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Affiliation(s)
- Liangrong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Yuanlu Shan
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Yuzhu Ye
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Lida Jin
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Qian Zhuo
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Xiangqing Xiong
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Xiyue Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - Lina Lin
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
| | - JianXia Miao
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, People's Republic of China.
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Hu ZJ, Zhang JF, Xu WB, Zhao FD, Wang JY, Fan SW, Fang XQ. Effect of pure muscle retraction on multifidus injury and atrophy after posterior lumbar spine surgery with 24 weeks observation in a rabbit model. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2015; 26:210-220. [DOI: 10.1007/s00586-015-4247-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 09/15/2015] [Accepted: 09/17/2015] [Indexed: 11/28/2022]
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Mahajan V, Gaymalov Z, Alakhova D, Gupta R, Zucker IH, Kabanov AV. Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers. Biomaterials 2015; 75:58-70. [PMID: 26480472 DOI: 10.1016/j.biomaterials.2015.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/30/2015] [Accepted: 10/01/2015] [Indexed: 12/31/2022]
Abstract
Intramuscular administration of plasmid DNA (pDNA) with non-ionic Pluronic block copolymers increases gene expression in injected muscles and lymphoid organs. We studied the role of immune cells in muscle transfection upon inflammation. Local inflammation in murine hind limb ischemia model (MHLIM) drastically increased DNA, RNA and expressed protein levels in ischemic muscles injected with pDNA/Pluronic. The systemic inflammation (MHLIM or peritonitis) also increased expression of pDNA/Pluronic in the muscles. When pDNA/Pluronic was injected in ischemic muscles the reporter gene, Green Fluorescent Protein (GFP) co-localized with desmin(+) muscle fibers and CD11b(+) macrophages (MØs), suggesting transfection of MØs along with the muscle cells. P85 enhanced (∼ 4 orders) transfection of MØs with pDNA in vitro. Moreover, adoptively transferred MØs were shown to pass the transgene to inflamed muscle cells in MHLIM. Using a co-culture of myotubes (MTs) and transfected MØs expressing a reporter gene under constitutive (cmv-luciferase) or muscle specific (desmin-luciferase) promoter we demonstrated that P85 enhances horizontal gene transfer from MØ to MTs. Therefore, MØs can play an important role in muscle transfection with pDNA/Pluronic during inflammation, with both inflammation and Pluronic contributing to the increased gene expression. pDNA/Pluronic has potential for therapeutic gene delivery in muscle pathologies that involve inflammation.
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Affiliation(s)
- Vivek Mahajan
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Zagit Gaymalov
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Daria Alakhova
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Richa Gupta
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Alexander V Kabanov
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119899 Moscow, Russia.
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Mendonça LR, Joviliano EE, Ramalho FS, Ramalho LNZ, Evora PRB, Piccinato CE. Bradykinin Impairs and HOE 140 does not Protect Rat Hindlimb Skeletal Muscle Against Tourniquet-induced Reperfusion Injury. J INVEST SURG 2015; 29:13-9. [PMID: 26375056 DOI: 10.3109/08941939.2015.1041656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Bradykinin (BK) is used in different tissues. Dose-dependent studies have demonstrated that low doses protect against ischemia/reperfusion (I/R) injury while higher doses lead to adverse effects. Although the beneficial effects of BK infusion were observed in myocardium, its role on the I/R impact in skeletal muscle (SM) has not been fully clarified. OBJECTIVE This study was carried out to evaluate the effects of BK, administered in the hindlimbs of rats subjected to I/R. METHODS The study design included three experimental groups: Group 1 control (saline), Group 2 (bradykinin), and Group 3 (HOE 140, a BK2 receptor blocker). In all three groups, rats were subjected to hindlimb ischemia for a total of 2 h followed by continuous 4 h of reperfusion with pharmacological interventions. The methods include analysis of enzymes (lactate dehydrogenase-LDH and creatinine phosphokinase-CPK), cell membrane marker of injury (malondialdeyde-MDA), recruitment of neutrophils (myeloperoxidase-MPO), and apoptosis index (immunohistochemistry TUNEL in situ peroxidase dead end). RESULTS Except for the apoptotic index, all parameters studied were shown to be elevated in the reperfusion group intervened with BK. The blocking of BK2 receptors by HOE 140 did not affect the I/R injury. CONCLUSION After 2 h of total ischemia, infusion of bradykinin during 4 h of reperfusion, worsened the I/R injury in the hindlimb skeletal muscle.
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Affiliation(s)
- Luciano R Mendonça
- a Divisions of Vascular and Endovascular Surgery and Cardiovascular Surgery, Ribeirão Preto School of Medicine, Department of Surgery and Anatomy, University of São Paulo
| | - Edwaldo E Joviliano
- a Divisions of Vascular and Endovascular Surgery and Cardiovascular Surgery, Ribeirão Preto School of Medicine, Department of Surgery and Anatomy, University of São Paulo
| | - Fernando S Ramalho
- b Ribeirão Preto School of Medicine, Department of Pathology and Legal Medicine, University of São Paulo
| | - Leandra N Z Ramalho
- b Ribeirão Preto School of Medicine, Department of Pathology and Legal Medicine, University of São Paulo
| | - Paulo R B Evora
- a Divisions of Vascular and Endovascular Surgery and Cardiovascular Surgery, Ribeirão Preto School of Medicine, Department of Surgery and Anatomy, University of São Paulo
| | - Carlos E Piccinato
- a Divisions of Vascular and Endovascular Surgery and Cardiovascular Surgery, Ribeirão Preto School of Medicine, Department of Surgery and Anatomy, University of São Paulo
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Evidence for a Profound Remodeling of Skeletal Muscle and Its Microvasculature in Sickle Cell Anemia. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1448-56. [DOI: 10.1016/j.ajpath.2015.01.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 01/09/2015] [Accepted: 01/23/2015] [Indexed: 11/20/2022]
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Lawendy AR, Bihari A, Sanders DW, McGarr G, Badhwar A, Cepinskas G. Contribution of inflammation to cellular injury in compartment syndrome in an experimental rodent model. Bone Joint J 2015; 97-B:539-43. [DOI: 10.1302/0301-620x.97b4.34965] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Compartment syndrome, a devastating consequence of limb trauma, is characterised by severe tissue injury and microvascular perfusion deficits. We hypothesised that leucopenia might provide significant protection against microvascular dysfunction and preserve tissue viability. Using our clinically relevant rat model of compartment syndrome, microvascular perfusion and tissue injury were directly visualised by intravital video microscopy in leucopenic animals. We found that while the tissue perfusion was similar in both groups (38.8% (standard error of the mean (sem) 7.1), 36.4% (sem 5.7), 32.0% (sem 1.7), and 30.5% (sem 5.35) continuously-perfused capillaries at 45, 90, 120 and 180 minutes compartment syndrome, respectively versus 39.2% (sem 8.6), 43.5% (sem 8.5), 36.6% (sem 1.4) and 50.8% (sem 4.8) at 45, 90, 120 and 180 minutes compartment syndrome, respectively in leucopenia), compartment syndrome-associated muscle injury was significantly decreased in leucopenic animals (7.0% (sem 2.0), 7.0%, (sem 1.0), 9.0% (sem 1.0) and 5.0% (sem 2.0) at 45, 90, 120 and 180 minutes of compartment syndrome, respectively in leucopenia group versus 18.0% (sem 4.0), 23.0% (sem 4.0), 32.0% (sem 7.0), and 20.0% (sem 5.0) at 45, 90, 120 and 180 minutes of compartment syndrome in control, p = 0.0005). This study demonstrates that the inflammatory process should be considered central to the understanding of the pathogenesis of cellular injury in compartment syndrome. Cite this article: Bone Joint J 2015;97-B:539–43
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Affiliation(s)
- A-R. Lawendy
- Victoria Hospital, London Health Sciences
Centre, Victoria Research Labs, Rm
A6-142, 800 Commissioners Rd East, London, N6A
4G5, Ontario, Canada
| | - A. Bihari
- Victoria Hospital, London Health Sciences
Centre, Victoria Research Labs, Rm
A6-152, 800 Commissioners Rd East, London, N6A
4G5, Ontario, Canada
| | - D. W. Sanders
- Victoria Hospital, London Health Sciences
Centre, Victoria Research Labs, Rm
E1-325, 800 Commissioners Rd East, London, N6A
4G5, Ontario, Canada
| | - G. McGarr
- Brock University, Faculty
of Applied Health Sciences, St. Catharines, Ontario, Canada
| | - A. Badhwar
- Davol, A Bard Company, Warwick, Rhode
Island, USA
| | - G. Cepinskas
- Victoria Hospital, London Health Sciences
Centre, Victoria Research Labs, Rm
A6-136, 800 Commissioners Rd East, London, N6A
4G5, Ontario, Canada
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Trajano GS, Nosaka K, B Seitz L, Blazevich AJ. Intermittent stretch reduces force and central drive more than continuous stretch. Med Sci Sports Exerc 2014; 46:902-10. [PMID: 24121249 DOI: 10.1249/mss.0000000000000185] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUCTION The relative contributions of central versus peripheral factors to the force loss induced by acute continuous and intermittent plantarflexor stretches were studied. METHODS Eighteen healthy young men with no apparent tissue stiffness limitations randomly performed 1) one 5-min stretch (continuous stretch [CS]), 2) five 1-min stretches (intermittent stretch [IS]), and 3) a control condition, on three separate days. The stretches were constant-torque ankle stretches performed on an isokinetic dynamometer. Gastrocnemius medialis oxygenation status was quantified during stretch using near-infrared spectroscopy. Measures of isometric plantarflexor peak torque (Tpeak), voluntary activation (%VA; interpolated twitch technique), EMG amplitude normalized by Mmax (EMG:M), V-wave amplitude, and excitation-contraction (E-C) coupling efficiency (torque ratio between 20- and 80-Hz tetanic stimulations [20:80]) were taken before, immediately, and 15 and 30 min after each condition. RESULTS IS caused substantial cyclic variations in tissue oxygenation, but CS resulted in a greater decrease in oxyhemoglobin concentration. Voluntary Tpeak decreased more after IS (-23.8%) than CS (-14.3%) and remained significantly depressed until 30 min after IS only (-5.6%). EMG:M (-27.7%) and %VA (-15.9%) were reduced only after IS. After CS and IS, the magnitude of decrease in Tpeak was correlated with decreases in EMG:M (r = 0.81 and 0.89, respectively), %VA (r = 0.78 and 0.93), and V-wave (r = 0.51, only after IS). Tetanic torque values (20 and 80 Hz) were decreased after IS (-13.1% and -6.4%, respectively) and CS (-10.9% and -6.7%, respectively), but 20:80 was not different from the control group. CONCLUSION These results suggest that IS reduced Tpeak more than CS, and these reductions were strongly associated with a depression in central drive.
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Affiliation(s)
- Gabriel S Trajano
- Centre for Exercise and Sports Science Research, School of Exercise and Health Sciences, Edith Cowan University, AUSTRALIA
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The severity of microvascular dysfunction due to compartment syndrome is diminished by the systemic application of CO-releasing molecule-3. J Orthop Trauma 2014; 28:e263-8. [PMID: 24675751 DOI: 10.1097/bot.0000000000000097] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES To examine the protective effects of carbon monoxide (CO), liberated from a novel CO-releasing molecule (CORM-3), on the function of compartment syndrome (CS)-challenged muscle in a rodent model, thus providing for a potential development of a pharmacologic adjunctive treatment for CS. METHODS Wistar rats were randomized into 4 groups: sham (no CS), CS, CS with inactive CORM-3 (iCORM-3), and CS + CORM-3 (10 mg/kg intraperitoneally). CS was induced by elevation of intracompartmental pressure to 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours. Both CORM-3 and iCORM-3 were injected immediately after fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy 45 minutes after fasciotomy. Systemic levels of tumor necrosis factor alpha (TNF-α) were also measured. RESULTS Elevation of intracompartmental pressure resulted in significant microvascular perfusion deficits (23% ± 2% continuously perfused capillaries in CS vs. 76% ± 4% in sham, P < 0.0001; 55% ± 2% nonperfused capillaries in CS vs. 13% ± 2% in sham, P < 0.0001), significant increase in tissue injury (ethidium bromide/bisbenzimide of 0.31 ± 0.05 in CS vs. 0.05 ± 0.03 in sham, P < 0.0001) and adherent leukocytes (13.7 ± 0.9 in CS vs. 1.8 ± 0.5 in sham, P < 0.0001), and a progressive rise in systemic TNF-α. CORM-3 (but not iCORM-3) treatment restored the number of continuously perfused capillaries (57% ± 5%, P < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.07 ± 0.01, P < 0.001), reversed the CS-associated rise in TNF-α, and decreased leukocyte adherence (0.6 ± 0.3, P < 0.001). CONCLUSIONS CORM-3 displays a potent protective/anti-inflammatory action in an experimental model of CS, suggesting a potential therapeutic application to patients at risk of developing CS.
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