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Ushio Y, Hirata S, Manabe S, Suyama M, Tanaka A, Seki M, Kato H, Nomura K, Nakai A, Sumori H, Kawaguchi Y, Kobayashi S, Makabe S, Kataoka H, Itoh N, Taneda S, Honda K, Hoshino J. Overexpression of plasmalemmal vesicle-associated protein-1 in patient with cyanotic nephropathy: a case report. BMC Nephrol 2025; 26:109. [PMID: 40033218 PMCID: PMC11874792 DOI: 10.1186/s12882-025-04046-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 02/25/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Cyanotic nephropathy (CN) is a known complication of cyanotic congenital heart disease (CCHD). However, many aspects of its pathophysiology remain unclear. CASE PRESENTATION We report the case of a 29-year-old male with a history of tetralogy of Fallot. Renal biopsy revealed glomerular hypertrophy and focal segmental glomerulosclerosis. Electron microscopy revealed extensive endothelial cell damage. To investigate the etiology of endothelial cell damage, PAL-E staining was conducted, revealing staining along the glomerular capillary wall. CONCLUSION This is the first report of PAL-E staining in CN, suggesting potential overexpression of PV-1. The association of PV-1 expression with endothelial cell damage indicates its role in the pathogenesis of CN.
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Affiliation(s)
- Yusuke Ushio
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan.
| | - So Hirata
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Shun Manabe
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Mayuko Suyama
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Ayano Tanaka
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Momoko Seki
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Haruka Kato
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Kana Nomura
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Anna Nakai
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Hitoko Sumori
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Yuki Kawaguchi
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Shizuka Kobayashi
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Shiho Makabe
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Hiroshi Kataoka
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
| | - Naoko Itoh
- Department of Surgical Pathology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, , Tokyo, Japan
| | - Sekiko Taneda
- Department of Surgical Pathology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, , Tokyo, Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Junichi Hoshino
- Department of Nephrology, Tokyo Women'S Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, Japan
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2
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Wu X, Luo Y, Liu L, Han C, Liu Y, Zhang Z. Single-Cell RNA-seq Reveals Increased and Activated Post-Capillary Venule Endothelial Cells in Erythrodermic Psoriasis. Inflammation 2025:10.1007/s10753-024-02216-x. [PMID: 39786459 DOI: 10.1007/s10753-024-02216-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/13/2024] [Accepted: 12/09/2024] [Indexed: 01/12/2025]
Abstract
Erythrodermic psoriasis (EP) is a life-threatening variant of psoriasis. In this study, we contrasted the vascular endothelial cells (ECs) in EP lesions against those in psoriasis vulgaris and healthy controls. Utilizing single-cell RNA sequencing, immunofluorescence, and flow cytometry on human and mouse samples, we observed a marked increase and activation of EP ECs, which upregulated genes relative to angiogenesis, leukocyte adhesion and antigen presentation. This was particularly evident in the subpopulation post-capillary venules (PCV), especially the cluster from EP. Cell-cell communication studies revealed intensified interactions between PCV and leukocytes, mediated by SELE and ICAM1, predominantly in EP. Trajectory analysis suggested differentiation direction of venules-PCV-CAP. 1 with a concomitant reduction in NF2R2 expression. Elevated and activated PCVs were found in EP patient biopsies and mouse models. These findings underscore the significance of PCV in EP pathogenesis, presenting new therapeutic avenues for this debilitating disease.
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Affiliation(s)
- Xiaoyan Wu
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Guangdong Province, Shenzhen, People's Republic of China
| | - Yun Luo
- Department of Dermatology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Shenzhen, People's Republic of China
| | - Leying Liu
- Department of Dermatology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Shenzhen, People's Republic of China
| | - Changxu Han
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Guangdong Province, Shenzhen, People's Republic of China
| | - Yuhua Liu
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Guangdong Province, Shenzhen, People's Republic of China
- Department of Dermatology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Guangdong Province, Shenzhen, People's Republic of China
| | - Zhenying Zhang
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Guangdong Province, Shenzhen, People's Republic of China.
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Kaur P, Dahiya R, Nandave M, Sharma K, Goyal RK. Unveiling the crucial role of intercellular adhesion molecule-1 in secondary diabetic complications. Cell Biochem Funct 2024; 42:e4037. [PMID: 38736204 DOI: 10.1002/cbf.4037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/06/2024] [Accepted: 05/02/2024] [Indexed: 05/14/2024]
Abstract
Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.
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Affiliation(s)
- Prabhnain Kaur
- Department of Pharmacology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Ritu Dahiya
- Department of Pharmacology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Mukesh Nandave
- Department of Pharmacology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Kalicharan Sharma
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Ramesh K Goyal
- Department of Pharmacology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
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4
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Vezzoli A, Mrakic-Sposta S, Brizzolari A, Balestra C, Camporesi EM, Bosco G. Oxy-Inflammation in Humans during Underwater Activities. Int J Mol Sci 2024; 25:3060. [PMID: 38474303 DOI: 10.3390/ijms25053060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/22/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Underwater activities are characterized by an imbalance between reactive oxygen/nitrogen species (RONS) and antioxidant mechanisms, which can be associated with an inflammatory response, depending on O2 availability. This review explores the oxidative stress mechanisms and related inflammation status (Oxy-Inflammation) in underwater activities such as breath-hold (BH) diving, Self-Contained Underwater Breathing Apparatus (SCUBA) and Closed-Circuit Rebreather (CCR) diving, and saturation diving. Divers are exposed to hypoxic and hyperoxic conditions, amplified by environmental conditions, hyperbaric pressure, cold water, different types of breathing gases, and air/non-air mixtures. The "diving response", including physiological adaptation, cardiovascular stress, increased arterial blood pressure, peripheral vasoconstriction, altered blood gas values, and risk of bubble formation during decompression, are reported.
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Affiliation(s)
- Alessandra Vezzoli
- Institute of Clinical Physiology-National Research Council (CNR-IFC), 20142 Milano, Italy
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Simona Mrakic-Sposta
- Institute of Clinical Physiology-National Research Council (CNR-IFC), 20142 Milano, Italy
| | - Andrea Brizzolari
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Costantino Balestra
- Environmental, Occupational, Aging (Integrative) Physiology Laboratory, Haute Ecole Bruxelles-Brabant (HE2B), 1160 Brussels, Belgium
- Physical Activity Teaching Unit, Motor Sciences Department, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
- DAN Europe Research Division (Roseto-Brussels), 1160 Brussels, Belgium
| | | | - Gerardo Bosco
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
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Lu J, Xu X, Sun X, Du Y. Protein and peptide-based renal targeted drug delivery systems. J Control Release 2024; 366:65-84. [PMID: 38145662 DOI: 10.1016/j.jconrel.2023.12.036] [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: 07/27/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 12/27/2023]
Abstract
Renal diseases have become an increasingly concerned public health problem in the world. Kidney-targeted drug delivery has profound transformative potential on increasing renal efficacy and reducing extra-renal toxicity. Protein and peptide-based kidney targeted drug delivery systems have garnered more and more attention due to its controllable synthesis, high biocompatibility and low immunogenicity. At the same time, the targeting methods based on protein/peptide are also abundant, including passive renal targeting based on macromolecular protein and active targeting mediated by renal targeting peptide. Here, we review the application and the drug loading strategy of different proteins or peptides in targeted drug delivery, including the ferritin family, albumin, low molecular weight protein (LMWP), different peptide sequence and antibodies. In addition, we summarized the factors influencing passive and active targeting in drug delivery system, the main receptors related to active targeting in different kidney diseases, and a variety of nano forms of proteins based on the controllable synthesis of proteins.
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Affiliation(s)
- Jingyi Lu
- Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, Zhejiang 310014, China; College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China
| | - Xiaoling Xu
- College of Medical Sciences, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, Zhejiang 310015, China.
| | - Xuanrong Sun
- Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, Zhejiang 310014, China.
| | - Yongzhong Du
- Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, Zhejiang 310014, China; College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Innovation Center of Translational Pharmacy, Jinhua Institute of Zhejiang University, Jinhua 321299, China.
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6
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Silva M, Faustino P. From Stress to Sick(le) and Back Again-Oxidative/Antioxidant Mechanisms, Genetic Modulation, and Cerebrovascular Disease in Children with Sickle Cell Anemia. Antioxidants (Basel) 2023; 12:1977. [PMID: 38001830 PMCID: PMC10669666 DOI: 10.3390/antiox12111977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Sickle cell anemia (SCA) is a genetic disease caused by the homozygosity of the HBB:c.20A>T mutation, which results in the production of hemoglobin S (HbS). In hypoxic conditions, HbS suffers autoxidation and polymerizes inside red blood cells, altering their morphology into a sickle shape, with increased rigidity and fragility. This triggers complex pathophysiological mechanisms, including inflammation, cell adhesion, oxidative stress, and vaso-occlusion, along with metabolic alterations and endocrine complications. SCA is phenotypically heterogeneous due to the modulation of both environmental and genetic factors. Pediatric cerebrovascular disease (CVD), namely ischemic stroke and silent cerebral infarctions, is one of the most impactful manifestations. In this review, we highlight the role of oxidative stress in the pathophysiology of pediatric CVD. Since oxidative stress is an interdependent mechanism in vasculopathy, occurring alongside (or as result of) endothelial dysfunction, cell adhesion, inflammation, chronic hemolysis, ischemia-reperfusion injury, and vaso-occlusion, a brief overview of the main mechanisms involved is included. Moreover, the genetic modulation of CVD in SCA is discussed. The knowledge of the intricate network of altered mechanisms in SCA, and how it is affected by different genetic factors, is fundamental for the identification of potential therapeutic targets, drug development, and patient-specific treatment alternatives.
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Affiliation(s)
- Marisa Silva
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
| | - Paula Faustino
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
- Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental (ISAMB), Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
- Laboratório Associado TERRA, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
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7
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Ndrepepa G, Kastrati A. Coronary No-Reflow after Primary Percutaneous Coronary Intervention-Current Knowledge on Pathophysiology, Diagnosis, Clinical Impact and Therapy. J Clin Med 2023; 12:5592. [PMID: 37685660 PMCID: PMC10488607 DOI: 10.3390/jcm12175592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/17/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic, develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infarct size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently, the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research.
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Affiliation(s)
- Gjin Ndrepepa
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany;
| | - Adnan Kastrati
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany;
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
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8
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Shen CL, Wu YF. Flow cytometry for evaluating platelet immunophenotyping and function in patients with thrombocytopenia. Tzu Chi Med J 2022; 34:381-387. [PMID: 36578648 PMCID: PMC9791859 DOI: 10.4103/tcmj.tcmj_117_22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/10/2022] [Accepted: 06/08/2022] [Indexed: 01/19/2023] Open
Abstract
Platelets play an essential role in primary hemostasis through bleeding and thromboembolism. Thus, the diagnosis or evaluation of impaired hereditary, acquired, and drug-related platelet dysfunction has become imperative. The assessment of the platelet function is too complex for routine platelet function study. The major methods involved in platelet function study include platelet function analyzer testing, thromboelastography, thromboelastometry, light transmission aggregometry, and flow cytometry. The current review article focuses on the methods with flow cytometry for immunophenotyping of platelet and evaluating platelet function for platelet disorders, especially in patients with thrombocytopenia. According to the consensus published by the International Society on Thrombosis and Haemostasis, for inherited and acquired platelet disorders, the two major measures by which flow cytometry determines platelet function are glycoprotein IIb/IIIa/P-selectin (CD62p) expression and percentage of leukocyte-platelet aggregates. Using flow cytometry to determine platelet function has several advantages, including good sensitivity to low platelet counts, small blood volume required, and the nonnecessity of centrifugation. However, flow cytometry has still many limitations and challenges, with standardization for routine laboratory testing also proving difficult. Although flow cytometry is available for multipurpose and sensitive study of platelet functions at the same time, the challenging analysis gradually increases and needs to be addressed before reality.
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Affiliation(s)
- Chih-Lung Shen
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yi-Feng Wu
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan,School of Medicine, Tzu Chi University, Hualien, Taiwan,Address for correspondence: Dr. Yi-Feng Wu, Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. E-mail:
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Hashmi SF, Rathore HA, Sattar MA, Johns EJ, Gan CY, Chia TY, Ahmad A. Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats. Biomolecules 2021; 11:1549. [PMID: 34680182 PMCID: PMC8534271 DOI: 10.3390/biom11101549] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/13/2023] Open
Abstract
Our main objective was to investigate the effect of chronic administration of hydrogen sulphide donor (sodium hydrosulphide) on the expression of intercellular adhesion molecule-1 (ICAM-1) and concentration of nuclear factor-kappa B (NF-kB) in a renal ischemia-reperfusion injury (IRI) model of WKY and L-nitro-arginine-methyl-ester (L-NAME)-induced hypertensive rats. Sodium hydrosulphide (NaHS) was administered intraperitoneally (i.p.) for 35 days while cystathionine gamma lyase (CSE) inhibitor dL-propargylglycine (PAG) was administered at a single dose of 50 mg/kg. Animals were anesthetised using sodium pentobarbitone (60 mg/kg) and then prepared to induce renal ischemia by clamping the left renal artery for 30 min followed by 3 h of reperfusion. Pre-treatment with NaHS improved the renal functional parameters in both WKY and L-NAME-induced hypertensive rats along with reduction of blood pressure in hypertensive groups. Oxidative stress markers like malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) were also improved by NaHS treatment following renal IRI. Levels of ICAM-1 and NF-kB concentration were reduced by chronic treatment with NaHS and increased by PAG administration after renal IRI in plasma and kidney. Treatment with NaHS improved tubular morphology and glomerulus hypertrophy. Pre-treatment with NaHS reduced the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression.
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Affiliation(s)
- Syed F. Hashmi
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Hassaan Anwer Rathore
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Munavvar A. Sattar
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
| | - Edward J. Johns
- Department of Physiology, University College Cork, T12 K8AF Cork, Ireland;
| | - Chee-Yuen Gan
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia (USM), Lebuh Bukit Jambul, Penang 11900, Malaysia;
| | - Tan Yong Chia
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia (USM), Lebuh Bukit Jambul, Penang 11900, Malaysia;
| | - Ashfaq Ahmad
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia; (S.F.H.); (H.A.R.); (M.A.S.)
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 31991, Saudi Arabia
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10
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Yang S, Huang X, Liao J, Li Q, Chen S, Liu C, Ling L, Zhou J. Platelet-leukocyte aggregates - a predictor for acute kidney injury after cardiac surgery. Ren Fail 2021; 43:1155-1162. [PMID: 34266358 PMCID: PMC8288121 DOI: 10.1080/0886022x.2021.1948864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Background Acute kidney injury (AKI) is one of the most common complications after cardiac surgery. However, effective biomarker used for early diagnosis of AKI has not been identified. Platelet-leukocyte aggregates (PLAs) participate in inflammation and coagulation, leading to vascular lesions and tissue destruction. We designed a prospective study to assess whether PLAs can serve as a good biomarker for early diagnosis of AKI after cardiac surgery. Methods Patients with rheumatic heart disease scheduled to undergo valve replacement surgery were enrolled. Blood samples were collected at five timepoints as follows: (a) At baseline. (b) At the end of extracorporeal circulation. (c) Arrival at intensive care unit (ICU). (d) Four-hours after the admission to ICU. (e) Twenty hours after the admission to ICU. After collection, the samples were immediately used for PLAs measurement by flow cytometry. Results A total of 244 patients were registered, and 15 of them were diagnosed with AKI according to the serum creatinine of KDIGO guidelines. The PLAs levels in AKI group were significantly increased 20 h after surgery (two-way repeated measure analysis of variance, p < 0.01) compared with that at baseline. Patients whose preoperative PLAs were higher than 6.8% showed increased risk of developing AKI (multivariate logistic regression; p = 0.01; adjusted odds ratio, 1.05; 95% confidence interval, 1.01–1.09). Conclusion PLAs is an independent risk factor for AKI after valve replacement among patients with rheumatic heart disease.
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Affiliation(s)
- Shenghan Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xunbei Huang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Liao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Si Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chaonan Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Liqin Ling
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
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11
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Gunata M, Parlakpinar H. A review of myocardial ischaemia/reperfusion injury: Pathophysiology, experimental models, biomarkers, genetics and pharmacological treatment. Cell Biochem Funct 2020; 39:190-217. [PMID: 32892450 DOI: 10.1002/cbf.3587] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/03/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
Cardiovascular diseases are known to be the most fatal diseases worldwide. Ischaemia/reperfusion (I/R) injury is at the centre of the pathology of the most common cardiovascular diseases. According to the World Health Organization estimates, ischaemic heart disease is the leading global cause of death, causing more than 9 million deaths in 2016. After cardiovascular events, thrombolysis, percutaneous transluminal coronary angioplasty or coronary bypass surgery are applied as treatment. However, after restoring coronary blood flow, myocardial I/R injury may occur. It is known that this damage occurs due to many pathophysiological mechanisms, especially increasing reactive oxygen types. Besides causing cardiomyocyte death through multiple mechanisms, it may be an important reason for affecting other cell types such as platelets, fibroblasts, endothelial and smooth muscle cells and immune cells. Also, polymorphonuclear leukocytes are associated with myocardial I/R damage during reperfusion. This damage may be insufficient in patients with co-morbidity, as it is demonstrated that it can be prevented by various endogenous antioxidant systems. In this context, the resulting data suggest that optimal cardioprotection may require a combination of additional or synergistic multi-target treatments. In this review, we discussed the pathophysiology, experimental models, biomarkers, treatment and its relationship with genetics in myocardial I/R injury. SIGNIFICANCE OF THE STUDY: This review summarized current information on myocardial ischaemia/reperfusion injury (pathophysiology, experimental models, biomarkers, genetics and pharmacological therapy) for researchers and reveals guiding data for researchers, especially in the field of cardiovascular system and pharmacology.
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Affiliation(s)
- Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
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Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury. Int J Mol Sci 2020; 21:ijms21155189. [PMID: 32707886 PMCID: PMC7432940 DOI: 10.3390/ijms21155189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
Intestinal ischemia reperfusion injury (IRI) is an inherent, unavoidable event of intestinal transplantation, contributing to allograft failure and rejection. The inflammatory state elicited by intestinal IRI is characterized by heightened leukocyte recruitment to the gut, which is amplified by a cross-talk with platelets at the endothelial border. Sulforaphane (SFN), a naturally occurring isothiocyanate, exhibits anti-inflammatory characteristics and has been shown to reduce platelet activation and block leukocyte adhesion. Thus, the aim of this study was to investigate protective effects and mechanism of action of SFN in a murine model of intestinal IRI. Intestinal IRI was induced by superior mesenteric artery occlusion for 30 min, followed by reperfusion for 2 h, 8 h or 24 h. To investigate cellular interactions, leukocytes were in vivo stained with rhodamine and platelets were harvested from donor animals and ex vivo stained. Mice (C57BL/6J) were divided into three groups: (1) control, (2) SFN treatment 24 h prior to reperfusion and (3) SFN treatment 24 h prior to platelet donation. Leukocyte and platelet recruitment was analyzed via intravital microscopy. Tissue was analyzed for morphological alterations in intestinal mucosa, barrier permeability, and leukocyte infiltration. Leukocyte rolling and adhesion was significantly reduced 2 h and 8 h after reperfusion. Mice receiving SFN treated platelets exhibited significantly decreased leukocyte and platelet recruitment. SFN showed protection for intestinal tissue with less damage observed in histopathological and ultrastructural evaluation. In summary, the data presented provide evidence for SFN as a potential therapeutic strategy against intestinal IRI.
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Lin QY, Lang PP, Zhang YL, Yang XL, Xia YL, Bai J, Li HH. Pharmacological blockage of ICAM-1 improves angiotensin II-induced cardiac remodeling by inhibiting adhesion of LFA-1 + monocytes. Am J Physiol Heart Circ Physiol 2019; 317:H1301-H1311. [PMID: 31729904 DOI: 10.1152/ajpheart.00566.2019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg-1·min-1) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases.NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.
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Affiliation(s)
- Qiu-Yue Lin
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Ping-Ping Lang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Yun-Long Zhang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Xiao-Lei Yang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Yun-Long Xia
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Jie Bai
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
| | - Hui-Hua Li
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China
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Fang W, Wang G, Tang L, Su H, Chen H, Liao W, Xu J. Hydrogen gas inhalation protects against cutaneous ischaemia/reperfusion injury in a mouse model of pressure ulcer. J Cell Mol Med 2018; 22:4243-4252. [PMID: 29921037 PMCID: PMC6111801 DOI: 10.1111/jcmm.13704] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/25/2018] [Indexed: 12/13/2022] Open
Abstract
Pressure ulcer formation depends on various factors among which repetitive ischaemia/reperfusion(I/R) injury plays a vital role. Molecular hydrogen (H2) was reported to have protective effects on I/R injuries of various internal organs. In this study, we investigated the effects of H2 inhalation on pressure ulcer and the underlying mechanisms. H2 inhalation significantly reduced wound area, 8‐oxo‐dG level (oxidative DNA damage) and cell apoptosis rates in skin lesions. H2 remarkably decreased ROS accumulation and enhanced antioxidant enzymes activities by up‐regulating expression of Nrf2 and its downstream components in wound tissue and/or H2O2‐treated endothelia. Meanwhile, H2 inhibited the overexpression of MCP‐1, E‐selectin, P‐selectin and ICAM‐1 in oxidant‐induced endothelia and reduced inflammatory cells infiltration and proinflammatory cytokines (TNF‐α, IL‐1, IL‐6 and IL‐8) production in the wound. Furthermore, H2 promoted the expression of pro‐healing factors (IL‐22, TGF‐β, VEGF and IGF1) and inhibited the production of MMP9 in wound tissue in parallel with acceleration of cutaneous collagen synthesis. Taken together, these data indicated that H2 inhalation suppressed the formation of pressure ulcer in a mouse model. Molecular hydrogen has potentials as a novel and alternative therapy for severe pressure ulcer. The therapeutic effects of molecular hydrogen might be related to its antioxidant, anti‐inflammatory, pro‐healing actions.
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Affiliation(s)
- Wei Fang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,The Shanghai Institute of Dermatology, Shanghai, China.,Department of Dermatology and Venereology, Changzheng Hospital, Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai, China
| | - Guizhen Wang
- Emergency room, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Luyan Tang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,The Shanghai Institute of Dermatology, Shanghai, China
| | - Huilin Su
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Huyan Chen
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wanqing Liao
- Department of Dermatology and Venereology, Changzheng Hospital, Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai, China
| | - Jinhua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,The Shanghai Institute of Dermatology, Shanghai, China
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15
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Finsterbusch M, Schrottmaier WC, Kral-Pointner JB, Salzmann M, Assinger A. Measuring and interpreting platelet-leukocyte aggregates. Platelets 2018; 29:677-685. [PMID: 29461910 PMCID: PMC6178087 DOI: 10.1080/09537104.2018.1430358] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Platelets, besides their specialised role in haemostasis and atherothrombosis, actively modulate innate and adaptive immune responses with crucial roles in immune surveillance, inflammation and host defence during infection. An important prerequisite for platelet-mediated changes of immune functions involves direct engagement with different types of leukocytes. Indeed, increased platelet-leukocyte aggregates (PLAs) within the circulation and/or locally at the site of inflammation represent markers of many thrombo-inflammatory diseases, such as cardiovascular diseases, acute lung injury, renal and cerebral inflammation. Therefore, measurement of PLAs could provide an attractive and easily accessible prognostic and/or diagnostic tool for many diseases. To measure PLAs in different (patho-)physiological settings in human and animal models flow cytometric and microscopic approaches have been applied. These techniques represent complementary tools to study different aspects relating to the involvement of leukocyte subtypes and molecules, as well as location of PLAs within tissues, dynamics of their interactions and/or dynamic changes in leukocyte and platelet behaviour. This review summarises various approaches to measure and interpret PLAs and discusses potential experimental factors influencing platelet binding to leukocytes. Furthermore, we summarise insights gained from studies regarding the underlying mechanism of platelet-leukocyte interactions and discuss implications of these interactions in health and disease.
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Affiliation(s)
- Michaela Finsterbusch
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Waltraud C Schrottmaier
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Julia B Kral-Pointner
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Manuel Salzmann
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
| | - Alice Assinger
- a Department for Vascular Biology and Thrombosis Research , Centre for Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria
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Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 81:331-364. [PMID: 29310801 DOI: 10.1016/bs.apha.2017.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ischemia/reperfusion (I/R) induces leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated dilatory responses (EDD) in upstream arterioles. A large body of evidence has implicated reactive oxygen species, adherent leukocytes, and proteases in postischemic EDD dysfunction in conduit arteries. However, arterioles represent the major site for the regulation of vascular resistance but have received less attention with regard to the mechanisms underlying their reduced responsiveness to EDD stimuli in I/R. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that I/R-induced venular LECA is causally linked to EDD in arterioles. An emerging body of evidence suggests that I/R-induced EDD in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes. This activity releases matricryptins from or exposes matricryptic sites in the extracellular matrix that interact with the integrin αvβ3 to induce mast cell chymase-dependent formation of angiotensin II (Ang II). Subsequent activation of NAD(P)H oxidase by Ang II leads to the formation of oxidants which inactivate NO and leads to eNOS uncoupling, resulting in arteriolar EDD dysfunction. This work establishes new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, mast cell degranulation, and impaired EDD in upstream arterioles. These fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.
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Granger DN, Kvietys PR. Reperfusion therapy-What's with the obstructed, leaky and broken capillaries? ACTA ACUST UNITED AC 2017; 24:213-228. [PMID: 29102280 DOI: 10.1016/j.pathophys.2017.09.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Microvascular dysfunction is well established as an early and rate-determining factor in the injury response of tissues to ischemia and reperfusion (I/R). Severe endothelial cell dysfunction, which can develop without obvious morphological cell injury, is a major underlying cause of the microvascular abnormalities that accompany I/R. While I/R-induced microvascular dysfunction is manifested in different ways, two responses that have received much attention in both the experimental and clinical setting are impaired capillary perfusion (no-reflow) and endothelial barrier failure with a transition to hemorrhage. These responses are emerging as potentially important determinants of the severity of the tissue injury response, and there is growing clinical evidence that they are predictive of clinical outcome following reperfusion therapy. This review provides a summary of animal studies that have focused on the mechanisms that may underlie the genesis of no-reflow and hemorrhage following reperfusion of ischemic tissues, and addresses the clinical evidence that implicates these vascular events in the responses of the ischemic brain (stroke) and heart (myocardial infarction) to reperfusion therapy. Inasmuch as reactive oxygen species (ROS) and matrix metalloproteinases (MMP) are frequently invoked as triggers of the microvascular dysfunction elicited by I/R, the potential roles and sources of these mediators are also discussed. The available evidence in the literature justifies the increased interest in the development of no-reflow and hemorrhage in heart and brain following reperfusion therapy, and suggests that these vascular events may be predictive of poor clinical outcome and warrant the development of targeted treatment strategies.
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Affiliation(s)
- D Neil Granger
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, United States.
| | - Peter R Kvietys
- Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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18
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Justicia C, Salas-Perdomo A, Pérez-de-Puig I, Deddens LH, van Tilborg GAF, Castellví C, Dijkhuizen RM, Chamorro Á, Planas AM. Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice. Transl Stroke Res 2016; 8:294-305. [PMID: 27981484 DOI: 10.1007/s12975-016-0515-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 12/03/2016] [Accepted: 12/06/2016] [Indexed: 12/20/2022]
Abstract
Hyperglycemia at stroke onset is associated with poor long-term clinical outcome in numerous studies. Hyperglycemia induces intracellular acidosis, lipid peroxidation, and peroxynitrite production resulting in the generation of oxidative and nitrosative stress in the ischemic tissue. Here, we studied the effects of acute hyperglycemia on in vivo intercellular adhesion molecule-1 (ICAM-1) expression, neutrophil recruitment, and brain damage after ischemia/reperfusion in mice and tested whether the natural antioxidant uric acid was protective. Hyperglycemia was induced by i.p. administration of dextrose 45 min before transient occlusion of the middle cerebral artery. Magnetic resonance imaging (MRI) was performed at 24 h to measure lesion volume. A group of normoglycemic and hyperglycemic mice received an i.v. injection of micron-sized particles of iron oxide (MPIOs), conjugated with either anti-ICAM-1 antibody or control IgG, followed by T2*w MRI. Neutrophil infiltration was studied by immunofluorescence and flow cytometry. A group of hyperglycemic mice received an i.v. infusion of uric acid (16 mg/kg) or the vehicle starting after 45 min of reperfusion. ICAM-1-targeted MPIOs induced significantly larger MRI contrast-enhancing effects in the ischemic brain of hyperglycemic mice, which also showed more infiltrating neutrophils and larger lesions than normoglycemic mice. Uric acid reduced infarct volume in hyperglycemic mice but it did not prevent vascular ICAM-1 upregulation and did not significantly reduce the number of neutrophils in the ischemic brain tissue. In conclusion, hyperglycemia enhances stroke-induced vascular ICAM-1 and neutrophil infiltration and exacerbates the brain lesion. Uric acid reduces the lesion size after ischemia/reperfusion in hyperglycemic mice.
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Affiliation(s)
- Carles Justicia
- Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain. .,Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.
| | - Angélica Salas-Perdomo
- Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain.,Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain
| | - Isabel Pérez-de-Puig
- Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain.,Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain
| | - Lisette H Deddens
- Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Geralda A F van Tilborg
- Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Clara Castellví
- Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain
| | - Rick M Dijkhuizen
- Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ángel Chamorro
- Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.,Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Anna M Planas
- Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain. .,Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.
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Shi CS, Huang TH, Lin CK, Li JM, Chen MH, Tsai ML, Chang CC. VEGF Production by Ly6C+high Monocytes Contributes to Ventilator-Induced Lung Injury. PLoS One 2016; 11:e0165317. [PMID: 27783650 PMCID: PMC5081209 DOI: 10.1371/journal.pone.0165317] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 10/10/2016] [Indexed: 01/05/2023] Open
Abstract
Background Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI. Methods A clinically relevant two-hit mouse model of VILI, with intravenous lipopolysaccharide (LPS, 20 ng/mouse) immediately before high tidal volume (HTV, 20 mL/kg) ventilation (LPS+HTV), was established. Blood gas and respiratory mechanics were measured to ensure the development of VILI. Flow cytometry and histopathological analyses revealed pulmonary infiltration of leukocytes subsets. Clodronate liposomes were intravenously injected to deplete pulmonary monocytes. In vitro endothelial cell permeability assay with sorted Ly6C+high monocytes condition media assessed the role of Ly6C+high monocytes in vascular permeability. Results LPS+HTV significantly increased total proteins, TNF-α, IL-6, vascular endothelial growth factor (VEGF) and mononuclear cells in the bronchoalveolar lavage fluid (BALF). Pulmonary Ly6C+high monocytes (SSClowCD11b+F4/80+Ly6C+high), but not Ly6C+low monocytes (SSClowCD11b+F4/80+Ly6C+low), were significantly elevated starting at 4 hr. Clodronate liposomes were able to significantly reduce pulmonary Ly6C+high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. There was a strong correlation between pulmonary Ly6C+high monocytes and BALF VEGF (R2 = 0.8791, p<0.001). Moreover, sorted Ly6C+high monocytes were able to produce VEGF, resulting in an increased permeability of endothelial cell monolayer in an in vitro endothelial cell permeability assay. Conclusion VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung injury. Ly6C+high monocytes play an important role in the pathogenesis of VILI.
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Affiliation(s)
- Chung-Sheng Shi
- Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Tzu-Hsiung Huang
- Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chin-Kuo Lin
- The Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Jhy-Ming Li
- Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Mei-Hsin Chen
- Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Mei-Ling Tsai
- Department of Physiology, Medical College, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Ching Chang
- Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, Tainan, Taiwan
- * E-mail:
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Van Griensven M, Rosado Balmayor E. Immunogenic Reaction of Implanted Biomaterials from Nature. BIOMATERIALS FROM NATURE FOR ADVANCED DEVICES AND THERAPIES 2016:429-443. [DOI: 10.1002/9781119126218.ch23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Girn HRS, Ahilathirunayagam S, Mavor AID, Homer-Vanniasinkam S. Reperfusion Syndrome: Cellular Mechanisms of Microvascular Dysfunction and Potential Therapeutic Strategies. Vasc Endovascular Surg 2016; 41:277-93. [PMID: 17704330 DOI: 10.1177/1538574407304510] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Reperfusion injury is the paradoxical and complex phenomenon of exacerbation of cellular dysfunction and increase in cell death after the restoration of blood flow to previously ischemic tissues. It involves biochemical and cellular changes causing oxidant production and complement activation, which culminates in an inflammatory response, mediated by neutrophil and platelet cell interactions with the endothelium and among the cells themselves. The mounted inflammatory response has both local and systemic manifestations. Despite improvements in imaging, interventional techniques, and pharmacological agents, morbidity from reperfusion remains high. Extensive research has furthered the understanding of the various pathophysiological mechanisms involved and the development of potential therapeutic strategies. Preconditioning has emerged as a powerful method of ameliorating ischemia reperfusion injury to the myocardium and in transplant surgery. More recently, postconditioning has been shown to provide a therapeutic counter to vasoocclusive emergencies. More research and well-designed trials are needed to bridge the gap between experimental evidence and clinical implementation.
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Abstract
Distal peripheral microembolism is caused by embolization of atherosclerotic debris into small arteries and arterioles. The recent advances in endovascular technique have been met with a gradual increase in the incidence of iatrogenic atheroembolism. This review seeks to explore the nature of distal peripheral microembolism, pathophysiology, and the management options, with a focus on iatrogenic distal peripheral microembolism.
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Affiliation(s)
- Joe R Chauvapun
- Department of Surgery, State University of New York, Buffalo, NY, USA.
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Abstract
PURPOSE The cholinergic anti-inflammatory pathway may play an important role in early burn edema. Therefore, we evaluated the influence of cdp-choline on early systemic burn edema and leukocyte activation in shock in rat mesenteries after burn plasma transfer. METHODS Burn plasma harvested from donor rats 4 hours after thermal injury (30% total body surface area, 100°C water, 12 seconds) was administered intravenously to healthy animals during 2 hours of intravital microscopy. Shamburn plasma (same procedure but water at 37°C) was transferred for negative controls. In the study group, bolus injection of 100 mg/kg body weight cdp-choline was undertaken 15 minutes before examination. Intravital microscopy was performed in the ileal portion of rat mesenteries at 0, 60, and 120 minutes. Capillary leakage was assessed by fluorescein isothiocyanate-albumin extravasation and leukocyte-endothelial interaction were observed via transillumination microscopy. To assure comparable hemodynamic conditions, microhemodynamic parameters, foremost venular wall shear rate, were assessed. RESULTS Capillary leakage increased significantly after burn plasma transfer when compared to the shamburn group. Additional intravenous administration of cdp-choline attenuates macromolecular efflux to shamburn levels. Leukocyte activation is reduced after cdp-choline treatment. CONCLUSIONS The significant increase of albumin efflux in rat mesenteries after burn plasma transfer is decreased by additional cdp-choline bolus administration. Further investigations for proof of the relevance of the cholinergic anti-inflammatory pathway in early burn trauma are strongly required.
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Huang T, Gao D, Hei Y, Zhang X, Chen X, Fei Z. D-allose protects the blood brain barrier through PPARγ-mediated anti-inflammatory pathway in the mice model of ischemia reperfusion injury. Brain Res 2016; 1642:478-486. [PMID: 27103568 DOI: 10.1016/j.brainres.2016.04.038] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/11/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023]
Abstract
Our early experiments confirmed that D-allose was closely involved in the blood brain barrier (BBB) protection from ischemia reperfusion (IR) injury, but the regulatory mechanism is not fully defined. In this study, we aimed to investigate the role of D-allose in the protection of BBB integrity and the relevant mechanisms involved in the mice model of middle cerebral artery occlusion and reperfusion (MCAO/Rep). D-allose was intravenously injected via a tail vein (0.2mg/g and 0.4mg/g, 1h before ischemia), GW9662 was intraperitoneal injected to the mice (4mg/kg) before inducing ischemia 24h. Pretreatment with D-allose ameliorated the neurological deficits, infarct volume and brain edema in brains of MCAO/Rep mice. D-allose inhibited cell apoptosis in the mice model of MCAO/Rep. We observed that D-allose remarkably decreased BBB permeability and prevented the reduction of ZO-1, Occludin and Claudin-5 in mice brains with MCAO/Rep injury. D-allose also repressed the levels of TNF-α, NF-κB, interleukin (IL)-1β and IL-8 in inflammatory responses. The increases of intercellular adhesion molecular-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and CD11b/CD18 were significantly inhibited by D-allose during the MCAO/Rep injury. And D-allose decreased the L-selectin and P-selectin levels after MCAO/Rep. Moreover, D-allose induced up-regulation of peroxisome proliferator-activated receptor γ (PPARγ), and down-regulation of TNF-α and NF-κB after MCAO/Rep, which were abolished by utilization of GW9662. In conclusion, we provided evidences that D-allose may has therapeutic potential against brain IR injury through attenuating BBB disruption and the inflammatory response via PPARγ-dependent regulation of NF-κB.
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Affiliation(s)
- Tao Huang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China
| | - Dakuan Gao
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China
| | - Yue Hei
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China
| | - Xin Zhang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China
| | - Xiaoyan Chen
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China
| | - Zhou Fei
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.15 Changle West Road, Xincheng District, Xi'an 710032, Shaanxi, China.
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Granger DN, Holm L, Kvietys P. The Gastrointestinal Circulation: Physiology and Pathophysiology. Compr Physiol 2016; 5:1541-83. [PMID: 26140727 DOI: 10.1002/cphy.c150007] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response.
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Affiliation(s)
- D Neil Granger
- Department of Molecular and Cellular Physiology, LSU Health Science Center-Shreveport, Shreveport, Louisiana, USA
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Peter Kvietys
- Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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26
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Heterogeneity of the Mac-1 expression on peripheral blood neutrophils in patients with different types of epithelial ovarian cancer. Immunobiology 2016; 221:323-32. [DOI: 10.1016/j.imbio.2015.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 10/08/2015] [Accepted: 10/23/2015] [Indexed: 01/03/2023]
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5-HT2a receptor antagonism reduces burn-induced macromolecular efflux in rats. Eur J Trauma Emerg Surg 2015; 41:565-73. [PMID: 26038010 DOI: 10.1007/s00068-014-0486-4] [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] [Received: 07/15/2014] [Accepted: 12/08/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Major thermal injuries lead to a systemic inflammatory response with systemic capillary leakage and multiple organ dysfunction. This systemic inflammatory response is induced by a variety of immunmodulative molecules including TNFα and serotonin. Unspecific serotonin antagonism leads to reduced macromolecular efflux in rat mesenteries after burn plasma transfer. The aim of the present study was to evaluate the effect of specific 5-HT2a antagonism on early burn edema. METHODS Donor rats (DR) underwent thermal injury (100 °C water, 30% BSA, 12 s) for positive controls. For negative controls, DR underwent sham burn (37 °C water, 30% BSA, 12 s). DR plasma (harvested 4 h post-trauma) was transferred to healthy individuals for positive controls. Study rats received burn plasma (BP) and a Bolus injection of Ketanserin (Ket) (1 mg kg(-1) body weight). Negative controls underwent sham burn plasma infusion. Intravital microscopy was performed in mesenteric venules (0/60/120 min). Edema was assessed by FITC-albumin extravasation. Additionally, leukocyte rolling and sticking (cells mm(-2)) as well as microhemodynamic parameters were assessed. RESULTS Significant systemic capillary leakage was observed after BP transfer at 120 min and additional administration of Ket attenuated the postburn edema to sham burn levels. Ket also leads to significantly decreased leukocyte-endothelial interactions when compared to positive controls. CONCLUSION 5-HT2a antagonism reduces plasma extravasation after burn plasma transfer in healthy individuals. The influence of leukocyte-endothelial interactions on postburn edema remains unclear.
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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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Hernekamp F, Klein H, Schmidt K, Vogelpohl J, Kneser U, Kremer T. Microcirculatory Effects of Physostigmine on Experimental Burn Edema. J Burn Care Res 2015; 36:279-86. [DOI: 10.1097/bcr.0000000000000068] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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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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Zhao L, Luo L, Jia W, Xiao J, Huang G, Tian G, Li J, Xiao Y. Serum diamine oxidase as a hemorrhagic shock biomarker in a rabbit model. PLoS One 2014; 9:e102285. [PMID: 25144315 PMCID: PMC4140717 DOI: 10.1371/journal.pone.0102285] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/16/2014] [Indexed: 01/15/2023] Open
Abstract
Background In prolonged hemorrhagic shock, reductions in intestinal mucosal blood perfusion lead to mucosal barrier damage and systemic inflammation. Gastrointestinal failure in critically ill patients has a poor prognosis, so early assessment of mucosal barrier injury in shock patients is clinically relevant. Unfortunately, there is no serum marker that can accurately assess intestinal ischemia-reperfusion injury. Objective The aim of this study was to assess if serum diamine oxidase levels can reflect intestinal mucosal injury subsequent to prolonged hemorrhagic shock. Methods Thirty New Zealand white rabbits were divided into three groups: a control group, a medium blood pressure (BP) group (exsanguinated to a shock BP of 50 to 41 mm Hg), and a low BP group (exsanguinated to a shock blood pressure of 40 to 31 mm Hg), in which the shock BP was sustained for 180 min prior to fluid resuscitation. Results The severity of hemorrhagic shock in the low BP group was significantly greater than that of the medium BP group according to the post-resuscitation BP, serum tumor necrosis factor (TNF)-α, and arterial lactate. Intestinal damage was significantly more severe in the low BP group according to Chiu’s scoring, claudin-1, intercellular adhesion molecule (ICAM)-1, and myeloperoxidase expression. Serum diamine oxidase was significantly increased in the low BP group compared to the medium BP and control groups and was negatively correlated with shock BP. Conclusion Serum diamine oxidase can be used as a serological marker in evaluating intestinal injury and shows promise as an indicator of hemorrhagic shock severity.
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Affiliation(s)
- Liang Zhao
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Lin Luo
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Weikun Jia
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Juan Xiao
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Gang Huang
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Geng Tian
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jingwei Li
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yingbin Xiao
- Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
- * E-mail:
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Zhao L, Luo L, Chen J, Xiao J, Jia W, Xiao Y. Utilization of Extracorporeal Membrane Oxygenation Alleviates Intestinal Ischemia–Reperfusion Injury in Prolonged Hemorrhagic Shock Animal Model. Cell Biochem Biophys 2014; 70:1733-40. [DOI: 10.1007/s12013-014-0121-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Müller-Edenborn B, Frick R, Piegeler T, Schläpfer M, Roth-Z'graggen B, Schlicker A, Beck-Schimmer B. Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling. Br J Anaesth 2014; 114:143-9. [PMID: 24989774 DOI: 10.1093/bja/aeu189] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.
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Affiliation(s)
- B Müller-Edenborn
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - R Frick
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - T Piegeler
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland Department of Anesthesiology, University of Illinois Hospital & Health Sciences Center, Chicago, IL, USA
| | - M Schläpfer
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - B Roth-Z'graggen
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - A Schlicker
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland
| | - B Beck-Schimmer
- Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland
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Abstract
Ischemic diseases are a leading cause of death worldwide. It is becoming increasingly appreciated that atherosclerosis is a major cause of ischemia reperfusion. Hypercholesterolemia is a major risk factor for the development of atherosclerosis, and is associated with an increased incidence of ischemia reperfusion. Furthermore, elevated cholesterol levels exacerbate the vascular responses to ischemia-reperfusion, which intensifies the resulting organ dysfunction. One of the underlying features of both ischemia-reperfusion injury and hypercholesterolemia is the proinflammatory and prothrombogenic phenotype invoked in the microvasculature. This is manifested as an endothelial dysfunction, characterized by leukocyte and platelet recruitment, oxidative stress and angiotensin II receptor Type 1a activation. These common pathways of inflammation offer attractive targets for the development of drugs to combat cardiovascular disease and the associated ischemic disorders.
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Affiliation(s)
- Karen Y Stokes
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
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Chang CF, Li CJ, Ko CJ, Teng TH, Lai SC, Yang MC, Chiu CW, Chou CC, Chang CY, Yao YC, Wu LH, Wu HP, Chen WL, Lin YR. The post-resuscitative urinalysis associate the survival of patients with non-traumatic out-of-hospital cardiac arrest. PLoS One 2013; 8:e75172. [PMID: 24124472 PMCID: PMC3790766 DOI: 10.1371/journal.pone.0075172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 08/13/2013] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE To analyze whether urine output and urinalysis results are predictive of survival and neurologic outcomes in patients with non-traumatic out-of-hospital cardiac arrest (OHCA). METHODS Information was obtained from 1,340 patients with non-traumatic OHCA who had achieved a sustained return of spontaneous circulation (ROSC). Factors that were associated with survival in the post-resuscitative period were evaluated. The association between urine output and fluid challenge in the early resuscitative period was analyzed and compared between the survivors and the non-survivors. The results of the initial urinalysis, including the presence of proteinuria and other findings, were used to evaluate the severity of vascular protein leakage and survival. The association between proteinuria and the neurologic outcomes of the survivors was also analyzed. The clinical features of capillary leakage were examined during the post-resuscitative period. RESULTS Of the 1,340 patients, 312 survived. A greater urine output was associated with a higher chance of survival. The initial urine output increased in proportion to the amount of fluid that was administered during early resuscitation in the emergency department for the survivors but not for the non-survivors (p<0.05). In the initial urinalysis, proteinuria was strongly associated with survival, and severe proteinuria indicated significantly poorer neurologic outcomes (p<0.05 for both comparisons). Proteinuria was associated with a risk of developing signs of capillary leakage, including body mass index gain and pitting edema (both p<0.001). CONCLUSION The severity of proteinuria during the early post-resuscitative period was predictive of survival.
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Affiliation(s)
- Chin-Fu Chang
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chao-Jui Li
- Department of Emergency Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Jan Ko
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Tsung-Han Teng
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
- Department of Pathology, Taichung Hospital, Department of Health, Executive Yuan, Taichung, Taiwan
| | - Shih-Chang Lai
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Mei-Chueh Yang
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chun-Wen Chiu
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chu-Chung Chou
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chih-Yu Chang
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Yung-Chiao Yao
- Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan
| | - Lan-Hsin Wu
- Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan
| | - Han-Ping Wu
- Department of Pediatrics, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan
| | - Wen-Liang Chen
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Yan-Ren Lin
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Methysergide attenuates systemic burn edema in rats. Microvasc Res 2013; 89:115-21. [DOI: 10.1016/j.mvr.2013.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Revised: 03/02/2013] [Accepted: 03/17/2013] [Indexed: 11/19/2022]
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Abstract
It is being increasingly suggested that the microcirculation, which is known to be in a large part responsible for maintaining an adequate and constant microenvironment for function of the central nervous system, functions as part of a neurovascular unit. The neurovascular unit includes neurons, astrocytes and elements of capillaries. The cerebral circulation exhibits unique functional characteristics and critical elements for the pathogenesis of cerebrovascular disease. For example, the blood-brain barrier formed by epithelial-like high resistance tight junctions within the endothelium is a key feature of microvessels of the central nervous system. Alterations in the microcirculation after ischemia/reperfusion include disruption of the blood-brain barrier, edema and swelling of perivascular astrocyte foot processes, decrease in arteriole endothelium-dependent relaxation and reduced inwardly-rectifying potassium channel function, altered expression of proteases and matrix metalloproteinases, increased inflammatory mediators and inflammation. Experiments studying the microcirculation in ischemia are few compared with those examining neuroprotection, although the two overlap because protection of the microcirculation might achieve some degree of neuroprotection and both processes may be mediated by at least some mechanisms in common.
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Affiliation(s)
- Masataka Takahashi
- Section of Neurosurgery, Department of Surgery, University of Chicago Medical Center and Pritzker School of Medicine, Chicago, IL 60637, USA
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Abstract
Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down-regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury.
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Molecular Imaging of Selectins in Endothelial Activation. CURRENT CARDIOVASCULAR IMAGING REPORTS 2012. [DOI: 10.1007/s12410-012-9143-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Conceição FGD, Conde CMS, Svensjö E, Bottino DA, Bouskela E. Preconditioning of the response to ischemia/ reperfusion-induced plasma leakage in hamster cheek pouch microcirculation. Clinics (Sao Paulo) 2012; 67:923-9. [PMID: 22948461 PMCID: PMC3416899 DOI: 10.6061/clinics/2012(08)12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/02/2012] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Ischemic preconditioning and some drugs can protect tissues from injury by preserving microcirculation. This study evaluated vascular permeability in a hamster cheek pouch preparation using either short ischemic periods or bradykinin as preconditioning stimuli followed by 30 min of ischemia/reperfusion. METHOD Sixty-six male hamsters were divided into 11 groups: five combinations of different ischemic frequencies and durations (one, three or five shorts periods of ischemia, separated by one or five minutes) with 10 min intervals between the ischemic periods, followed by 30 min ischemia/reperfusion; three or five 1 min ischemic periods with 10 min intervals between them followed by the topical application of histamine (2 µM); bradykinin (400 nM) followed by 30 min of ischemia/reperfusion; and three control groups (30 min of ischemia/reperfusion or histamine or bradykinin by themselves). Macromolecular permeability was assessed by injection of fluorescein-labeled dextran (FITC-dextran, MW= 150 kDa; 250 mg/Kg body weight), and the number of leaks/cm2 was counted using an intravital microscope and fluorescent light in the cheek pouch. RESULTS Plasma leakage (number of leaks/cm²) was significantly reduced by preconditioning with three and five 1 min ischemic periods, one and three 5 min ischemic periods and by bradykinin. Histamine-induced macromolecular permeability was also reduced after three periods of 5 min of ischemia. CONCLUSION Short ischemic periods and bradykinin can function as preconditioning stimuli of the ischemia/reperfusion response in the hamster cheek pouch microcirculation. Short ischemic periods also reduced histamineinduced macromolecular permeability.
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Affiliation(s)
- Fabiana Gomes da Conceição
- Laboratory for Clinical and Experimental Research on Vascular Biology, Biomedical Center, State University of Rio de Janeiro, RJ, Brazil
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Grosche A, Freeman DE, Morton AJ, Polyak MMR, Matyjaszek SA. Effects of ischemia and reperfusion on production of nitrotyrosine, activation of eosinophils, and apoptosis in the large colonic mucosa of horses. Am J Vet Res 2012; 73:53-61. [PMID: 22204288 DOI: 10.2460/ajvr.73.1.53] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To assess the effects of ischemia and reperfusion on indicators of oxidative stress, activation of eosinophils, and apoptosis in the large colonic mucosa of horses. ANIMALS 40 horses. PROCEDURES In 1 or two 20-cm-long segments of the pelvic flexure, ischemia was induced for 1 or 2 hours followed by no reperfusion or 30 minutes and 18 hours of reperfusion in anesthetized horses. Mucosal specimens were collected before (controls; n = 20 horses) and after each period of ischemia, and full-thickness tissue samples were collected after each period of reperfusion. Sections of colonic tissues were stained for histomorphometric analysis or assessment of eosinophil accumulation. Nitrotyrosine was identified immunohistochemically, and severity of apoptosis was determined via the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. RESULTS Numbers of mucosal eosinophils were similar before induction of ischemia, after ischemia, and after ischemia-reperfusion. Eosinophil nitrotyrosine production increased significantly during ischemia and continued through 30 minutes of reperfusion; production was decreased at 18 hours of reperfusion but remained greater than that of the controls. In other leukocytes, nitrotyrosine generation peaked at 1 hour of ischemia and again at 18 hours of reperfusion. Compared with control findings, epithelial apoptosis increased gradually at 1 through 2 hours of ischemia with no further progression after reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that resident eosinophils in the large colon of horses react to mucosal injury from ischemia and reperfusion and may undergo oxidative stress under those conditions. Epithelial apoptosis could contribute to tissue damage.
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Affiliation(s)
- Astrid Grosche
- Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA. agrosche@.ufl.edu
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van Golen RF, van Gulik TM, Heger M. Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury. Free Radic Biol Med 2012; 52:1382-402. [PMID: 22326617 DOI: 10.1016/j.freeradbiomed.2012.01.013] [Citation(s) in RCA: 173] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 01/20/2012] [Accepted: 01/20/2012] [Indexed: 02/06/2023]
Abstract
Endothelial cells are covered by a delicate meshwork of glycoproteins known as the glycocalyx. Under normophysiological conditions the glycocalyx plays an active role in maintaining vascular homeostasis by deterring primary and secondary hemostasis and leukocyte adhesion and by regulating vascular permeability and tone. During (micro)vascular oxidative and nitrosative stress, which prevails in numerous metabolic (diabetes), vascular (atherosclerosis, hypertension), and surgical (ischemia/reperfusion injury, trauma) disease states, the glycocalyx is oxidatively and nitrosatively modified and degraded, which culminates in an exacerbation of the underlying pathology. Consequently, glycocalyx degradation due to oxidative/nitrosative stress has far-reaching clinical implications. In this review the molecular mechanisms of reactive oxygen and nitrogen species-induced destruction of the endothelial glycocalyx are addressed in the context of hepatic ischemia/reperfusion injury as a model disease state. Specifically, the review focuses on (i) the mechanisms of glycocalyx degradation during hepatic ischemia/reperfusion, (ii) the molecular and cellular players involved in the degradation process, and (iii) its implications for hepatic pathophysiology. These topics are projected against a background of liver anatomy, glycocalyx function and structure, and the biology/biochemistry and the sources/targets of reactive oxygen and nitrogen species. The majority of the glycocalyx-related mechanisms elucidated for hepatic ischemia/reperfusion are extrapolatable to the other aforementioned disease states.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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Kim TH, Ku SK, Bae JS. Inhibitory effects of kaempferol-3-O-sophoroside on HMGB1-mediated proinflammatory responses. Food Chem Toxicol 2011; 50:1118-23. [PMID: 22178603 DOI: 10.1016/j.fct.2011.12.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 12/01/2011] [Accepted: 12/02/2011] [Indexed: 10/14/2022]
Abstract
High mobility group box 1 (HMGB1) protein is secreted by activated cells of the innate immune system and/or released by injured tissues and necrotic cells; HMGB1 up-regulates proinflammatory cytokines in several inflammatory diseases. Kaempferol-3-O-sophoroside (KP) was isolated from the leaves of cultivated mountain ginseng. KP has antitumor, antioxidative, antiallergic and antidiabetic activities, but the effects of KP on HMGB1-mediated proinflammatory responses have not been studied. In this study, we monitored the effect of KP on the lipopolysaccharide (LPS)-mediated release of HMGB1 and the HMGB1-mediated modulation of proinflammatory responses in human endothelial cells. We found that KP potently inhibited the release of HMGB1 by LPS and inhibited LPS- or HMGB1-mediated barrier permeability and expression of cell adhesion molecules. Further studies revealed that KP inhibited cell surface receptor of HMGB1, toll-like receptor (TLR) 2/4, but not the receptor for advanced glycation end products (RAGE). Collectively, these results suggest that KP possesses anti-inflammatory responses against HMGB1-mediated proinflammatory responses, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
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Affiliation(s)
- Tae Hoon Kim
- Department of Herbal Medicinal Pharmacology, College of Herbal Bio-Industry, Daegu Haany University, Gyeongsan 712-715, Republic of Korea
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Lawendy AR, Sanders DW, Bihari A, Parry N, Gray D, Badhwar A. Compartment syndrome-induced microvascular dysfunction: an experimental rodent model. Can J Surg 2011; 54:194-200. [PMID: 21443836 DOI: 10.1503/cjs.048309] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Acute compartment syndrome (CS) is a limb-threatening disease that results from increased intracompartmental pressure. The pathophysiologic mechanisms by which this occurs are poorly understood. This study was designed to measure the effects of increased intracompartmental pressure on skeletal muscle microcirculation, inflammation and cellular injury using intravital videomicroscopy (IVVM) in a clinically relevant small animal model. METHODS We induced CS in 10 male Wistar rats (175-250 g), using a saline infusion technique. Intracompartmental pressure was controlled between 30 and 40 mm Hg and maintained for 45 minutes. After fasciotomy, the extensor digitorum longus muscle was visualized using IVVM, and perfusion was quantified. We quantified leukocyte recruitment to measure the inflammatory response. We measured muscle cellular injury using a differential fluorescent staining technique. RESULTS The number of nonperfused capillaries increased from 12.7 (standard error of the mean [SEM] 1.4 ) per mm in the control group to 30.0 (SEM 6.7) per mm following 45 minutes of elevated intracompartmental pressure (CS group; p = 0.031). The mean number of continuously perfused capillaries (and SEM) decreased from 78.4 (3.2) per mm in the control group to 41.4 (6.9) per mm in the CS group (p = 0.001). The proportion of injured cells increased from 5.0% (SEM 2.1%) in the control group to 16.3% (SEM 6.8%) in the CS group (p = 0.006). The mean number of activated leukocytes increased from 3.6 (SEM 0.7) per 100 μm(2) in the control group to 8.6 (SEM 1.8) per 100 μm(2) in the CS group (p = 0.033). CONCLUSION Early CS-induced microvascular dysfunction resulted in a decrease in nutritive capillary perfusion and an increase in cellular injury and was associated with a severe acute inflammatory component.
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High-dose vitamin C treatment reduces capillary leakage after burn plasma transfer in rats. J Burn Care Res 2011; 31:470-9. [PMID: 20354446 DOI: 10.1097/bcr.0b013e3181db5199] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress after burn injuries leads to systemic capillary leakage and leukocyte activation. This study evaluates whether antioxidative treatment with high-dose vitamin C leads to burn edema reduction and prevention of leukocyte activation after burn plasma transfer. Donor rats underwent a burn (n = 7; 100 degrees C water, 12 seconds, 30% body surface area) or sham burn (37 degrees C water; n = 2) procedure and were killed after 4 hours for plasma harvest. This plasma was administered to study rats (continuous infusion). Rats were randomized to four groups (n = 8 each; burn plasma alone [BP]; burn plasma/vitamin C-bolus 66 mg/kg and maintenance dose 33 mg/kg/hr [VC66]; burn plasma/vitamin C-bolus 33 mg/kg and maintenance dose 17.5 mg/kg/hr [VC33]; and sham burn plasma [SB]). Intravital fluorescence microscopy in the mesentery was performed at 0, 60, and 120 minutes for microhemodynamic parameters, leukocyte adherence, and fluorescein isothiocyanate-albumin extravasation. No differences were observed in microhemodynamics at any time. Burn plasma induced capillary leakage, which was significantly higher compared with sham burn controls (P < .001). VC66 treatment reduced microvascular barrier dysfunction to sham burn levels, whereas VC33 had no significant effect. Leukocyte sticking increased after burn plasma infusion, which was not found for sham burn. Vitamin C treatment did not influence leukocyte activation (P > .05). Burn plasma transfer leads to systemic capillary leakage. High-dose vitamin C treatment (bolus 66 mg/kg and maintenance dose 33 mg/kg/hr) reduces endothelial damage to sham burn levels, whereas half the dose is inefficient. Leukocyte activation is not influenced by antioxidative treatment. Therefore, capillary leakage seems to be independent from leukocyte-endothelial interactions after burn plasma transfer. High-dose vitamin C should be considered for parenteral treatment in every burn patient.
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Dewitte A, Biais M, Coquin J, Fleureau C, Cassinotto C, Ouattara A, Janvier G. [Diagnosis and management of acute mesenteric ischemia]. ACTA ACUST UNITED AC 2011; 30:410-20. [PMID: 21481561 DOI: 10.1016/j.annfar.2011.02.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 02/09/2011] [Indexed: 12/19/2022]
Abstract
The prevalence of significant splanchnic arterial stenoses is increasing, but remains mostly asymptomatic due to abundant collateral circulation. Acute insufficiency of mesenteric arterial blood flow accounts for 60 to 70% of cases of mesenteric ischemia and results mostly from a superior mesenteric embolus. Despite major advances have been achieved in understanding the pathogenic mechanisms of bowel ischemia, its prognosis remains dismal with mortality rates about 60%. The diagnosis of acute mesenteric ischemia depends upon a high clinical suspicion, especially in patients with known risk factors. Rapid diagnosis is essential to prevent intestinal infarction. However, early signs and symptoms of mesenteric ischemia are non specific, and definitive diagnosis often requires radiologic examinations. Early and liberal implementation of angiography has been the major advance over the past 30 years which allowed increasing diagnostic accuracy of acute mesenteric ischemia. CT and MR-based angiographic techniques have emerged as alternatives less invasive and more accurate to analyse splanchnic vessels and evaluate bowel infarction. The goal of treatment of patients with acute mesenteric ischemia is to restore intestinal oxygenation as quickly as possible after initial management that includes rapid hemodynamic monitoring and support. Surgery should not be delayed in patients suspected of having intestinal necrosis.
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Affiliation(s)
- A Dewitte
- Service d'anesthésie-réanimation II, CHU de Bordeaux, Maison du Haut-Lévêque, groupe hospitalier Sud, université Bordeaux-Segalen, avenue de Magellan, Pessac cedex, France.
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Mankia KS, McAteer MA, Choudhury RP. Microparticle-Based Molecular MRI of Atherosclerosis, Thrombosis, and Tissue Ischemia. CURRENT CARDIOVASCULAR IMAGING REPORTS 2011. [DOI: 10.1007/s12410-010-9059-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Akhtar AM, Schneider JE, Chapman SJ, Jefferson A, Digby JE, Mankia K, Chen Y, McAteer MA, Wood KJ, Choudhury RP. In vivo quantification of VCAM-1 expression in renal ischemia reperfusion injury using non-invasive magnetic resonance molecular imaging. PLoS One 2010; 5:e12800. [PMID: 20877722 PMCID: PMC2943468 DOI: 10.1371/journal.pone.0012800] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 08/17/2010] [Indexed: 01/01/2023] Open
Abstract
Rationale and Objective Vascular cell adhesion molecule-1 (VCAM-1) is upregulated in ischemia reperfusion injury (IRI), persisting after restoration of blood flow. We hypothesized that microparticles of iron oxide targeting VCAM-1 (VCAM-MPIO) would depict “ischemic memory” and enable in vivo assessment of VCAM-1 expression. Methodology and Findings Mice subject to unilateral, transient (30 minutes) renal ischemia and subsequent reperfusion received intravenous VCAM-MPIO (4.5 mg iron/kg body weight). Contrast agent bound rapidly (<30 minutes) in IRI-kidneys and appeared as intensely low signal areas by MRI in vivo. Automated segmentation and quantification yielded MPIO contrast volumes of 5991±354×106 µm3 in IRI vs. 87±7×106 µm3 in kidneys with no surgical intervention (P<0.001); 90±8×106 µm3 in IRI kidneys exposed to control (IgG-MPIO) and 625±80×106 µm3, in IRI kidneys pre-treated with a blocking dose of VCAM-1 antibody (P<0.001). In keeping with quantitative MRI data, VCAM-1 mRNA expression in IRI was 65-fold higher than in kidneys without surgical intervention (3.06±0.63 vs. 0.05±0.02, P<0.001). Indeed VCAM-1 mRNA expression and VCAM-MPIO contrast volume were highly correlated (R2 = 0.901, P<0.01), indicating that quantification of contrast volume reflected renal VCAM-1 transcription. Serial imaging showed VCAM-MPIO accumulation at target within 30 minutes, persisting for ≥90 minutes, while unbound VCAM-MPIO was cleared rapidly from blood, with sequestration by mac-3 positive Kupffer cells in the liver and monocyte/macrophages in the spleen. Conclusions (1) VCAM-MPIO detected VCAM-1 expression and defined its 3-dimensional distribution, revealing “ischemic memory” in renal IRI; (2) automated volumetric quantification of VCAM-MPIO accurately reflected tissue levels of VCAM-1 mRNA; and (3) VCAM-MPIO bound rapidly to target with active sequestration of unbound MPIO in the liver and spleen.
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Affiliation(s)
- Asim M. Akhtar
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Jurgen E. Schneider
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Stephanie J. Chapman
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Andrew Jefferson
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Janet E. Digby
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Kulveer Mankia
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Ye Chen
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Martina A. McAteer
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Kathryn J. Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Robin P. Choudhury
- Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
- * E-mail:
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Erling N, Nakagawa NK, Costa Cruz JWM, Zanoni FL, Baptista-Silva JCC, Sannomiya P, Poli-de-Figueiredo LF. Microcirculatory effects of local and remote ischemic preconditioning in supraceliac aortic clamping. J Vasc Surg 2010; 52:1321-9. [PMID: 20674244 DOI: 10.1016/j.jvs.2010.05.120] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 05/26/2010] [Accepted: 05/30/2010] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Supraceliac aortic clamping in major vascular procedures promotes splanchnic ischemia and reperfusion (I/R) injury that may induce endothelial dysfunction, widespread inflammation, multiorgan dysfunction, and death. We tested the hypothesis that local or remote ischemic preconditioning (IPC) may be protective against injury after supraceliac aortic clamping through the modulation of mesenteric leukocyte-endothelial interactions, as evaluated with intravital microscopy and expression of adhesion molecules. METHODS Fifty-six male Wistar rats (weight, 190 to 250 g), were divided into four groups of 14 rats each: control-sham surgery without aortic occlusion; I/R through supraceliac aortic occlusion for 20 minutes, followed by 120 minutes of reperfusion; local IPC through supraceliac aortic occlusion for two cycles of 5 minutes of ischemia and 5 minutes of reperfusion, followed by the same protocol of the IR group; remote IPC through infrarenal aortic occlusion for two cycles of 10 minutes of ischemia and 10 minutes of reperfusion, followed by the same protocol of the IR group. Seven animals per group were used to evaluate in vivo leukocyte-endothelial interactions in postcapillary venules with intravital microscopy and another seven animals per group were used to collect mesentery samples for immunohistochemistry demonstration of adhesion molecules expression. RESULTS Supraceliac aortic occlusion increased the number of rolling leukocytes with slower velocities and increased the number of adherent leukocytes to the venular surface and leukocyte migration to the interstitium. The expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 was also increased significantly after I/R. Local or remote IPC reduced the leukocyte recruitment in vivo and normalized the expression of adhesion molecules. CONCLUSIONS Local or remote IPC reduces endothelial dysfunction on mesenteric microcirculation caused by I/R injury after supraceliac aortic clamping.
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Affiliation(s)
- Nilon Erling
- Department of Surgery, Federal University of São Paulo, São Paulo, SP, Brazil.
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Gropler RJ, Beanlands RSB, Dilsizian V, Lewandowski ED, Villanueva FS, Ziadi MC. Imaging myocardial metabolic remodeling. J Nucl Med 2010; 51 Suppl 1:88S-101S. [PMID: 20457796 DOI: 10.2967/jnumed.109.068197] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Myocardial metabolic remodeling is the process in which the heart loses its ability to utilize different substrates, becoming dependent primarily on the metabolism of a single substrate such as glucose or fatty acids for energy production. Myocardial metabolic remodeling is central to the pathogenesis of a variety of cardiac disease processes such as left ventricular hypertrophy, myocardial ischemia, and diabetic cardiomyopathy. As a consequence, there is a growing demand for accurate noninvasive imaging approaches of various aspects of myocardial substrate metabolism that can be performed in both humans and small-animal models of disease, facilitating the crosstalk between the bedside and the bench and leading to improved patient management paradigms. SPECT, PET, and MR spectroscopy are the most commonly used imaging techniques. Discussed in this review are the strengths and weaknesses of these various imaging methods and how they are furthering our understanding of the role of myocardial remodeling in cardiovascular disease. In addition, the role of ultrasound to detect the inflammatory response to myocardial ischemia will be discussed.
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Affiliation(s)
- Robert J Gropler
- Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
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