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Yao Z, Zhao Y, Lu L, Li Y, Yu Z. Extracerebral multiple organ dysfunction and interactions with brain injury after cardiac arrest. Resusc Plus 2024; 19:100719. [PMID: 39149223 PMCID: PMC11325081 DOI: 10.1016/j.resplu.2024.100719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 08/17/2024] Open
Abstract
Cardiac arrest and successful resuscitation cause whole-body ischemia and reperfusion, leading to brain injury and extracerebral multiple organ dysfunction. Brain injury is the leading cause of death and long-term disability in resuscitated survivors, and was conceptualized and treated as an isolated injury, which has neglected the brain-visceral organ crosstalk. Extracerebral organ dysfunction is common and is significantly associated with mortality and poor neurological prognosis after resuscitation. However, detailed description of the characteristics of post-resuscitation multiple organ dysfunction is lacking, and the bidirectional interactions between brain and visceral organs need to be elucidated to explore new treatment for neuroprotection. This review aims to describe current concepts of post-cardiac arrest brain injury and specific characteristics of post-resuscitation dysfunction in cardiovascular, respiratory, renal, hepatic, adrenal, gastrointestinal, and neurohumoral systems. Additionally, we discuss the crosstalk between brain and extracerebral organs, especially focusing on how visceral organ dysfunction and other factors affect brain injury progression. We think that clarifying these interactions is of profound significance on how we treat patients for neural/systemic protection to improve outcome.
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Affiliation(s)
- Zhun Yao
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yuanrui Zhao
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Liping Lu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yinping Li
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430060, China
| | - Zhui Yu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
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Kumari P, Panigrahi AR, Yadav P, Beura SK, Singh SK. Platelets and inter-cellular communication in immune responses: Dialogue with both professional and non-professional immune cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 140:347-379. [PMID: 38762274 DOI: 10.1016/bs.apcsb.2023.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2024]
Abstract
Platelets, derived from bone marrow megakaryocytes, are essential for vascular integrity and play multifaceted roles in both physiological and pathological processes within the vasculature. Despite their small size and absence of a nucleus, platelets are increasingly recognized for their diverse immune functions. Recent research highlights their pivotal role in interactions with various immune cells, including professional cells like macrophages, dendritic cells, natural killer cells, T cells, and B cells, influencing host immune responses. Platelets also engage with non-professional immune cells, contributing to immune responses and structural maintenance, particularly in conditions like inflammation and atherosclerosis. This review underscores the emerging significance of platelets as potent immune cells, elucidating their interactions with the immune system. We explore the mechanisms of platelet activation, leading to diverse functions, such as aggregation, immunity, activation of other immune cells, and pathogen clearance. Platelets have become the predominant immune cells in circulation, involved in chronic inflammation, responses to infections, and autoimmune disorders. Their immunological attributes, including bioactive granule molecules and immune receptors, contribute to their role in immune responses. Unlike professional antigen-presenting cells, platelets process and present antigens through an MHC-I-dependent pathway, initiating T-cell immune responses. This review illuminates the unique features of platelets and their central role in modulating host immune responses in health and disease.
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Affiliation(s)
- Puja Kumari
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | | | - Pooja Yadav
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Samir Kumar Beura
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Sunil Kumar Singh
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India; Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India.
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3
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West PW, Bulfone-Paus S. Mast cell tissue heterogeneity and specificity of immune cell recruitment. Front Immunol 2022; 13:932090. [PMID: 35967445 PMCID: PMC9374002 DOI: 10.3389/fimmu.2022.932090] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
Mast cells occupy a unique niche within tissues as long lived perpetrators of IgE mediated hypersensitivity and anaphylaxis, as well as other immune responses. However, mast cells are not identical in different tissues and the impact of this tissue heterogeneity on the interaction with other immune cells and on defined immune responses is still unclear. In this review, we synthesize the characteristics of mast cell heterogeneity in the gut and the skin. Furthermore, we attempt to connect mast cell heterogeneity with functional diversity by exploring differences in mast cell-induced immune cell recruitment in these two model organs. The differential expression of certain receptors on mast cells of different tissues, notably tissue-specific expression patterns of integrins, complement receptors and MRGPRX2, could indicate that tissue environment-dependent factors skew mast cell-immune cell interactions, for example by regulating the expression of these receptors.
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Affiliation(s)
| | - Silvia Bulfone-Paus
- Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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4
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Zhou Q, Verne GN. Disruption of the Mucosal Serotonin Reuptake Transporter (SERT) Through Gut Dysbiosis. Gastroenterology 2022; 162:1833-1834. [PMID: 35341788 DOI: 10.1053/j.gastro.2022.03.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Qiqi Zhou
- Department of Medicine, University of Tennessee College of Medicine, Memphis, Tennessee; Research Service, Memphis Veterans Affairs Medical Center, Memphis, Tennessee
| | - George Nicholas Verne
- Department of Medicine, University of Tennessee College of Medicine, Memphis, Tennessee; Research Service, Memphis Veterans Affairs Medical Center, Memphis, Tennessee.
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Kong M, Wei D, Li X, Zhu X, Hong Z, Ni M, Wang Y, Dong A. The dynamic changes in autophagy activity and its role in lung injury after deep hypothermic circulatory arrest. J Cell Mol Med 2022; 26:1113-1127. [PMID: 35014165 PMCID: PMC8831962 DOI: 10.1111/jcmm.17165] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/22/2021] [Accepted: 12/09/2021] [Indexed: 12/27/2022] Open
Abstract
Deep hypothermic circulatory arrest (DHCA) can cause acute lung injury (ALI), and its pathogenesis mimics ischaemia/reperfusion (I/R) injury. Autophagy is also involved in lung I/R injury. The present study aimed to elucidate whether DHCA induces natural autophagy activation and its role in DHCA‐mediated lung injury. Here, rats were randomly assigned to the Sham or DHCA group. The sham group (n = 5) only received anaesthesia and air intubation. DHCA group rats underwent cardiopulmonary bypass (CPB) followed by the DHCA procedure. The rats were then sacrificed at 3, 6 and 24 h after the DHCA procedure (n = 5) to measure lung injury and autophagy activity. Chloroquine (CQ) was delivered to evaluate autophagic flux. DHCA caused lung injury, which was prominent 3–6 h after DHCA, as confirmed by histological examination and inflammatory cytokine quantification. Lung injury subsided at 24 h. Autophagy was suppressed 3 h but was exaggerated at 6 h. At both time points, autophagic flux appeared uninterrupted. To further assess the role of autophagy in DHCA‐mediated lung injury, the autophagy inducer rapamycin and its inhibitor 3‐methyladenine (3‐MA) were applied, and lung injury was reassessed. When rapamycin was administered at an early time point, lung injury worsened, whereas administration of 3‐MA at a late time point ameliorated lung injury, indicating that autophagy contributed to lung injury after DHCA. Our study presents a time course of lung injury following DHCA. Autophagy showed adaptive yet protective suppression 3 h after DHCA, as induction of autophagy caused worsening of lung tissue. In contrast, autophagy was exaggerated 6 h after DHCA, and autophagy inhibition attenuated DHCA‐mediated lung injury.
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Affiliation(s)
- Minjian Kong
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Dongdong Wei
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xuebiao Li
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xian Zhu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ze Hong
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ming Ni
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Wang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Aiqiang Dong
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Lou X, Liu Y, Cui Y, Li J, Li L, Ma L, Zou M, Chen X, Li J. Contemporary Trends and Risk Factors of Hemodynamic and Myocardial Mechanics Derived by the Pressure Recording Analytical Method After Pediatric Cardiopulmonary Bypass. Front Cardiovasc Med 2021; 8:687150. [PMID: 34355027 PMCID: PMC8330813 DOI: 10.3389/fcvm.2021.687150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/25/2021] [Indexed: 01/14/2023] Open
Abstract
Objective: Adverse factors of postoperative hemodynamic and myocardial performance remain largely unexplored in children with congenital heart disease following cardiopulmonary bypass due to technical limitations. Pressure recording analytical method (PRAM) is a continuous hemodynamic and myocardial performance monitoring technique based on beat-to-beat arterial pressure waveform. Using PRAM, we examined the temporal trends and adverse factors, in clinical management, of these performances. Methods: We monitored blood pressure, cardiac index, cardiac cycle efficiency (CCE), dP/dTmax, and systematic vascular resistance index in 91 children (aged 186 ± 256 days) during their first 48 h after cardiopulmonary bypass. Above parameters, inotropic and vasoactive drug dosages, and serum lactate were recorded 3-hourly. NT-proBNP was measured daily. Results: CCE and dP/dTmax gradually increased (Ps < 0.0001), while systematic vascular resistance index, diastolic blood pressure and inotrope dosages decreased (Ps < 0.0001) over time. Cardiac index, systolic blood pressure, and heart rate did not change significantly (Ps ≥ 0.231). Patients undergoing deep hypothermic circulatory arrest had significantly higher heart rate and lower CCE (Ps ≤ 0.006) over time. Multivariate analyses indicated that epinephrine dose significantly correlated with systolic blood pressure, cardiac index, CCE, and dP/dTmax after polynomial transformation, with the peak ranging from 0.075 to 0.097. Conclusions: Systemic hemodynamic and myocardial performance gradually improved in the first 48 h after cardiopulmonary bypass without the “classic” nadir at 9–12 h. Deep hypothermic circulatory arrest and higher epinephrine doses were adversely associated with these performances. CCE, rather than cardiac index or other common-used parameters, was the most sensitive and consistent indicator.
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Affiliation(s)
- Xiaobin Lou
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Clinical Physiology Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yingying Liu
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Clinical Physiology Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yanqin Cui
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiac Intensive Care Unit, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jianbin Li
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiac Intensive Care Unit, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Lijuan Li
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiac Intensive Care Unit, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Li Ma
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiovascular Surgery, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Minghui Zou
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiovascular Surgery, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xinxin Chen
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Cardiovascular Surgery, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jia Li
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Clinical Physiology Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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7
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Jin X, Gharibani P, Yin J, Chen JDZ. Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats. Front Neurosci 2021; 15:645393. [PMID: 34276280 PMCID: PMC8282909 DOI: 10.3389/fnins.2021.645393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 06/01/2021] [Indexed: 11/21/2022] Open
Abstract
Background: Visceral hypersensitivity (VH) is one of the underlying pathophysiologies of irritable bowel syndrome. Mast cell overactivation has been found to be one of the main causes of VH. We investigated the effects and mechanisms of actions of sacral nerve stimulation (SNS) on visceral pain in a rodent model of VH. Methods: The VH was established by an intrarectal infusion of AA in 10-day-old pups. Rats were chronically implanted with electrodes for SNS and recording electromyogram (EMG) and electrocardiogram. The acute study was performed in 2-randomized sessions with SNS (14 Hz, 330 μs, 40% motor threshold or MT, 30 min) or sham-SNS. Later on, rats were randomized into SNS/sham-SNS groups and a chronic study was performed with 2 h-daily SNS or sham-SNS for 21 days. Visceromotor reflexes were assessed by abdominal EMG and withdrawal reflex (AWR). Colon tissues were collected to study colonic acetylcholine (ACh), the enteric neurons (ChAT, nNOS, and PGP9.5), mast cells activity [Tryptase, prostaglandins E2 (PGE2), and cyclooxygenases-2 (COX2)] and pain markers [nerve growth factor (NGF) and Sub-P]. Key Results: Sacral nerve stimulation significantly improved visceromotor reflexes assessed by the EMG and AWR, compared with sham-SNS. SNS normalized the protein expressions of ChAT and nNOS and regulated mast cells activity by downregulating Tryptase, COX2, and PGE2. Neonatal AA administration upregulated NGF and Sub-P; chronic SNS significantly decreased these pain biomarkers. Concurrently, chronic SNS increased ACh in colon tissues and vagal efferent activity. Conclusions: Sacral nerve stimulation reduces VH in rats and this ameliorating effect might be attributed to the suppression of mast cell overactivation in the colon tissue via the modulation of autonomic nervous system functions.
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Affiliation(s)
- Xue Jin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Payam Gharibani
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut. Int J Mol Sci 2021; 22:ijms22116116. [PMID: 34204101 PMCID: PMC8200986 DOI: 10.3390/ijms22116116] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023] Open
Abstract
Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.
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Tu L, Gharibani P, Yin J, Chen JDZ. Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis. Neurogastroenterol Motil 2020; 32:e13916. [PMID: 32537873 DOI: 10.1111/nmo.13916] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/30/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mucosal barrier damage is recognized as one of the key factors in the pathogenesis of colitis. While sacral nerve stimulation (SNS) was reported to have therapeutic potential for colitis, its mechanisms of actions on colonic permeability remained largely unknown. METHODS In this study, colitis was induced by intrarectal administration of TNBS in rats. Five days later, they were treated with SNS or sham-SNS for 10 days. The effects of SNS on colonic permeability were assessed by measuring the expression of tight-junction proteins involved in regulating permeability and the FITC-dextran test. The mechanism of actions of SNS was investigated by studying the function of the enteric nervous system (ENS) cells and analyzing the autonomic nervous system. KEY RESULTS SNS decreased the disease activity index, microscopic and macroscopic scores, myeloperoxidase activity, and pro-inflammatory cytokines (TNF-α, IL-6). SNS increased the expression of Zonula Occludens-1, Occludin, Claudin-1, and Junctional adhesion molecule-A in the colon tissue. The FITC-dextran test showed that the colonic permeability was lower with SCS than sham-SNS. SNS increased ChAT, pancreatic polypeptide, and GDNF and reduced norepinephrine NGF, sub-P, and mast cell overactivation in the colon tissue. Concurrently, SNS increased acetylcholine in colon tissues and elevated vagal efferent activity. CONCLUSIONS & INFERENCES SNS ameliorates colonic inflammation and enhances colonic barrier function with the proposed mechanisms involving the increase in parasympathetic activity and modulation of the activity of the ENS and immune system, including mast cells.
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Affiliation(s)
- Lei Tu
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Payam Gharibani
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Krychtiuk KA, Richter B, Lenz M, Hohensinner PJ, Huber K, Hengstenberg C, Wojta J, Heinz G, Speidl WS. Epinephrine treatment but not time to ROSC is associated with intestinal injury in patients with cardiac arrest. Resuscitation 2020; 155:32-38. [PMID: 32522698 DOI: 10.1016/j.resuscitation.2020.05.046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/15/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022]
Abstract
AIM Current guidelines suggest the use of epinephrine in patients with cardiac arrest (CA). However, evidence for increased survival in good neurological condition is lacking. In experimental settings, epinephrine-induced impairment of microvascular flow was shown. The aim of our study was to analyze the association between epinephrine treatment and intestinal injury in patients after CA. METHODS We have included 52 patients with return of spontaneous circulation (ROSC) after CA admitted to our medical intensive care unit (ICU). Blood was taken on admission and levels of circulating intestinal fatty acid binding protein (iFABP) were analyzed. RESULTS Patients were 64 (49.8-73.8) years old and predominantly male (76.9%). After six months, 50% of patients died and 38.5% of patients had a cerebral performance category (CPC)-score of 1-2. iFABP levels were lower in survivors (234 IQR 90-399 pg/mL) as compared to non-survivors (283, IQR 86-11500 pg/mL; p < 0.05). Plasma levels of iFABP were not associated with time to ROSC but correlated with epinephrine-dose (R = 0.32; p < 0.05). 40% of patients receiving ≥3 mg of epinephrine as compared to 10.5% of patients treated with <3 mg (p < 0.05) developed iFABP plasma levels >1500 pg/mL, which was associated with dramatically increased mortality (HR4.87, 95%CI 1.95-12.1; p < 0.001). iFABP levels predicted mortality independent from time to ROSC and the disease severity score SAPS II. In contrast to mortality, iFABP plasma levels were not associated with neurological outcome. CONCLUSIONS In this small, single centre study, cumulative dose of epinephrine used in cardiac arrest patients was associated with an increase in biomarker indicative of intestinal injury and 6-month mortality.
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Affiliation(s)
- Konstantin A Krychtiuk
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
| | - Bernhard Richter
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Max Lenz
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Philipp J Hohensinner
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
| | - Kurt Huber
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria; 3rd Medical Department, Wilhelminen Hospital, Vienna, Austria
| | - Christian Hengstenberg
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Johann Wojta
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria; Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Gottfried Heinz
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Walter S Speidl
- Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria.
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11
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Li Y, Liu M, Gao S, Cai L, Zhang Q, Yan S, Liu G, Ji B. Cold-inducible RNA-binding protein maintains intestinal barrier during deep hypothermic circulatory arrest. Interact Cardiovasc Thorac Surg 2020; 29:583-591. [PMID: 31271215 DOI: 10.1093/icvts/ivz147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 05/14/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES The intestinal injury during deep hypothermic circulatory arrest (DHCA) is harmful to clinical outcomes. Cold-inducible RNA-binding protein (CIRBP) plays a protective role in hypothermia. The aim of this study was to explore the effects of CIRBP on intestinal barrier during DHCA. METHODS Sprague-Dawley (wild type, n = 13) and knockout of Cirbp (Cirbp-/-, n = 8) rats were used in the model of DHCA. The histomorphology of the epithelial barrier was evaluated by haematoxylin-eosin, Chiu's scores, Gram's stain and Ki67. The function of the intestinal barrier was evaluated by serum intestinal fatty acid-binding protein, diamine oxidase and d-lactate. The structure of the epithelial barrier, phosphocreatine-creatine kinase system and adenosine triphosphate were assessed in the intestine. RESULTS The expression of CIRBP significantly increased in the intestine during DHCA. Cirbp-/- rats showed obvious destruction of intestinal barrier after DHCA. Chiu's scores, intestinal fatty acid-binding protein, diamine oxidase and d-lactate significantly increased in the Cirbp-/- group. Ki67 showed that cell proliferation decreased in the Cirbp-/- rats. In the Cirbp-/- group, zonula occludens-1, E-cadherin and occludin levels were significantly decreased, and these proteins either disappeared or redistributed in the monolayer. Besides, Cirbp-/- resulted in decreased levels of creatine kinase B, glycine amidinotransferase, adenosine triphosphate and creatine contents in the intestine, affecting energy metabolism and balance, which is associated with the maintenance of epithelial barrier during acute injury. CONCLUSIONS CIRBP is related to the maintenance of the intestinal epithelial barrier during DHCA, which is expected to be a new target for the prevention of intestinal injury.
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Affiliation(s)
- Yongnan Li
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.,Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Mingyue Liu
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Sizhe Gao
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Liming Cai
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.,Department of Cardiac Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Qiaoni Zhang
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Shujie Yan
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Gang Liu
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Bingyang Ji
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Karhausen J, Choi HW, Maddipati KR, Mathew JP, Ma Q, Boulaftali Y, Lee RH, Bergmeier W, Abraham SN. Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury. SCIENCE ADVANCES 2020; 6:eaay6314. [PMID: 32206714 PMCID: PMC7080499 DOI: 10.1126/sciadv.aay6314] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 12/20/2019] [Indexed: 06/08/2023]
Abstract
Platelet responses have been associated with end-organ injury and mortality following complex insults such as cardiac surgery, but how platelets contribute to these pathologies remains unclear. Our studies originated from the observation of microvascular platelet retention in a rat cardiac surgery model. Ensuing work supported the proximity of platelet aggregates with perivascular mast cells (MCs) and demonstrated that platelet activation triggered systemic MC activation. We then identified platelet activating factor (PAF) as the platelet-derived mediator stimulating MCs and, using chimeric animals with platelets defective in PAF generation or MCs lacking PAF receptor, defined the role of this platelet-MC interaction for vascular leakage, shock, and tissue inflammation. In application of these findings, we demonstrated that inhibition of platelet activation in modeled cardiac surgery blunted MC-dependent inflammation and tissue injury. Together, our work identifies a previously undefined mechanism of inflammatory augmentation, in which platelets trigger local and systemic responses through activation of perivascular MCs.
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Affiliation(s)
- Jörn Karhausen
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Hae Woong Choi
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
- Department of Life Sciences, Korea University, Seoul 02841, South Korea
| | | | - Joseph P. Mathew
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Qing Ma
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Yacine Boulaftali
- Université Paris Diderot, Sorbonne Paris Cité, Laboratory of Vascular Translational Science, U1148 Institute National de la Santé et de la Recherche Medicale (INSERM), Paris, France
| | - Robert Hugh Lee
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA
| | - Wolfgang Bergmeier
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA
- UNC Center for Blood Research, University of North Carolina, Chapel Hill, NC, USA
| | - Soman N. Abraham
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
- Department of Immunology, Duke University Medical Center, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
- Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore
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Mai N, Miller-Rhodes K, Knowlden S, Halterman MW. The post-cardiac arrest syndrome: A case for lung-brain coupling and opportunities for neuroprotection. J Cereb Blood Flow Metab 2019; 39:939-958. [PMID: 30866740 PMCID: PMC6547189 DOI: 10.1177/0271678x19835552] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung-brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.
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Affiliation(s)
- Nguyen Mai
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Kathleen Miller-Rhodes
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Sara Knowlden
- 2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,3 Department of Neurology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Marc W Halterman
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,3 Department of Neurology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
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Abstract
OBJECTIVE The aim of this study was to investigate the clinical effects of prostaglandin E1 (PGE1) in patients who underwent surgery for gastrointestinal (GI) trauma, perforation, or obstruction. BACKGROUND PGE1 is thought to enhance intestinal blood supply and reduce GI complications during the postoperative period. METHODS The medical records of 889 patients undergoing major GI surgery were reviewed retrospectively. Propensity score matching was performed to adjust for any baseline differences. Clinical outcomes, including early GI function recovery, postoperative complications, and length of hospital stay, were evaluated in all patients. In 278 paired patients, selected nutritional, immunologic, and inflammatory variables were compared based on PGE1 administration. RESULTS After propensity score 1:1 matching, the baseline characteristics were similar for both groups. PGE1 was associated with prompt postoperative GI function recovery, including first bowel movement [2.6 ± 0.9 vs 3.1 ± 1.0 days after surgery in patients with and without PGE1 treatment, risk ratio 0.51, 95% confidence interval (CI) 0.41-0.65, P < 0.001] and first feeding within postoperative day 3 [179 (64.39%) vs 152 (54.68%); risk ratio 0.61, 95% CI 0.42-0.90, P = 0.012]. A lower overall postoperative complication rate, including infectious complications [45 (16.2%) vs 68 (24.5%); odds ratio 0.60, 95% CI 0.39-0.91, P = 0.010] and major complications [23 (8.3%) vs 48 (17.3%); odds ratio 0.43, 95% CI 0.26-0.73, P = 0.001], was noted in patients with PGE1 treatment than in patients without PGE1 treatment. Furthermore, the immunologic and inflammatory variable C-reactive protein on postoperative day 3 was reduced by PGE1 treatment (52.5 ± 36.4 vs 89.6 ± 42.4 mg/L; P = 0.037, t test). CONCLUSIONS PGE1 is associated with beneficial clinical effects, such as prompt postoperative GI function recovery and reduced overall postoperative complications after emergency GI surgery, which may be attributed to a reduced inflammatory response.
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Jin C, Fu WL, Zhang DD, Xing WW, Xia WR, Wei Z, Zou MJ, Zhu XM, Xu DG. The protective role of IL-1Ra on intestinal ischemia reperfusion injury by anti-oxidative stress via Nrf2/HO-1 pathway in rat. Biomed J 2019; 42:36-45. [PMID: 30987703 PMCID: PMC6468113 DOI: 10.1016/j.bj.2018.11.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/29/2018] [Accepted: 11/12/2018] [Indexed: 12/16/2022] Open
Abstract
Background Intestinal ischemia reperfusion injury is a frequent clinical damage, in which the oxidative stress and inflammation play an important role. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory factor, however, its effect on intestinal ischemia reperfusion injury remains unclear. Methods The rat model of intestinal I/R was induced by occlusion (for 60 min) and reopening (for 60 min) of superior mesenteric artery. The rats were randomly divided into the following 5 groups: sham-operation(S), model (I/R),10 mg/kgIL-1Ra + I/R (C1),20 mg/kgIL-1Ra + I/R (C2), and30 mg/kgIL-1Ra + I/R (C3). Results In this study it was the first time to confirm that IL-1Ra had a significant protection against the intestinal ischemia reperfusion injury. IL-1Ra not only effectively inhibited the expression of inflammatory factors (such as IL-1β, IL-6 and TNF-α) and the activation of neutrophil in intestinal tissues, but also decreased the death of intestinal cells and the damages of intestinal tissues. Interestingly, besides anti-inflammation effect, it was also found that IL-1Ra possessed a significant inhibitory effect on the oxidative stress caused by ischemia/reperfusion injury. Furthermore, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1), and the phosphorylation level of Nrf2 were greatly promoted by IL-1Ra. At the same time, IL-1Ra inhibited the mitogen-activated protein kinase (MAPKs) pathway. Conclusion IL-1Ra had the protective effect against intestinal ischemia reperfusion injury, its mechanism included anti-inflammation and anti-oxidative stress in which the Nrf2/HO-1 pathway played an important role. The above-mentioned results may extend the clinical application of IL-1Ra in the treatment of intestinal ischemia reperfusion injury.
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Affiliation(s)
- Chen Jin
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China; Anhui Medical University, Hefei, PR China
| | - Wen-Liang Fu
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Dong-Dong Zhang
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Wei-Wei Xing
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Wen-Rong Xia
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Zhao Wei
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Min-Ji Zou
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Xiao-Ming Zhu
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China
| | - Dong-Gang Xu
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, PR China; Anhui Medical University, Hefei, PR China.
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Degranulation of gastrointestinal mast cells contributes to hepatic ischemia-reperfusion injury in mice. Clin Sci (Lond) 2018; 132:2241-2259. [PMID: 30301760 PMCID: PMC6376614 DOI: 10.1042/cs20180662] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 10/01/2018] [Accepted: 10/08/2018] [Indexed: 01/30/2023]
Abstract
The pathological changes following liver damage, including those caused by ischemia and reperfusion (I/R), are closely related to gastrointestinal dysregulation. Mast cells (MCs) are tissue-resident immune cells abundant in the gastrointestinal system that play diverse roles. In view of the characteristic localization of MCs around the microvasculature, we hypothesized that a stimulus-specific set of mediators released through degranulation of gastrointestinal MCs, which are enriched in hepatic sinusoids via the hepatic system, subsequently participate in associated pathological development within the liver. To elucidate the biological role of gastrointestinal MC granules in liver damage, we employed an experimental liver I/R model that allows conditional ablation of MCs. Marked degranulation was detected during I/R, which showed a significant positive correlation with liver damage. Our experiments further disclosed that MC degranulation primarily enhanced the cycle of inflammatory damage in I/R liver consisting of liver sinusoidal endothelial cell death, neutrophil infiltration, and formation of a neutrophil extracellular trap, with a concomitant increase in adhesion molecules, inflammatory cytokines, chemokines, and oxidative stress. Based on the collective results, we propose that suppression of activity or number of MCs may present an effective strategy for protection against hepatic I/R injury.
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17
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Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. J Transl Med 2018; 98:799-813. [PMID: 29472640 PMCID: PMC6397426 DOI: 10.1038/s41374-018-0035-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 12/27/2017] [Accepted: 01/10/2018] [Indexed: 11/08/2022] Open
Abstract
The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.
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18
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Role of p-MKK7 in myricetin-induced protection against intestinal ischemia/reperfusion injury. Pharmacol Res 2018; 129:432-442. [DOI: 10.1016/j.phrs.2017.11.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 11/08/2017] [Accepted: 11/10/2017] [Indexed: 12/19/2022]
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Huang X, Zhao W, Hu D, Han X, Wang H, Yang J, Xu Y, Li Y, Yao W, Chen C. Resveratrol efficiently improves pulmonary function via stabilizing mast cells in a rat intestinal injury model. Life Sci 2017; 185:30-37. [DOI: 10.1016/j.lfs.2017.07.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/09/2017] [Accepted: 07/18/2017] [Indexed: 12/30/2022]
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Mai N, Prifti L, Rininger A, Bazarian H, Halterman MW. Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion. Exp Neurol 2017; 297:82-91. [PMID: 28757259 DOI: 10.1016/j.expneurol.2017.07.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 07/04/2017] [Accepted: 07/25/2017] [Indexed: 12/22/2022]
Abstract
Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.
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Affiliation(s)
- Nguyen Mai
- Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States
| | - Landa Prifti
- Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States
| | - Aric Rininger
- Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States
| | - Hannah Bazarian
- Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States
| | - Marc W Halterman
- Center for Neurotherapeutics Discovery, University of Rochester, Rochester, NY 14642, United States; Department of Neurology, University of Rochester, Rochester, NY 14642, United States.
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21
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Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, Sun Y, Tang Z, Wang L, Jiang C, Lin Y. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling. Pharmacol Res 2017; 119:137-148. [PMID: 28167239 DOI: 10.1016/j.phrs.2017.01.026] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/25/2017] [Indexed: 01/08/2023]
Abstract
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
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Affiliation(s)
- Yanli Li
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Bin Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Ming Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Dapeng Chen
- Laboratory Animal Center, Dalian Medical University, Dalian 116044, China
| | - Yongjian Xiong
- Central Laboratory, The First Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Mengqiao Lian
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Yuchao Sun
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Zeyao Tang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Li Wang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Chunling Jiang
- Department of Physiology, Dalian Medical University, Dalian 116044, China
| | - Yuan Lin
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
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Lansink MO, Patyk V, de Groot H, Effenberger-Neidnicht K. Melatonin reduces changes to small intestinal microvasculature during systemic inflammation. J Surg Res 2017; 211:114-125. [DOI: 10.1016/j.jss.2016.11.055] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 10/26/2016] [Accepted: 11/30/2016] [Indexed: 12/15/2022]
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Hong S, Shang Q, Geng Q, Yang Y, Wang Y, Guo C. Impact of hypertonic saline on postoperative complications for patients undergoing upper gastrointestinal surgery. Medicine (Baltimore) 2017; 96:e6121. [PMID: 28328800 PMCID: PMC5371437 DOI: 10.1097/md.0000000000006121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The aim of this study was to explore the impact of 3% hypertonic saline (HS) intragastric administration for patients who underwent upper gastrointestinal surgery.During the postoperative period, 3% HS has been suggested as a means to improve the intestinal edema and reduce gastrointestinal complications.The medical records of 111 patients with HS intragastric administration following upper gastrointestinal surgery and 268 patients, served as control, were reviewed retrospectively. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including early gastrointestinal function recovery, postoperative complications, and length of hospital stay, were compared according to the HS intragastric administration or not.HS intragastric administration was associated with prompt postoperative gastrointestinal function recovery, including first flatus (risk ratio [RR], 1.32; 95% confidence interval [CI], 0.89-1.65; P = 0.048) and feeding within 3 postoperative days (RR (95% CI), 0.57 (0.49-0.77); P = 0.036). Early ileus occurred in 25 of 108 patients with HS treatment versus 36 of 108 patients without HS treatment (RR (95% CI), 1.43 (0.63-2.15); P = 0.065). The patients with HS experienced a lower overall postoperative complication (odds ratio [OD] 0.57; 95% CI, 0.33-1.09; P = 0.063), including trend toward a decrease for infectious complications (15[13.9] vs 23[21.3]; P = 0.11; OD, 0.59; 95% CI, 0.29-1.22). There was a decreased incidence of anastomotic leakage (1[0.9] vs 7[6.5]; P = 0.033) and postoperative ileuas (5[4.6%] vs 11[10.2%]; P = 0.096) in the HS administration patients.Our study demonstrated beneficial postoperative clinical effects of HS intragastric administration in patients who had undergone upper gastrointestinal surgery, such as prompt postoperative gastrointestinal function recovery and reduced overall postoperative complications, which may be attributed to a reduced intestinal edema.
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Affiliation(s)
- Siqi Hong
- Department of neurology, Children's Hospital, Chongqing Medical University, Chongqing
| | - Qingjuan Shang
- Department of Pathology, Linyi People's Hospital, Linyi, Shandong province
| | - Qiankun Geng
- Department of Pediatric General Surgery and Liver Transplantation, Children's Hospital
| | - Yang Yang
- Department of Pediatric General Surgery and Liver Transplantation, Children's Hospital
| | - Yan Wang
- Department of Neonatology, Yongchuan Hospital, Chongqing Medical University
| | - Chunbao Guo
- Department of Pediatric General Surgery and Liver Transplantation, Children's Hospital
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, P.R. China
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Danelli L, Madjene LC, Madera-Salcedo I, Gautier G, Pacreau E, Ben Mkaddem S, Charles N, Daugas E, Launay P, Blank U. Early Phase Mast Cell Activation Determines the Chronic Outcome of Renal Ischemia–Reperfusion Injury. THE JOURNAL OF IMMUNOLOGY 2017; 198:2374-2382. [DOI: 10.4049/jimmunol.1601282] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 01/04/2017] [Indexed: 01/25/2023]
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25
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Kertai MD, Cheruku S, Qi W, Li YJ, Hughes GC, Mathew JP, Karhausen JA. Mast cell activation and arterial hypotension during proximal aortic repair requiring hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2016; 153:68-76.e2. [PMID: 27697359 DOI: 10.1016/j.jtcvs.2016.05.063] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 05/12/2016] [Accepted: 05/30/2016] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Aortic surgeries requiring hypothermic circulatory arrest evoke systemic inflammatory responses that often manifest as vasoplegia and hypotension. Because mast cells can rapidly release vasoactive and proinflammatory effectors, we investigated their role in intraoperative hypotension. METHODS We studied 31 patients undergoing proximal aortic repair with hypothermic circulatory arrest between June 2013 and April 2015 at Duke University Medical Center. Plasma samples were obtained at different intraoperative time points to quantify chymase, interleukin-6, interleukin-8, tumor necrosis factor alpha, and white blood cell CD11b expression. Hypotension was defined as the area (minutes × millimeters mercury) below a mean arterial pressure of 55 mm Hg. Biomarker responses and their association with intraoperative hypotension were analyzed by 2-sample t test and Wilcoxon rank sum test. Multivariable logistic regression analysis was used to examine the association between clinical variables and elevated chymase levels. RESULTS Mast cell-specific chymase increased from a median 0.97 pg/mg (interquartile range [IQR], 0.01-1.84 pg/mg) plasma protein at baseline to 5.74 pg/mg (IQR, 2.91-9.48 pg/mg) plasma protein after instituting cardiopulmonary bypass, 6.16 pg/mg (IQR, 3.60-9.41 pg/mg) plasma protein after completing circulatory arrest, and 7.64 pg/mg (IQR, 4.63-12.71 pg/mg) plasma protein after weaning from cardiopulmonary bypass (each P value < .0001 vs baseline). Chymase was the only biomarker associated with hypotension during (P = .0255) and after (P = .0221) cardiopulmonary bypass. Increased temperatures at circulatory arrest and low presurgical hemoglobin levels were independent predictors of increased chymase responses. CONCLUSIONS Mast cell activation occurs in cardiac surgery requiring cardiopulmonary bypass and hypothermic circulatory arrest and is associated with intraoperative hypotension.
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Affiliation(s)
- Miklos D Kertai
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, NC
| | - Sreekanth Cheruku
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, NC
| | - Wenjing Qi
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
| | - Yi-Ju Li
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC; Molecular Physiology Institute, Duke University Medical Center, Durham, NC
| | - G Chad Hughes
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC
| | - Joseph P Mathew
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, NC
| | - Jörn A Karhausen
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, NC.
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Zhou F, Zhang P, Chen X, Yan J, Yao J, Yu Z, Chen X. Ginsenoside Rb1 protects the intestinal mucosal barrier following peritoneal air exposure. Exp Ther Med 2016; 12:2563-2567. [PMID: 27703510 PMCID: PMC5038908 DOI: 10.3892/etm.2016.3639] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 06/15/2016] [Indexed: 01/02/2023] Open
Abstract
Ginsenoside Rb1 (GRb1), which is one of the main ingredients derived from Panax ginseng, has been widely used to treat various gastrointestinal disorders. The present study aimed to determine whether GRb1 was able to prevent intestinal mucosal barrier damage in rats following peritoneal air exposure for 3 h. GRb1 (5, 10, and 20 mg/kg) was orally administrated via gavage four times prior to and following surgery. Blood and terminal ileum were sampled 24 h following surgery. Levels of serum D-lactate (D-LA) were detected using an enzyme-linked immunosorbent assay kit. Intestinal permeability was assessed by determining the intestinal clearance of fluorescein isothiocyanate-dextran (FD4). Activity of intestinal myeloperoxidase was measured to assess intestinal inflammation, and intestinal histopathology was assessed by light microscopy. The results showed that GRb1 reduced the level of serum D-LA, intestinal clearance of FD4, and the activity of intestinal myeloperoxidase. Intestinal edema and inflammation were also ameliorated by GRb1, and the Chiu's scores employed for assessing intestinal mucosal damage were also reduced in the GRb1-treated peritoneal air exposure group. In addition, GRb1 induced a significant difference at 10 and 20 mg/kg, indicating a dose-dependent effect. The results of the present study suggest that GRb1 may be able to protect the intestinal mucosal barrier against damage induced by peritoneal air exposure, which may be associated with its anti-inflammatory action.
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Affiliation(s)
- Feng Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Peichen Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoxi Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jingyi Yan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiangao Yao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhen Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China; Department of General Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China
| | - Xiaolei Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1). J Mol Med (Berl) 2016; 95:83-95. [PMID: 27553040 DOI: 10.1007/s00109-016-1464-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 07/20/2016] [Accepted: 08/15/2016] [Indexed: 12/20/2022]
Abstract
Intestinal ischemia/reperfusion (I/R) injury is a potentially life-threatening condition that can cause injuries to remote organs at the end stage. The damage caused by intestinal I/R insult induces changes in the barrier functions of the intestine, and the intrinsic mechanism of regeneration is often insufficient to restore barrier functions, as indicated by the high mortality rate of patients experiencing intestinal I/R injury. However, little is known about the mechanisms of intestinal regeneration after I/R injury. Here, we reported that nuclear receptor-related protein 1 (Nurr1), a nuclear orphan receptor, was induced during intestinal regeneration after I/R. Our findings showed that Nurr1 expression was consistent with the expression of Ki-67 and phosphorylated histone H3 (pH 3) in the intestine after I/R injury. Nurr1 knockdown led to G1-phase arrest mediated by p21 (Waf1/Cip1) activation, but Nurr1 overexpression reduced the proportion of IEC-6 cells in G1 phase as a result of p21 inhibition in a p53-independent manner. Using chromatin immunoprecipitation assays, luciferase assays, and mutational analysis, we demonstrated that Nurr1 directly inhibited the transcription of p21. These results define a novel Nurr1/p21 pathway that is involved in intestinal regeneration after I/R injury. These findings provide novel molecular insights into the pathogenesis of intestinal regeneration after I/R and possibly support the development of new potential therapies for intestinal I/R injury. KEY MESSAGE Nurr1 was induced during intestinal regeneration after I/R injury. Nurr1 promoted proliferation of intestinal epithelial cells after H/R injury. Nurr1 inhibited p21 expression in a p53-independent manner. Nurr1 inhibited p21 gene transcription by binding to p21 promoter directly.
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Balsam LB, DeAnda A. The mast cell demystified: A novel target for anti-inflammatory strategies after circulatory arrest? J Thorac Cardiovasc Surg 2016; 153:77-78. [PMID: 27449563 DOI: 10.1016/j.jtcvs.2016.06.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 06/16/2016] [Indexed: 10/21/2022]
Affiliation(s)
- Leora B Balsam
- Department of Cardiothoracic Surgery, New York University-Langone Medical Center, New York, NY.
| | - Abe DeAnda
- Division of Cardiothoracic Surgery, University of Texas Medical Branch at Galveston, Galveston, Tex
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He Y, Ye ZQ, Li X, Zhu GS, Liu Y, Yao WF, Luo GJ. Alpha7 nicotinic acetylcholine receptor activation attenuated intestine-derived acute lung injury. J Surg Res 2015; 201:258-65. [PMID: 27020805 DOI: 10.1016/j.jss.2015.10.046] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 10/07/2015] [Accepted: 10/30/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Intestinal ischemia-reperfusion (IIR) could lead to acute lung injury, associated with severe alveolar epithelial cells inflammatory and oxidative injury. Alpha7 nicotinic acetylcholine receptor (α7nAChR) is an essential component of the cholinergic anti-inflammatory pathway. The aim of this study was to investigate the important role of α7nAChR on the lung subjected to IIR. METHODS Thirty-two Sprague-Dawley rats were randomly divided into four groups (n = 8 in each): sham group (group S), model group (group M), α7nAChR agonist PNU-282987-treated group (group PNU), and specific α7nAChR antagonist methyllycaconitine-treated group (group MLA). Intestinal IR damage was induced by clamping the superior mesenteric artery for 75 min, followed by a 120-min reperfusion. All rats were killed at 2 h after release of the clamps. The histologic examination of lungs was made, and lung water content was detected. Expression levels of malondialdehyde, tumor necrosis factor alpha, interleukin-6, and superoxide dismutase activity of the lungs were detected. Additionally, expression level of toll-like receptor (TLR)4 and nuclear factor-kappaB (NF-κB p65) in the nucleus of lung tissue and apoptosis-related protein (Bax, Bcl-2, and cleaved-caspase3) were detected using Western blot. RESULTS Lungs were damaged after intestine IR, manifested by higher lung water content, histologic score, concentrations of interleukin-6, tumor necrosis factor alpha, and malondialdehyde of group M than those of group S, accompanied with decreased superoxide dismutase activity (P < 0.05). PNU treatment could significantly improve the pulmonary function of rats subjected to IIR. These effects of activation of α7nAChR were associated with suppression of TLR4/NF-κB pathway and subsequent reduction of apoptosis-related protein. However, MLA treatment aggravated lung injury. CONCLUSIONS α7nAChR plays a role in acute lung injury induced by IIR via attenuating lung oxidative stress and inflammation through suppression of TLR4/NF-κB pathway, resulting in reduction of apoptosis in the lung.
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Affiliation(s)
- Ye He
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhi-Qiang Ye
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiang Li
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guo-Song Zhu
- Department of Anesthesiology, Henan Provincal People's Hospital, Zhengzhou, China
| | - Yue Liu
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei-Feng Yao
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Gang-Jian Luo
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Lin WB, Liang MY, Chen GX, Yang X, Qin H, Yao JP, Feng KN, Wu ZK. MicroRNA profiling of the intestine during hypothermic circulatory arrest in swine. World J Gastroenterol 2015; 21:2183-2190. [PMID: 25717255 PMCID: PMC4326157 DOI: 10.3748/wjg.v21.i7.2183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 08/12/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To perform a profiling analysis of changes in intestinal microRNA (miRNA) expression during hypothermic circulatory arrest (HCA).
METHODS: A total of eight piglets were randomly divided into HCA and sham operation (SO) groups. Under general anesthesia, swine in the HCA group were subjected to hypothermic cardiopulmonary bypass at 24 °C followed by 80 min of circulatory arrest, and the reperfusion lasted for 180 min after cross-clamp removal. The counterparts in the SO group were only subjected to median sternotomy. Histopathological analysis was used to detect mucosal injury, and Pick-and-Mix custom miRNA real-time polymerase chain reaction (PCR) panels containing 306 unique primer sets were utilized to assay unpooled intestinal samples harvested from the two groups.
RESULTS: The intestinal mucosa of the animals that were subjected to 24 °C HCA exhibited representative ischemic reperfusion injury of grade 2 or 3 according to the Chiu score. Such intestinal mucosal injuries, with the subepithelial space and epithelial layer lifting away from the lamina propria, were accompanied by shortened and irregular villi. On the contrary, the intestinal mucosa remained normal in the sham-operated animals. In total, twenty-five miRNAs were differentially expressed between the two groups (15 upregulated and 10 downregulated in the HCA group). Among these, eight miRNAs (miR-122, miR-221-5p, miR-31, miR-421-5p, miR-4333, miR-499-3p, miR-542 and let-7d-3p) were significantly dysregulated (four higher and four lower). The expression of miR-122 was significantly (5.37-fold) increased in the HCA group vs the SO group, indicating that it may play a key role in HCA-induced mucosal injury.
CONCLUSION: Exposure to HCA caused intestinal miRNA dysregulation and barrier dysfunction in swine. These altered miRNAs might be related to the protection or destruction of the intestinal barrier.
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Tan S, Yu W, Lin Z, Chen Q, Shi J, Dong Y, Duan K, Bai X, Xu L, Yu Z, Li J, Li N. Berberine Ameliorates Intestinal Mucosal Barrier Damage Induced by Peritoneal Air Exposure. Biol Pharm Bull 2015; 38:122-6. [DOI: 10.1248/bpb.b14-00643] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Shanjun Tan
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Wenkui Yu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Zhiliang Lin
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Qiyi Chen
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Jialiang Shi
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Yi Dong
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Kaipeng Duan
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Xiaowu Bai
- Research Institute of General Surgery, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University
| | - Lin Xu
- Research Institute of General Surgery, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University
| | - Zhen Yu
- Department of General Surgery, Shanghai Tenth People’s Hospital Affiliated to Tongji University
| | - Jieshou Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Ning Li
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University
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Generation of outbred Ace2 knockout mice by RNA transfection of TALENs displaying colitis reminiscent pathophysiology and inflammation. Transgenic Res 2014; 24:433-46. [PMID: 25448263 PMCID: PMC7102211 DOI: 10.1007/s11248-014-9855-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 11/21/2014] [Indexed: 01/04/2023]
Abstract
The angiotensin I converting enzyme 2 (ACE2) is a key factor in the maintenance of intestinal homeostasis. Dysregulation of homeostasis can lead to inflammation of the colon (colitis), which can cause life-threatening enfeeblement or even cancer. Animal models are valuable surrogates in deciphering the pathology behind such human conditions and for screening of putative therapeutic targets or treatment paradigms. However, development of disease models can be time-consuming and technical demanding, which might hamper their application-value. In this study, we genetically disrupted the mouse Ace2 gene by direct injection of in vitro transcribed mRNA coding for transcription activator-like effector nucleases (TALENs) into the cytoplasm of outbred Kunming mouse zygotes. Consequently, somatic mutations were induced with an efficiency of 57 %, of which 39 % were frameshift mutations. Moreover, all modifications were stably transferred during germline transmission. In Ace2-knockout male mice (Ace2−/y), we observed severe chemical induced colitis, characterized by considerable weight loss, diarrhea and a shortened colon length. Histologically, Ace2 mutations resulted in the infiltration of leukocytes and the overt damage of the intestinal mucosal barrier. In addition, we detected an increased expression of inflammatory cytokines in the colon tissue of Ace2−/y mice. Collectively, the data indicate that high targeting efficiency and heritability can be achieved in an outbred mouse model by zygote injection of TALEN mRNA. Furthermore, the generated Ace2−/y mice display phenotypic traits reminiscent of colitis and we anticipate that such mice can be of value in studies of the intestinal microbiome or fecal transplantation.
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Effenberger-Neidnicht K, Jägers J, Verhaegh R, de Groot H. Glycine selectively reduces intestinal injury during endotoxemia. J Surg Res 2014; 192:592-8. [PMID: 25012270 DOI: 10.1016/j.jss.2014.06.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 06/04/2014] [Accepted: 06/06/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Glycine is well known to protect the intestine against ischemia-reperfusion injury and during mechanical manipulation. Here, we studied whether glycine protects the small intestine during endotoxemia, even without being the site of the infection. MATERIALS AND METHODS Lipopolysaccharide (LPS) was infused at a rate of 1 mg/kg × h over a period of 7 h (subacute endotoxemia) in male Wistar rats. Glycine (single dose: 50 mg/kg × 15 min) was applied intravenously at 180 and 270 min after the beginning of the LPS infusion. Systemic parameters were periodically determined. The small intestine was analyzed for macroscopic (hemorrhages) and histopathologic changes (hematoxylin and eosin staining), and markers of inflammation (myeloperoxidase activity). RESULTS Glycine neither decreased mortality nor beneficially affected vital parameters (e.g., mean arterial blood pressure and breathing rate), electrolytes, blood gases including pH and base excess, and plasma parameters of tissue injury such as lactate concentration, hemolysis, and aminotransferases activities during experimental endotoxemia. It, however, specifically diminished the LPS-induced small intestinal injury, as indicated by less intestinal accumulation of blood, less intestinal hemorrhages, and reduced intestinal hemoglobin content. CONCLUSIONS The present results demonstrate that glycine selectively protects the small intestine during subacute endotoxemia, even after manifestation of a severe systemic impairment. Because glycine is non-toxic at low doses, an administration of a moderate glycine dose (50-100 mg/kg) may be suitable to protect from intestinal damage during sepsis. Its true clinical potential, however, needs to be verified in further experimental studies and clinical trials.
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Affiliation(s)
| | - Johannes Jägers
- Institute of Physiological Chemistry, University Hospital Essen, Germany
| | - Rabea Verhaegh
- Institute of Physiological Chemistry, University Hospital Essen, Germany
| | - Herbert de Groot
- Institute of Physiological Chemistry, University Hospital Essen, Germany
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Pivotal role of mast cell carboxypeptidase A in mediating protection against small intestinal ischemia-reperfusion injury in rats after ischemic preconditioning. J Surg Res 2014; 192:177-86. [PMID: 24953986 DOI: 10.1016/j.jss.2014.05.050] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 04/30/2014] [Accepted: 05/16/2014] [Indexed: 12/13/2022]
Abstract
AIM OF THE STUDY Mast cell (MC) degranulation contributes to the protection mediated by ischemic preconditioning (IPC); however, the precise mechanisms underlying this protection remain largely unknown. Mast cell carboxypeptidase A (MC-CPA) is released solely from MCs and plays a critical role in degrading toxins and endothelin 1 (ET-1). The present study sought to explore whether MC-CPA is involved in the process of IPC in a rodent model of small intestinal ischemia reperfusion (IIR) injury. MATERIALS AND METHODS IIR injuries were induced in Sprague-Dawley rats by clamping the superior mesenteric artery for 60 min followed by reperfusion for 2 h. One cycle of 10 min intestinal ischemia and 10 min of reperfusion was used in the IPC group, and the MC stabilizer cromolyn sodium and MC potato carboxypeptidase inhibitor were administered before the start of IPC. At the end of experiment, intestine tissue was obtained for assays of the MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents and myeloperoxidase activities. Intestinal histologic injury scores and MC degranulation were assessed. Apoptosis indices and cleaved caspase- 3 protein expressions were quantified. RESULTS IIR resulted in severe injury, as evidenced by significant increases in injury scores and MC-CPA3, tumor necrosis factor-α, interleukin-6, and ET-1 contents that were accompanied with concomitant elevations in cleaved caspase 3 expression, apoptosis indices, and myeloperoxidase activities. IPC induced a significant increase in MC-CPA3, induced MC degranulation, and attenuated IIR injury by downregulating IIR-induced biochemical changes, whereas cromolyn sodium and potato carboxypeptidase inhibitor abolished the IPC-mediated changes. CONCLUSIONS These data suggest that IPC protected against IIR injury via the MC degranulation-mediated release of MC-CPA.
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Bartels K, Karhausen J, Clambey ET, Grenz A, Eltzschig HK. Perioperative organ injury. Anesthesiology 2014; 119:1474-89. [PMID: 24126264 DOI: 10.1097/aln.0000000000000022] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Despite the fact that a surgical procedure may have been performed for the appropriate indication and in a technically perfect manner, patients are threatened by perioperative organ injury. For example, stroke, myocardial infarction, acute respiratory distress syndrome, acute kidney injury, or acute gut injury are among the most common causes for morbidity and mortality in surgical patients. In the current review, the authors discuss the pathogenesis of perioperative organ injury, and provide select examples for novel treatment concepts that have emerged over the past decade. Indeed, the authors are of the opinion that research to provide mechanistic insight into acute organ injury and identification of novel therapeutic approaches for the prevention or treatment of perioperative organ injury represent the most important opportunity to improve outcomes of anesthesia and surgery.
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Affiliation(s)
- Karsten Bartels
- * Fellow in Critical Care Medicine and Cardiothoracic Anesthesiology, † Assistant Professor of Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. ‡ Assistant Professor of Anesthesiology, § Associate Professor of Anesthesiology, ‖ Professor of Anesthesiology, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado
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Hilberath JN, Muehlschlegel JD. Noteworthy articles in 2013 for cardiothoracic anesthesiologists. Semin Cardiothorac Vasc Anesth 2013; 18:6-11. [PMID: 24345780 DOI: 10.1177/1089253213516805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In 2013, the field of cardiothoracic anesthesiology has continued to grow at the same astounding rate as in previous years. It has become increasingly difficult for practicing anesthesiologists to stay current on impactful publications related to our exciting subspecialty. The scientific output has expanded to such a great extent that following the literature in specialty journals barely scrapes the surface of available knowledge. With the recent emphasis on teamwork spanning multiple medical specialties in the care for complex patients, the door has opened for our research to be presented in nontraditional, nonanesthesiology venues. In this review, we have selected a small sample of noteworthy contributions to the field of cardiothoracic and vascular anesthesiology published in 2013 with potential impact on our clinical practice.
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Affiliation(s)
- Jan N Hilberath
- 1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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The mechanism of sevoflurane preconditioning-induced protections against small intestinal ischemia reperfusion injury is independent of mast cell in rats. Mediators Inflamm 2013; 2013:378703. [PMID: 24369442 PMCID: PMC3867927 DOI: 10.1155/2013/378703] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 11/01/2013] [Accepted: 11/04/2013] [Indexed: 12/13/2022] Open
Abstract
The study aimed to investigate whether sevoflurane preconditioning can protect against small intestinal ischemia reperfusion (IIR) injury and to explore whether mast cell (MC) is involved in the protections provided by sevoflurane preconditioning. Sprague-Dawley rats exposed to sevoflurane or treated with MC stabilizer cromolyn sodium (CS) were subjected to 75-minute superior mesenteric artery occlusion followed by 2-hour reperfusion in the presence or absence of MC degranulator compound 48/80 (CP). Small intestinal ischemia reperfusion resulted in severe intestinal injury as demonstrated by significant elevations in intestinal injury scores and p47phox and gp91phox, ICAM-1 protein expressions and malondialdehyde and IL-6 contents, and MPO activities as well as significant reductions in SOD activities, accompanied with concomitant increases in mast cell degranulation evidenced by significant increases in MC counts, tryptase expression, and β-hexosaminidase concentrations, and those alterations were further upregulated in the presence of CP. Sevoflurane preconditioning dramatically attenuated the previous IIR-induced alterations except MC counts, tryptase, and β-hexosaminidase which were significantly reduced by CS treatment. Furthermore, CP exacerbated IIR injury was abrogated by CS but not by sevoflurane preconditioning. The data collectively indicate that sevoflurane preconditioning confers protections against IIR injury, and MC is not involved in the protective process.
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Karhausen J, Stafford-Smith M. The role of nonocclusive sources of acute gut injury in cardiac surgery. J Cardiothorac Vasc Anesth 2013; 28:379-91. [PMID: 24119676 DOI: 10.1053/j.jvca.2013.04.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Indexed: 12/16/2022]
Affiliation(s)
- Jörn Karhausen
- Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
| | - Mark Stafford-Smith
- Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
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de Haan JJ, Hadfoune M, Lubbers T, Hodin C, Lenaerts K, Ito A, Verbaeys I, Skynner MJ, Cailotto C, van der Vliet J, de Jonge WJ, Greve JWM, Buurman WA. Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. Am J Physiol Gastrointest Liver Physiol 2013; 305:G383-91. [PMID: 23812038 DOI: 10.1152/ajpgi.00333.2012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and α-bungarotoxin and vagal intestinal denervation. Accordingly, release of β-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR α7, in bone marrow-derived mast cells from nAChR β2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR α7 and is independent of the nAChR β2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex.
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Affiliation(s)
- Jacco J de Haan
- Dept. of Surgery at Maastricht Univ. Medical Centre+, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.
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