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Patrick R, Pando BD, Yang C, Aponte A, Wang F, Ewing T, Ma Y, Yuan SY, Wu MH. Focal adhesion kinase mediates microvascular leakage and endothelial barrier dysfunction in ischemia-reperfusion injury. Microvasc Res 2025; 159:104791. [PMID: 39884384 PMCID: PMC12057644 DOI: 10.1016/j.mvr.2025.104791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 01/16/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Intestinal ischemia-reperfusion (I/R) injury occurs under various surgical or disease conditions, where tissue hypoxia followed by reoxygenation results in the production of oxygen radicals and inflammatory mediators. These substances can target the endothelial barrier, leading to microvascular leakage. In this study, we induced intestinal I/R injury in mice by occluding the superior mesenteric artery, followed by removing the clamp to resume blood circulation. We assessed microvascular permeability to plasma proteins in vivo using intravital microscopy, measuring the time-dependent tracer distribution in the intravascular versus extravascular space in the mouse mesentery. Additionally, we examined endothelial cell-cell adhesive barrier resistance and junction morphology in cultured endothelial cell monolayers. At the molecular level, FAK inhibition similarly inhibited endothelial junction opening and barrier dysfunction in response to hydrogen peroxide-induced oxidative stress. To further investigate FAK's role with tissue/cell specificity, we developed an endothelial-specific inducible FAK knockout mouse model by crossbreeding FAK-floxed (FAKfl/fl) mice with Tie-2-CreERT2 transgenic mice. Compared to their wild-type controls, endothelial-specific FAK-deficient mice showed a blunted microvascular hyperpermeability response following I/R injury in the gut. Overall, our study demonstrates that FAK plays a significant signaling role in mediating endothelial barrier dysfunction and microvascular leakage during ischemia-reperfusion injury.
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Affiliation(s)
- Rebecca Patrick
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America
| | - Briana D Pando
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America.
| | - Clement Yang
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America
| | - Alexandra Aponte
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America.
| | - Fang Wang
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America
| | - Tom Ewing
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America.
| | - Yonggang Ma
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America
| | - Sarah Y Yuan
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America.
| | - Mack H Wu
- University of South Florida, Morsani College of Medicine, James A Haley Veterans' Hospital, United States of America.
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Soliman GA, Alamri MA, Abdel-Rahman RF, Elbaset MA, Ogaly HA, Abdel-Kader MS. Tephrosia purpurea, with (-)-Pseudosemiglabrin as the Major Constituent, Alleviates Severe Acute Pancreatitis-Mediated Acute Lung Injury by Modulating HMGB1 and IL-22. Int J Mol Sci 2025; 26:2572. [PMID: 40141214 PMCID: PMC11942157 DOI: 10.3390/ijms26062572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 03/02/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Ischemia-reperfusion (IR) injury is a major cause of multiple organ failure. The purpose of this study was to look into the role of Tephrosia purpurea (TEP) and its active constituent pseudosemiglabrin (PS) in alleviating severe acute pancreatitis and its associated acute lung injury. We established a rat pancreatic IR model, and the rats were treated with TEP (200 mg/kg and 400 mg/kg) and PS (20 and 40 mg/kg), in addition to the IR control and sham groups. The results showed that the respiratory parameters, including inspiratory time (Ti), expiratory time (Te), duration (Dr), and respiratory rate (RR), were comparable among all groups, while peak inspiratory flow (PIF), forced vital capacity (FVC), and forced expiratory volume at 0.1 s (FEV0.1) were significantly impaired. Notably, PS at 40 mg/kg showed normal PIF, FVC, and FEV0.1/FVC compared to the IR group, indicating an improved lung function. Additionally, TEP and PS showed protective effects on pancreatic and lung tissues compared to the IR control group, with the following effects: alleviating pathological damage; reducing serum levels of trypsinogen activation peptide (TAP), lipase, and amylase; decreasing oxidative stress markers such as MDA and MPO; restoring antioxidant enzyme activity (GPx); suppressing inflammatory markers TNF-α, IL-6, and NF-κB; downregulating HMGB1 gene in pancreatic tissue; and upregulating the IL-22 gene in lung tissues. In conclusion, the obtained findings demonstrate that oral supplementation of TEP and PS to rats with pancreatic IR alleviates pancreatic and lung injuries by reducing oxidative stress and modulating inflammatory processes, which offers an attractive therapeutic option for severe acute pancreatitis and its associated acute lung injury.
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Affiliation(s)
- Gamal A. Soliman
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (G.A.S.); (M.A.A.)
| | - Mohammed A. Alamri
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (G.A.S.); (M.A.A.)
| | - Rehab F. Abdel-Rahman
- Department of Pharmacology, National Research Centre, Giza 12622, Egypt; (R.F.A.-R.); (M.A.E.)
| | - Marawan A. Elbaset
- Department of Pharmacology, National Research Centre, Giza 12622, Egypt; (R.F.A.-R.); (M.A.E.)
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hanan A. Ogaly
- Department of Biochemistry, College of Veterinary Medicine, Cairo University, Giza 12613, Egypt;
| | - Maged S. Abdel-Kader
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
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Li Y, Liu Y, He Z, Li Z, Xiang H. Circadian Alterations in Brain Metabolism Linked to Cognitive Deficits During Hepatic Ischemia-Reperfusion Injury Using [ 1H- 13C]-NMR Metabolomics. Biomedicines 2024; 12:2536. [PMID: 39595102 PMCID: PMC11592224 DOI: 10.3390/biomedicines12112536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/26/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Hepatic ischemia-reperfusion injury (HIRI) is known to affect cognitive functions, with particular concern for its impact on brain metabolic dynamics. Circadian rhythms, as a crucial mechanism for internal time regulation within organisms, significantly influence metabolic processes in the brain. This study aims to explore how HIRI affects hippocampal metabolism and its circadian rhythm differences in mice, and to analyze how these changes are associated with cognitive impairments. Methods: A C57BL/6 male mouse model was used, simulating HIRI through hepatic ischemia-reperfusion surgery, with a sham operation conducted for the control group. Cognitive functions were evaluated using open field tests, Y-maze tests, and novel object recognition tests. Magnetic resonance spectroscopic imaging (MRSI) technology, combined with intravenous injection of [2-13C]-acetate and [1-13C]-glucose, was utilized to analyze metabolic changes in the hippocampus of HIRI mice at different circadian time points (Zeitgeber Time ZT0, 8:00 and ZT12, 20:00). Circadian rhythms regulate behavioral, physiological, and metabolic rhythms through transcriptional feedback loops, with ZT0 at dawn (lights on) and ZT12 at dusk (lights off). Results: HIRI mice exhibited significant cognitive impairments in behavioral tests, particularly in spatial memory and learning abilities. MRSI analysis revealed significant circadian rhythm differences in the concentration of metabolites in the hippocampus, with the enrichment concentrations of lactate, alanine, glutamate, and taurine showing different trends at ZT0 compared to ZT12, highlighting the important influence of circadian rhythms on metabolic dysregulation induced by HIRI. Conclusions: This study highlights the significant impact of HIRI on brain metabolic dynamics in mice, especially in the hippocampal area, and for the first time reveals the differences in these effects within circadian rhythms. These findings not only emphasize the association between HIRI-induced cognitive impairments and changes in brain metabolism but also point out the crucial role of circadian rhythms in this process, offering new metabolic targets and timing considerations for therapeutic strategies against HIRI-related cognitive disorders.
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Affiliation(s)
- Yijing Li
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.L.); (Y.L.); (Z.H.)
| | - Yanbo Liu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.L.); (Y.L.); (Z.H.)
| | - Zhigang He
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.L.); (Y.L.); (Z.H.)
| | - Zhixiao Li
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.L.); (Y.L.); (Z.H.)
| | - Hongbing Xiang
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.L.); (Y.L.); (Z.H.)
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan 430030, China
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Yang Y, Xu L, Atkins C, Kuhlman L, Zhao J, Jeong JM, Wen Y, Moreno N, Kim KH, An YA, Wang F, Bynon S, Villani V, Gao B, Brombacher F, Harris R, Eltzschig HK, Jacobsen E, Ju C. Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury. Gut 2024; 73:1543-1553. [PMID: 38724220 PMCID: PMC11347249 DOI: 10.1136/gutjnl-2024-332033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/18/2024] [Indexed: 06/13/2024]
Abstract
OBJECTIVE Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.
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Affiliation(s)
- Yang Yang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Long Xu
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Constance Atkins
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Lily Kuhlman
- The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jie Zhao
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jong-Min Jeong
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yankai Wen
- The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Nicolas Moreno
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kang Ho Kim
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Fenfen Wang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Steve Bynon
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Vincenzo Villani
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Bin Gao
- Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Frank Brombacher
- University of Cape Town Faculty of Health Sciences, Observatory, Western Cape, South Africa
| | - Raymond Harris
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Holger K Eltzschig
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Elizabeth Jacobsen
- Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Cynthia Ju
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
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Kumar MS. Paneth cell: The missing link between obesity, MASH and portal hypertension. Clin Res Hepatol Gastroenterol 2024; 48:102259. [PMID: 38070827 DOI: 10.1016/j.clinre.2023.102259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023]
Abstract
Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible, but stages of liver disease before the development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities that influences the pathophysiology of portal hypertension. This review provides evidence supporting that, Paneth cells[PCs] in the intestinal epithelium, which remained enigmatic for a century, are the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability, which are the potential triggers of systemic inflammation. Thus, it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.
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Affiliation(s)
- Minu Sajeev Kumar
- Department of Gastroenterology, Government Medical College, Thiruvanathapuram, India.
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Chang H, Chen E, Zhu T, Liu J, Chen C. Communication Regarding the Myocardial Ischemia/Reperfusion and Cognitive Impairment: A Narrative Literature Review. J Alzheimers Dis 2024; 97:1545-1570. [PMID: 38277294 PMCID: PMC10894588 DOI: 10.3233/jad-230886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/28/2024]
Abstract
Coronary artery disease is a prevalent ischemic disease that results in insufficient blood supply to the heart muscle due to narrowing or occlusion of the coronary arteries. Various reperfusion strategies, including pharmacological thrombolysis and percutaneous coronary intervention, have been developed to enhance blood flow restoration. However, these interventions can lead to myocardial ischemia/reperfusion injury (MI/RI), which can cause unpredictable complications. Recent research has highlighted a compelling association between MI/RI and cognitive function, revealing pathophysiological mechanisms that may explain altered brain cognition. Manifestations in the brain following MI/RI exhibit pathological features resembling those observed in Alzheimer's disease (AD), implying a potential link between MI/RI and the development of AD. The pro-inflammatory state following MI/RI may induce neuroinflammation via systemic inflammation, while impaired cardiac function can result in cerebral under-perfusion. This review delves into the role of extracellular vesicles in transporting deleterious substances from the heart to the brain during conditions of MI/RI, potentially contributing to impaired cognition. Addressing the cognitive consequence of MI/RI, the review also emphasizes potential neuroprotective interventions and pharmacological treatments within the MI/RI model. In conclusion, the review underscores the significant impact of MI/RI on cognitive function, summarizes potential mechanisms of cardio-cerebral communication in the context of MI/RI, and offers ideas and insights for the prevention and treatment of cognitive dysfunction following MI/RI.
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Affiliation(s)
- Haiqing Chang
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Erya Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chan Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Carré J, Kerforne T, Hauet T, Macchi L. Tissue Injury Protection: The Other Face of Anticoagulant Treatments in the Context of Ischemia and Reperfusion Injury with a Focus on Transplantation. Int J Mol Sci 2023; 24:17491. [PMID: 38139319 PMCID: PMC10743711 DOI: 10.3390/ijms242417491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/06/2023] [Accepted: 12/10/2023] [Indexed: 12/24/2023] Open
Abstract
Organ transplantation has enhanced the length and quality of life of patients suffering from life-threatening organ failure. Donors deceased after brain death (DBDDs) have been a primary source of organs for transplantation for a long time, but the need to find new strategies to face organ shortages has led to the broadening of the criteria for selecting DBDDs and advancing utilization of donors deceased after circulatory death. These new sources of organs come with an elevated risk of procuring organs of suboptimal quality. Whatever the source of organs for transplant, one constant issue is the occurrence of ischemia-reperfusion (IR) injury. The latter results from the variation of oxygen supply during the sequence of ischemia and reperfusion, from organ procurement to the restoration of blood circulation, triggering many deleterious interdependent processes involving biochemical, immune, vascular and coagulation systems. In this review, we focus on the roles of thrombo-inflammation and coagulation as part of IR injury, and we give an overview of the state of the art and perspectives on anticoagulant therapies in the field of transplantation, discussing benefits and risks and proposing a strategic guide to their use during transplantation procedures.
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Affiliation(s)
- Julie Carré
- Service D’Hématologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86000 Poitiers, France;
- INSERM 1313 Ischémie Reperfusion, Métabolisme, Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, 86000 Poitiers, France; (T.K.); (T.H.)
| | - Thomas Kerforne
- INSERM 1313 Ischémie Reperfusion, Métabolisme, Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, 86000 Poitiers, France; (T.K.); (T.H.)
- Service D’Anesthésie-Réanimation et Médecine Péri-Opératoire, Centre Hospitalo-Universitaire de Poitiers, 86000 Poitiers, France
- FHU Survival Optimization in Organ Transplantation (SUPORT), 86000 Poitiers, France
| | - Thierry Hauet
- INSERM 1313 Ischémie Reperfusion, Métabolisme, Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, 86000 Poitiers, France; (T.K.); (T.H.)
- FHU Survival Optimization in Organ Transplantation (SUPORT), 86000 Poitiers, France
- Service de Biochimie, Centre Hospitalo-Universitaire de Poitiers, 86000 Poitiers, France
| | - Laurent Macchi
- Service D’Hématologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86000 Poitiers, France;
- INSERM 1313 Ischémie Reperfusion, Métabolisme, Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, 86000 Poitiers, France; (T.K.); (T.H.)
- FHU Survival Optimization in Organ Transplantation (SUPORT), 86000 Poitiers, France
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Silva M, Faustino P. From Stress to Sick(le) and Back Again-Oxidative/Antioxidant Mechanisms, Genetic Modulation, and Cerebrovascular Disease in Children with Sickle Cell Anemia. Antioxidants (Basel) 2023; 12:1977. [PMID: 38001830 PMCID: PMC10669666 DOI: 10.3390/antiox12111977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Sickle cell anemia (SCA) is a genetic disease caused by the homozygosity of the HBB:c.20A>T mutation, which results in the production of hemoglobin S (HbS). In hypoxic conditions, HbS suffers autoxidation and polymerizes inside red blood cells, altering their morphology into a sickle shape, with increased rigidity and fragility. This triggers complex pathophysiological mechanisms, including inflammation, cell adhesion, oxidative stress, and vaso-occlusion, along with metabolic alterations and endocrine complications. SCA is phenotypically heterogeneous due to the modulation of both environmental and genetic factors. Pediatric cerebrovascular disease (CVD), namely ischemic stroke and silent cerebral infarctions, is one of the most impactful manifestations. In this review, we highlight the role of oxidative stress in the pathophysiology of pediatric CVD. Since oxidative stress is an interdependent mechanism in vasculopathy, occurring alongside (or as result of) endothelial dysfunction, cell adhesion, inflammation, chronic hemolysis, ischemia-reperfusion injury, and vaso-occlusion, a brief overview of the main mechanisms involved is included. Moreover, the genetic modulation of CVD in SCA is discussed. The knowledge of the intricate network of altered mechanisms in SCA, and how it is affected by different genetic factors, is fundamental for the identification of potential therapeutic targets, drug development, and patient-specific treatment alternatives.
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Affiliation(s)
- Marisa Silva
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
| | - Paula Faustino
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
- Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental (ISAMB), Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
- Laboratório Associado TERRA, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
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Cui C, Li L, Wu L, Wang X, Zheng Y, Wang F, Wei H, Peng J. Paneth cells in farm animals: current status and future direction. J Anim Sci Biotechnol 2023; 14:118. [PMID: 37582766 PMCID: PMC10426113 DOI: 10.1186/s40104-023-00905-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/04/2023] [Indexed: 08/17/2023] Open
Abstract
A healthy intestine plays an important role in the growth and development of farm animals. In small intestine, Paneth cells are well known for their regulation of intestinal microbiota and intestinal stem cells (ISCs). Although there has been a lot of studies and reviews on human and murine Paneth cells under intestinal homeostasis or disorders, little is known about Paneth cells in farm animals. Most farm animals possess Paneth cells in their small intestine, as identified by various staining methods, and Paneth cells of various livestock species exhibit noticeable differences in cell shape, granule number, and intestinal distribution. Paneth cells in farm animals and their antimicrobial peptides (AMPs) are susceptible to multiple factors such as dietary nutrients and intestinal infection. Thus, the comprehensive understanding of Paneth cells in different livestock species will contribute to the improvement of intestinal health. This review first summarizes the current status of Paneth cells in pig, cattle, sheep, horse, chicken and rabbit, and points out future directions for the investigation of Paneth cells in the reviewed animals.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Lin Wu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yao Zheng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Fangke Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 400700, China.
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10
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Abenavoli L, Scarlata GGM, Paravati MR, Boccuto L, Luzza F, Scarpellini E. Gut Microbiota and Liver Transplantation: Immune Mechanisms behind the Rejection. Biomedicines 2023; 11:1792. [PMID: 37509432 PMCID: PMC10376769 DOI: 10.3390/biomedicines11071792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/17/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Liver transplantation (LT) is the treatment of choice for patients with cirrhosis, decompensated disease, acute liver failure, and hepatocellular carcinoma (HCC). In 3-25% of cases, an alarming problem is acute and chronic cellular rejection after LT, and this event can lead to the need for new transplantation or the death of the patient. On the other hand, gut microbiota is involved in several mechanisms sustaining the model of the "gut-liver axis". These include modulation of the immune response, which is altered in case of gut dysbiosis, possibly resulting in acute graft rejection. Some studies have evaluated the composition of the gut microbiota in cirrhotic patients before and after LT, but few of them have assessed its impact on liver rejection. This review underlines the changes in gut microbiota composition before and after liver transplantation, hypothesizing possible immune mechanisms linking dysbiosis to transplantation rejection. Evaluation of changes in the gut microbiota composition in these patients is therefore essential in order to monitor the success of LT and eventually adopt appropriate preventive measures.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University "Magna Graecia", 88100 Catanzaro, Italy
| | | | | | - Luigi Boccuto
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC 29634, USA
- School of Health Research, Clemson University, Clemson, SC 29634, USA
| | - Francesco Luzza
- Department of Health Sciences, University "Magna Graecia", 88100 Catanzaro, Italy
| | - Emidio Scarpellini
- Translationeel Onderzoek van Gastro-Enterologische Aandoeningen (TARGID.), Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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11
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Cui C, Wang X, Li L, Wei H, Peng J. Multifaceted involvements of Paneth cells in various diseases within intestine and systemically. Front Immunol 2023; 14:1115552. [PMID: 36993974 PMCID: PMC10040535 DOI: 10.3389/fimmu.2023.1115552] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn’s disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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12
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Cui C, Wang F, Zheng Y, Wei H, Peng J. From birth to death: The hardworking life of Paneth cell in the small intestine. Front Immunol 2023; 14:1122258. [PMID: 36969191 PMCID: PMC10036411 DOI: 10.3389/fimmu.2023.1122258] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/28/2023] [Indexed: 03/12/2023] Open
Abstract
Paneth cells are a group of unique intestinal epithelial cells, and they play an important role in host-microbiota interactions. At the origin of Paneth cell life, several pathways such as Wnt, Notch, and BMP signaling, affect the differentiation of Paneth cells. After lineage commitment, Paneth cells migrate downward and reside in the base of crypts, and they possess abundant granules in their apical cytoplasm. These granules contain some important substances such as antimicrobial peptides and growth factors. Antimicrobial peptides can regulate the composition of microbiota and defend against mucosal penetration by commensal and pathogenic bacteria to protect the intestinal epithelia. The growth factors derived from Paneth cells contribute to the maintenance of the normal functions of intestinal stem cells. The presence of Paneth cells ensures the sterile environment and clearance of apoptotic cells from crypts to maintain the intestinal homeostasis. At the end of their lives, Paneth cells experience different types of programmed cell death such as apoptosis and necroptosis. During intestinal injury, Paneth cells can acquire stem cell features to restore the intestinal epithelial integrity. In view of the crucial roles of Paneth cells in the intestinal homeostasis, research on Paneth cells has rapidly developed in recent years, and the existing reviews on Paneth cells have mainly focused on their functions of antimicrobial peptide secretion and intestinal stem cell support. This review aims to summarize the approaches to studying Paneth cells and introduce the whole life experience of Paneth cells from birth to death.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Fangke Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yao Zheng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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13
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The Role of Microbiota in Liver Transplantation and Liver Transplantation-Related Biliary Complications. Int J Mol Sci 2023; 24:ijms24054841. [PMID: 36902269 PMCID: PMC10003075 DOI: 10.3390/ijms24054841] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs.
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14
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Wu X, Guo LZ, Liu YH, Liu YC, Yang PL, Leung YS, Tai HC, Wang TD, Lin JCW, Lai CL, Chuang YH, Lin CH, Chou PT, Lai IR, Liu TM. Plasma riboflavin fluorescence as a diagnostic marker of mesenteric ischemia-reperfusion injury in rats. Thromb Res 2023; 223:146-154. [PMID: 36753876 DOI: 10.1016/j.thromres.2023.01.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Due to the delayed and vague symptoms, it is difficult to early diagnose mesenteric ischemia injuries in the dynamics of acute illness, leading to a 60-80 % mortality rate. Here, we found plasma fluorescence spectra can rapidly assess the severity of mesenteric ischemia injury in animal models. Ischemia-reperfusion damage of the intestine leads to multiple times increase in NADH, flavins, and porphyrin auto-fluorescence of blood. The fluorescence intensity ratio between blue-fluorophores and flavins can reflect the occurrence of shock. Using liquid chromatography and mass spectroscopy, we confirm that riboflavin is primarily responsible for the increased flavin fluorescence. Since humans absorb riboflavin from the intestine, its increase in plasma may indicate intestinal mucosa injury. Our work suggests a self-calibrated and reagent-free approach to identifying the emergence of fatal mesenteric ischemia in emergency departments or intensive care units.
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Affiliation(s)
- Xueqin Wu
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Lun-Zhang Guo
- Department of Biomedical Engineering, National Taiwan University, Taipei 10617, Taiwan
| | - Yi-Hung Liu
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Yu-Cheng Liu
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Po-Lun Yang
- Department of Biomedical Engineering, National Taiwan University, Taipei 10617, Taiwan
| | - Yun-Shiuan Leung
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | - Hwan-Ching Tai
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, P. R. China.
| | - Tzung-Dau Wang
- Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 10002, Taiwan
| | - Jesse Chih-Wei Lin
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chao-Lun Lai
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
| | - Yueh-Hsun Chuang
- Department of Anesthesiology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Chih-Hsueh Lin
- Department of Nutrition, College of Medical and Health Care, Hungkuang University, Taichung City 433304, Taiwan
| | - Pi-Tai Chou
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan.
| | - I-Rue Lai
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei 100229, Taiwan.
| | - Tzu-Ming Liu
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
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15
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Wallaeys C, Garcia‐Gonzalez N, Libert C. Paneth cells as the cornerstones of intestinal and organismal health: a primer. EMBO Mol Med 2022; 15:e16427. [PMID: 36573340 PMCID: PMC9906427 DOI: 10.15252/emmm.202216427] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 12/28/2022] Open
Abstract
Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells.
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Affiliation(s)
- Charlotte Wallaeys
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Natalia Garcia‐Gonzalez
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Claude Libert
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
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16
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Inoue Y, Kuramoto T, Ota M, Kitada K, Fujii K, Miyaoka Y, Yamamoto M, Kimura F, Uchiyama K. The Effects of Intermittent Hepatic Inflow Occlusion Using the Pringle Maneuver During Hepatectomy. Indian J Surg 2022. [DOI: 10.1007/s12262-021-03012-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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17
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Şengel N, Köksal Z, Dursun AD, Kurtipek Ö, Sezen ŞC, Arslan M, Kavutçu M. Effects of Dexmedetomidine Administered Through Different Routes on Kidney Tissue in Rats with Spinal Cord Ischaemia-Reperfusion Injury. Drug Des Devel Ther 2022; 16:2229-2239. [PMID: 35860522 PMCID: PMC9289575 DOI: 10.2147/dddt.s361618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 07/02/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Ischaemia-reperfusion (IR) injury, which can be encountered during surgical procedures involving the abdominal aorta, is a complex process that affects distant organs, such as the heart, liver, kidney, and lungs, as well as the lower extremities. In this study, we aimed to contribute to the limited literature by investigating the protective effect of dexmedetomidine, which was administered through different routes, on kidney tissue in rats with spinal cord IR injury. METHODS A total of 30 rats were randomly divided into five groups: control (C group), IR (IR group), IR-intraperitoneal dexmedetomidine (IRIPD group), IR-intrathecal dexmedetomidine (IRITD group), and IR-intravenous dexmedetomidine (IRIVD group). The spinal cord IR model was established. Dexmedetomidine was administered at doses of 100 µg/kg intraperitoneally, 3 µg/kg intrathecally, and 9 µg/kg intravenously. Histopathologic parameters in kidney tissue samples taken at the end of the reperfusion period and biochemical parameters in serum were evaluated. RESULTS When examined histopathologically, tubular dilatation was found to be significantly reduced in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.012, all). Vascular vacuolization and hypertrophy were significantly decreased in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.006, all). Tubular cell degeneration and necrosis were significantly reduced in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.008, p = 0.08, and p = 0.030, respectively). Lymphocyte infiltration was significantly decreased in the IRIVD and IRITD groups compared with the IR group (p = 0.006 and p = 0.06, respectively). CONCLUSION It was observed that dexmedetomidine administered by different routes improved the damage caused by IR in kidney histopathology. We think that the renoprotective effects of dexmedetomidine administered intravenously and intrathecally before IR in rats are greater.
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Affiliation(s)
- Necmiye Şengel
- Department of Oral and Maxillofacial Surgery, Gazi University Faculty of Dentistry, Ankara, Turkey
| | - Zeynep Köksal
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Ali Doğan Dursun
- Department of Physiology, Atılım University Faculty of Medicine, Ankara, Turkey
| | - Ömer Kurtipek
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Şaban Cem Sezen
- Department of Histology and Embryology, Kırıkkale University Faculty of Medicine, Kırıkkale, Turkey
| | - Mustafa Arslan
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Mustafa Kavutçu
- Department of Medical Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey
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18
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Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation. Transplantation 2022; 106:e430-e440. [PMID: 35849574 DOI: 10.1097/tp.0000000000004258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Ischemia and reperfusion injury (IRI) determines primary allograft function after liver transplantation (LT). Primary graft dysfunction (PGD) is associated with increased morbidity and impaired graft survival and can eventually progress to graft failure requiring retransplantation. Hypoxia-inducible transcription factor-prolyl hydroxylase containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors, which control the adaptive hypoxia response through the hypoxia-inducible factor (HIF). In this study, we have investigated pharmacological activation of the HIF pathway through inhibition of PHDs as a strategy to reduce PGD after LT. METHODS Primary rat hepatocytes were isolated and the impact of the pan-PHD small-molecule inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on HIF-1 and its downstream target gene expression assessed. Subsequently, various rodent models of segmental warm liver ischemia and reperfusion and orthotopic LT were applied to study the impact of EDHB on normothermic or combined cold and warm liver IRI. Liver enzyme levels and histology were analyzed to quantify hepatic IRI. RESULTS In vitro, EDHB induced HIF-1 signaling and significantly upregulated its downstream target heme-oxygenase 1 in primary rat hepatocytes. In vivo, after establishment of the optimal EDHB pretreatment conditions in a murine IRI model, EDHB pretreatment significantly mitigated hepatic IRI after warm segmental liver ischemia and reperfusion and allograft injury after orthotopic LT in rats. Mechanistically, EDHB stabilized HIF-1 in the liver and subsequently increased hepatoprotective heme-oxygenase 1 levels, which correlated with reduced hepatic IRI in these models. CONCLUSIONS This proof-of-concept study establishes a strong therapeutic rationale for targeting PHDs with small-molecule inhibitors to mitigate PGD after LT.
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19
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Wong HJ, Lim WH, Ng CH, Tan DJH, Bonney GK, Kow AWC, Huang DQ, Siddiqui MS, Noureddin M, Syn N, Muthiah MD. Predictive and Prognostic Roles of Gut Microbial Variation in Liver Transplant. Front Med (Lausanne) 2022; 9:873523. [PMID: 35620719 PMCID: PMC9127379 DOI: 10.3389/fmed.2022.873523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/06/2022] [Indexed: 11/16/2022] Open
Abstract
Patients undergoing liver transplant (LTX) typically confront a challenging postoperative journey. A dysbiotic gut microbiome is associated with the development of complications, including post-LTX allograft rejection, metabolic diseases and de novo or recurrent cancer. A major explanation of this are the bipartite interactions between the gut microbiota and host immunity, which modulates the alloimmune response towards the liver allograft. Furthermore, bacterial translocation from dysbiosis causes pathogenic changes in the concentrations of microbial metabolites like lipopolysaccharides, short-chain fatty acids (SCFAs) and Trimethylamine-N-Oxide, with links to cardiovascular disease development and diabetes mellitus. Gut dysbiosis also disrupts bile acid metabolism, with implications for various post-LTX metabolic diseases. Certain taxonomy of microbiota such as lactobacilli, F.prausnitzii and Bacteroides appear to be associated with these undesired outcomes. As such, an interesting but as yet unproven hypothesis exists as to whether induction of a “beneficial” composition of gut microbiota may improve prognosis in LTX patients. Additionally, there are roles of the microbiome as predictive and prognostic indicators for clinicians in improving patient care. Hence, the gut microbiome represents an exceptionally exciting avenue for developing novel prognostic, predictive and therapeutic applications.
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Affiliation(s)
- Hon Jen Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Glenn K Bonney
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, National University Hospital Singapore, Singapore, Singapore
| | - Alfred W C Kow
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, National University Hospital Singapore, Singapore, Singapore
| | - Daniel Q Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Centre, Cedars-Sinai Medical Centre, Los Angeles, CA, United States
| | - Nicholas Syn
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
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20
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Sadat-Ebrahimi SR, Amini H, Rahbarghazi R, Habibollahi P, Ghaderi S, Rajabi H, Rezabakhsh A. Putative therapeutic impacts of cardiac CTRP9 in ischaemia/reperfusion injury. J Cell Mol Med 2022; 26:3120-3132. [PMID: 35535510 PMCID: PMC9170823 DOI: 10.1111/jcmm.17355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 11/28/2022] Open
Abstract
Recently, cytokines belonging to C1q/tumour necrosis factor‐related proteins (CTRPs) superfamily have attracted increasing attention due to multiple metabolic functions and desirable anti‐inflammatory effects. These various molecular effectors exhibit key roles upon the onset of cardiovascular diseases, making them novel adipo/cardiokines. This review article aimed to highlight recent findings correlated with therapeutic effects and additional mechanisms specific to the CTRP9, particularly in cardiac ischaemia/reperfusion injury (IRI). Besides, the network of the CTPR9 signalling pathway and its possible relationship with IRI were discussed. Together, the discovery of all involved underlying mechanisms could shed light to alleviate the pathological sequelae after the occurrence of IRI.
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Affiliation(s)
| | - Hassan Amini
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Paria Habibollahi
- Department of Pharmacology and Toxicology, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahrouz Ghaderi
- Institute of Molecular Medicine III, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - Hadi Rajabi
- Koç University Research Center for Translational Medicine (KUTTAM), Koç University, School of Medicine, Istanbul, Turkey
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Emergency Medicine & Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Abstract
Hepatorenal syndrome (HRS) is defined as a functional renal failure without major histologic changes in individuals with severe liver disease and it is associated with a high mortality rate. Renal hypoperfusion due to marked vasoconstriction as a result of complex circulatory dysfunction has been suggested to be the cornerstone of HRS. Splanchnic and peripheral arterial vasodilation and cirrhotic cardiomyopathy result in effective arterial hypovolemia and compensatory activation of vasoconstrictor mechanisms. The efficacy of current therapeutic strategies targeting this circulatory dysfunction is limited. Increasing evidence suggests a substantial role of systemic inflammation in HRS via either vascular or direct renal effects. Here we summarize the current understanding of HRS pathophysiology.
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Affiliation(s)
- Timea Csak
- Sandra Atlas Bass Center for Liver Diseases, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
| | - David Bernstein
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 400 Community Drive, Manhasset, NY 11030, USA
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22
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Koval M, Cwiek A, Carr T, Good ME, Lohman AW, Isakson BE. Pannexin 1 as a driver of inflammation and ischemia-reperfusion injury. Purinergic Signal 2021; 17:521-531. [PMID: 34251590 PMCID: PMC8273370 DOI: 10.1007/s11302-021-09804-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023] Open
Abstract
Pannexin 1 (Panx1) is a ubiquitously expressed protein forming large conductance channels that are central to many distinct inflammation and injury responses. There is accumulating evidence showing ATP released from Panx1 channels, as well as metabolites, provide effective paracrine and autocrine signaling molecules that regulate different elements of the injury response. As channels with a broad range of permselectivity, Panx1 channels mediate the secretion and uptake of multiple solutes, ranging from calcium to bacterial derived molecules. In this review, we describe how Panx1 functions in response to different pro-inflammatory stimuli, focusing mainly on signaling coordinated by the vasculature. How Panx1 mediates ATP release by injured cells is also discussed. The ability of Panx1 to serve as a central component of many diverse physiologic responses has proven to be critically dependent on the context of expression, post-translational modification, interacting partners, and the mode of stimulation.
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Affiliation(s)
- Michael Koval
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, 205 Whitehead Building, 615 Michael Street, Atlanta, GA, 30322, USA.
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Aleksandra Cwiek
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Thomas Carr
- Department of Cell Biology and Anatomy, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
- Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Miranda E Good
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA
| | - Alexander W Lohman
- Department of Cell Biology and Anatomy, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
- Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, School of Medicine, University of Virginia, PO Box 801394, Charlottesville, VA, 22908, USA.
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
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23
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de Vries RJ, Cronin SEJ, Romfh P, Pendexter CA, Jain R, Wilks BT, Raigani S, van Gulik TM, Chen P, Yeh H, Uygun K, Tessier SN. Non-invasive quantification of the mitochondrial redox state in livers during machine perfusion. PLoS One 2021; 16:e0258833. [PMID: 34705828 PMCID: PMC8550443 DOI: 10.1371/journal.pone.0258833] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 10/06/2021] [Indexed: 11/19/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is a critical problem in liver transplantation that can lead to life-threatening complications and substantially limit the utilization of livers for transplantation. However, because there are no early diagnostics available, fulminant injury may only become evident post-transplant. Mitochondria play a central role in IRI and are an ideal diagnostic target. During ischemia, changes in the mitochondrial redox state form the first link in the chain of events that lead to IRI. In this study we used resonance Raman spectroscopy to provide a rapid, non-invasive, and label-free diagnostic for quantification of the hepatic mitochondrial redox status. We show this diagnostic can be used to significantly distinguish transplantable versus non-transplantable ischemically injured rat livers during oxygenated machine perfusion and demonstrate spatial differences in the response of mitochondrial redox to ischemia reperfusion. This novel diagnostic may be used in the future to predict the viability of human livers for transplantation and as a tool to better understand the mechanisms of hepatic IRI.
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Affiliation(s)
- Reinier J. de Vries
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
- Department of Surgery, Amsterdam University Medical Centers–Location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Stephanie E. J. Cronin
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
| | - Padraic Romfh
- Pendar Technologies, Cambridge, MA, United States of America
| | - Casie A. Pendexter
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
| | - Rohil Jain
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
| | - Benjamin T. Wilks
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
| | - Siavash Raigani
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States of America
| | - Thomas M. van Gulik
- Department of Surgery, Amsterdam University Medical Centers–Location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Peili Chen
- Pendar Technologies, Cambridge, MA, United States of America
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States of America
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
| | - Shannon N. Tessier
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States of America
- Shriners Hospitals for Children—Boston, Boston, MA, United States of America
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24
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Lai HJ, Zhan YQ, Qiu YX, Ling YH, Zhang XY, Chang ZN, Zhang YN, Liu ZM, Wen SH. HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage. Surgery 2021; 170:239-248. [PMID: 33745733 DOI: 10.1016/j.surg.2021.01.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.
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Affiliation(s)
- Han-Jin Lai
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ya-Qing Zhan
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yu-Xin Qiu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Hong Ling
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xu-Yu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ze-Nan Chang
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Nan Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Zi-Meng Liu
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
| | - Shi-Hong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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25
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Secretory Sorcery: Paneth Cell Control of Intestinal Repair and Homeostasis. Cell Mol Gastroenterol Hepatol 2021; 12:1239-1250. [PMID: 34153524 PMCID: PMC8446800 DOI: 10.1016/j.jcmgh.2021.06.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022]
Abstract
Paneth cells are professional secretory cells that classically play a role in the innate immune system by secreting antimicrobial factors into the lumen to control enteric bacteria. In this role, Paneth cells are able to sense cues from luminal bacteria and respond by changing production of these factors to protect the epithelial barrier. Paneth cells rely on autophagy to regulate their secretory capability and capacity. Disruption of this pathway through mutation of genes, such as Atg16L1, results in decreased Paneth cell function, dysregulated enteric microbiota, decreased barrier integrity, and increased risk of diseases such as Crohn's disease in humans. Upon differentiation Paneth cells migrate downward and intercalate among active intestinal stem cells at the base of small intestinal crypts. This localization puts them in a unique position to interact with active intestinal stem cells, and recent work shows that Paneth cells play a critical role in influencing the intestinal stem cell niche. This review discusses the numerous ways Paneth cells can influence intestinal stem cells and their niche. We also highlight the ways in which Paneth cells can alter cells and other organ systems.
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26
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Solubilized ubiquinol for preserving corneal function. Biomaterials 2021; 275:120842. [PMID: 34087583 DOI: 10.1016/j.biomaterials.2021.120842] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/25/2021] [Accepted: 04/16/2021] [Indexed: 12/22/2022]
Abstract
Defective cellular metabolism, impaired mitochondrial function, and increased cell death are major problems that adversely affect donor tissues during hypothermic preservation prior to transplantation. These problems are thought to arise from accumulated reactive oxygen species (ROS) inside cells. Oxidative stress acting on the cells of organs and tissues preserved in hypothermic conditions before surgery, as is the case for cornea transplantation, is thought to be a major reason behind cell death prior to surgery and decreased graft survival after transplantation. We have recently discovered that ubiquinol - the reduced and active form of coenzyme Q10 and a powerful antioxidant - significantly enhances mitochondrial function and reduces apoptosis in human donor corneal endothelial cells. However, ubiquinol is highly lipophilic, underscoring the need for an aqueous-based formulation of this molecule. Herein, we report a highly dispersible and stable formulation comprising a complex of ubiquinol and gamma cyclodextrin (γ-CD) for use in aqueous-phase ophthalmic products. Docking studies showed that γ-CD has the strongest binding affinity with ubiquinol compared to α- or β-CD. Complexed ubiquinol showed significantly higher stability compared to free ubiquinol in different aqueous ophthalmic products including Optisol-GS® corneal storage medium, balanced salt solution for intraocular irrigation, and topical Refresh® artificial tear eye drops. Greater ROS scavenging activity was noted in a cell model with high basal metabolism and ROS generation (A549) and in HCEC-B4G12 human corneal endothelial cells after treatment with ubiquinol/γ-CD compared to free ubiquinol. Furthermore, complexed ubiquinol was more effective at lowering ROS, and at far lower concentrations, compared to free ubiquinol. Complexed ubiquinol inhibited lipid peroxidation and protected HCEC-B4G12 cells against erastin-induced ferroptosis. No evidence of cellular toxicity was detected in HCEC-B4G12 cells after treatment with complexed ubiquinol. Using a vertical diffusion system, a topically applied inclusion complex of γ-CD and a lipophilic dye (coumarin-6) demonstrated transcorneal penetrance in porcine corneas and the capacity for the γ-CD vehicle to deliver drug to the corneal endothelium. Using the same model, topically applied ubiquinol/γ-CD complex penetrated the entire thickness of human donor corneas with markedly greater ubiquinol retention in the endothelium compared to free ubiquinol. Lastly, the penetrance of ubiquinol/γ-CD complex was assayed using human donor corneas preserved for 7 days in Optisol-GS® per standard industry practices, and demonstrated higher amounts of ubiquinol retained in the corneal endothelium compared to free ubiquinol. In summary, ubiquinol complexed with γ-CD is a highly stable composition that can be incorporated into a variety of aqueous-phase products for ophthalmic use including donor corneal storage media and topical eye drops to scavenge ROS and protect corneal endothelial cells against oxidative damage.
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27
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Ju C, Wang M, Tak E, Kim B, Emontzpohl C, Yang Y, Yuan X, Kutay H, Liang Y, Hall DR, Dar WA, Bynon JS, Carmeliet P, Ghoshal K, Eltzschig HK. Hypoxia-inducible factor-1α-dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest 2021; 131:140300. [PMID: 33792566 PMCID: PMC8011886 DOI: 10.1172/jci140300] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 02/10/2021] [Indexed: 12/29/2022] Open
Abstract
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
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Affiliation(s)
- Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Meng Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Eunyoung Tak
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Christoph Emontzpohl
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Yang Yang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Huban Kutay
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Yafen Liang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - David R. Hall
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Wasim A. Dar
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - J. Steve Bynon
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, and
- Center for Cancer Biology, Department of Oncology, Katholieke University Leuven, Leuven, Belgium
| | - Kalpana Ghoshal
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
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28
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A Mouse Model of Acute Liver Injury by Warm, Partial Ischemia-Reperfusion for Testing the Efficacy of Virus-Derived Therapeutics. Methods Mol Biol 2021; 2225:275-292. [PMID: 33108669 DOI: 10.1007/978-1-0716-1012-1_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.
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29
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Li Z, Wang Y, Zhang Y, Wang X, Gao B, Li Y, Li R, Wang J. Protective Effects of Fisetin on Hepatic Ischemia-reperfusion Injury Through Alleviation of Apoptosis and Oxidative Stress. Arch Med Res 2020; 52:163-173. [PMID: 33645502 DOI: 10.1016/j.arcmed.2020.10.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/17/2020] [Accepted: 10/02/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Hepatic ischemia-reperfusion injury (IRI) is the main leading cause of morbidity and mortality of patients after liver surgery and transplantation. Fisetin, a kind of flavonoid, has been reported to protect against myocardial and cerebral IRI. However, the effects of fisetin on liver IRI were poorly investigated. METHODS C57BL/6 mice were used to establish the liver IRI model in vivo. Intraperitoneal injection of fisetin was performed one hour before IR treatment (1 h ischemia and 6h reperfusion). In vitro experimental study was conducted using AML-12 hepatocytes with 1 h hypoxia and 12 h reoxygenation (HR) treatment. Tissue damage was evaluated through serum AST and ALT levels and hematoxylin-eosin (HE) staining. Cell apoptosis was assessed by TUNEL staining and protein levels of Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP. Oxidative stress was evaluated by ROS and MDA levels and the activity of SOD and GSH-Px. Immunohistochemistry and immunofluorescence assay were performed to observe the translocation of Nrf2 from the cytoplasm into the nucleus. RESULTS The histopathological assessment showed that fisetin attenuated IR-induced liver damage obviously. Besides, fisetin served a protective role in IR liver to alleviate cell apoptosis and oxidative stress in vivo and in vitro. Introduction of high concentration of fisetin promoted the translocation of Nrf2 from the cytoplasm into the nucleus, increasing protein expression of its downstream elements, at least HO-1 in IR liver tissues and hepatocytes after HR. Inhibition of Nrf2 could reverse the effects of fisetin on cell viability, cell apoptosis, and also oxidative stress of HR hepatocytes, suggesting that Nrf2 signaling was necessary in fisetin-mediated regulations of liver IRI. CONCLUSION Fisetin alleviates liver damage, cell apoptosis, and oxidative stress induced by liver IRI, at least through Nrf2/HO-1 signaling pathway, suggesting that fisetin could be considered as a targeted drug for liver IRI treatment.
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Affiliation(s)
- Zexin Li
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China.
| | - Ying Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China
| | - Yu Zhang
- Department of Neurology, The People's Hospital of Anyang City, Anyang, Henan, People's Republic of China
| | - Xiao Wang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, People's Republic of China
| | - Baoqin Gao
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China
| | - Yan Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China
| | - Rong Li
- School of Nursing, Xinxiang Medical University, Xinxiang, Henan, People's Republic of China
| | - Jianguo Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China.
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30
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Han SJ, Kim M, Novitsky E, D'Agati V, Lee HT. Intestinal TLR9 deficiency exacerbates hepatic IR injury via altered intestinal inflammation and short-chain fatty acid synthesis. FASEB J 2020; 34:12083-12099. [PMID: 32738096 DOI: 10.1096/fj.202000314r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 06/22/2020] [Accepted: 06/28/2020] [Indexed: 12/13/2022]
Abstract
Mice deficient in intestinal epithelial TLR9 develop small intestinal Paneth cell hyperplasia and higher Paneth cell IL-17A levels. Since small intestinal Paneth cells and IL-17A play critical roles in hepatic ischemia reperfusion (IR) injury, we tested whether mice lacking intestinal TLR9 have increased hepatic IR injury. Mice lacking intestinal TLR9 had profoundly increased liver injury after hepatic IR compared to WT mice with exacerbated hepatocyte necrosis, apoptosis, neutrophil infiltration, and inflammatory cytokine generation. Moreover, we observed increased small intestinal inflammation and apoptosis after hepatic IR in intestinal TLR9 deficient mice. As a potential explanation for increased hepatic IR injury, fecal short-chain fatty acids butyrate and propionate levels were lower in intestinal TLR9 deficient mice. Suggesting a potential therapy for hepatic IR, exogenous administration of butyrate or propionate protected against hepatic IR injury in intestinal TLR9 deficient mice. Mechanistically, butyrate induced small intestinal IL-10 expression and downregulated the claudin-2 expression. Finally, IL-10 neutralization abolished the protective effects of butyrate against hepatic IR injury. Our studies show intestinal TLR9 deficiency results in exacerbated hepatic IR injury with increased small intestinal apoptosis and inflammation. Furthermore, short-chain fatty acids butyrate and propionate protect against hepatic IR injury and intestinal apoptosis/inflammation in intestinal TLR9 deficient mice.
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Affiliation(s)
- Sang Jun Han
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Mihwa Kim
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Ella Novitsky
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Vivette D'Agati
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - H Thomas Lee
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
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31
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Ribonuclease alleviates hepatic ischemia-reperfusion injury by suppressing excessive cytokine release and TLR3-mediated apoptosis in mice. Cytokine 2020; 133:155178. [PMID: 32615412 DOI: 10.1016/j.cyto.2020.155178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/27/2020] [Accepted: 06/13/2020] [Indexed: 02/05/2023]
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32
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Keryakos HKH, Mohammed AA, Higazi AM, Mahmoud EAM, Saad ZM. Serum and ascitic fluid interleukin-17 in spontaneous bacterial peritonitis in Egyptian patients with HCV-related liver cirrhosis. Curr Res Transl Med 2020; 68:237-243. [PMID: 32620468 DOI: 10.1016/j.retram.2020.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 02/23/2020] [Accepted: 03/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Spontaneous bacterial peritonitis (SBP) is a potentially lethal complication of ascites. The inflammatory response is very intense in case of SBP despite low concentration of bacteria in the ascitic fluid with IL-17A overproduced by intestinal Paneth cells and may have role in host immune defense and inflammatory response. AIMS To study the diagnostic performance of serum and ascitic fluid IL-17A as a marker of SBP and its correlation with renal function. METHODS 120 cirrhotic patients including 80 patients with HCV-induced cirrhotic ascites but not with SBP and 40 patients with HCV-induced cirrhotic ascites with SBP were recruited. Serum and ascitic fluid IL17A were measured before and after treatment. RESULTS The mean serum and ascitic fluid levels of IL-17 in cirrhotic patients with SBP were significantly higher than in patients with cirrhosis without SBP (p < 0.001). Also, we found significant decline in both serum and ascitic fluid IL17 levels with successful treatment of SBP (p < 0.001). The sensitivity and specificity of serum IL17 was 100 % when using 92 pg/mL as cutoff. Meanwhile, sensitivity and specificity of ascitic fluid IL-17were 100 % when using 132 pg/mL as cutoff. CONCLUSIONS IL-17 could be used as a possible diagnostic biomarker for SBP especially in culture negative and non-neutrocytic SBP and in monitoring therapeutic response. Also, it was shown to be related to hepatic and renal functions deterioration.
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Affiliation(s)
| | - Ahmed Ali Mohammed
- Department of Internal Medicine, Minia Faculty of Medicine, Minia University Hospital, El-Minia, Egypt
| | - Aliaa Monir Higazi
- Department of Clinical Pathology, Minia Faculty of Medicine, Minia University Hospital, El-Minia, Egypt
| | - Esraa Abdel Magid Mahmoud
- Department of Internal Medicine, Minia Faculty of Medicine, Minia University Hospital, El-Minia, Egypt
| | - Zienab Mostafa Saad
- Department of Tropical Medicine, Minia Faculty of Medicine, Minia University Hospital, El-Minia, Egypt
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Kollmann D, Neong SF, Rosales R, Hansen BE, Sapisochin G, McCluskey S, Bhat M, Cattral MS, Lilly L, McGilvray ID, Ghanekar A, Grant DR, Selzner M, Wong FSH, Selzner N. Renal Dysfunction After Liver Transplantation: Effect of Donor Type. Liver Transpl 2020; 26:799-810. [PMID: 32189415 PMCID: PMC7317208 DOI: 10.1002/lt.25755] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 01/27/2020] [Accepted: 02/10/2020] [Indexed: 12/15/2022]
Abstract
Recipients of donation after circulatory death (DCD) grafts are reportedly at higher risk of developing renal dysfunction after liver transplantation (LT). We compared the development of acute kidney injury (AKI) and chronic kidney disease (CKD) after LT in recipients of DCD versus donation after brain death (DBD) or living donor liver transplantation (LDLT) livers. Adult recipients of DBD, LDLT, and DCD between 2012 and 2016 at Toronto General Hospital were included. AKI was defined as a post-LT increase of serum creatinine (sCr) ≥26.5 µmol/L within 48 hours or a ≥50% increase from baseline, and CKD was defined as an estimated glomerular filtration rate <60 mL/minute for >3 months. A total of 681 patients (DCD, n = 57; DBD, n = 446; and LDLT, n = 178) with similar baseline comorbidities were included. Perioperative AKI (within the first 7 postoperative days) was observed more frequently in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak AST levels (P < 0.001). Additionally, patients in the DCD group had a significantly higher peak sCr (P < 0.001) and a trend toward higher rates of AKI stage 3 (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). The proportions of recovery from AKI (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and patients developing CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar. Nevertheless, patients who received DCD or DBD LT and required perioperative renal replacement therapy showed significantly lower patient survival in multivariate analysis (hazard ratio, 7.90; 95% confidence interval, 4.51-13.83; P < 0.001). In conclusion, recipients of DCD liver grafts experience higher rates of short-term post-LT renal dysfunction compared with DBD or LDLT. Additional risk factors for the development of severe kidney injury, such as high Model for End-Stage Liver Disease score, massive transfusions, or donor age ≥60 years should be avoided.
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Affiliation(s)
- Dagmar Kollmann
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada,Department of SurgeryMedical University of ViennaViennaAustria
| | - Shuet Fong Neong
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Roizar Rosales
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Bettina E. Hansen
- Institute of Health PolicyManagement and EvaluationUniversity of TorontoTorontoONCanada,Toronto Centre for Liver DiseaseToronto General HospitalTorontoONCanada
| | | | - Stuart McCluskey
- Department of Anesthesia and Pain ManagementToronto General HospitalTorontoONCanada
| | - Mamatha Bhat
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Mark S. Cattral
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Les Lilly
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Ian D. McGilvray
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Anand Ghanekar
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - David R. Grant
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Markus Selzner
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - Florence S. H. Wong
- Division of GastroenterologyToronto General HospitalUniversity Health NetworkToronto General HospitalTorontoONCanada
| | - Nazia Selzner
- Multi‐Organ Transplant ProgramToronto General HospitalTorontoONCanada
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Abstract
Neutrophil extracellular traps, or NETs, are heterogenous, filamentous structures which consist of extracellular DNA, granular proteins, and histones. NETs are extruded by a neutrophil in response to various stimuli. Although NETs were initially implicated in immune defense, subsequent studies have implicated NETs in a spectrum of disease processes, including autoimmune disease, thrombosis, and cancer. NETs also contribute to the pathogenesis of several common liver diseases, including alcohol-associated liver disease and portal hypertension. Although there is much interest in the therapeutic potential of NET inhibition, future clinical applications must be balanced against potential increased risk of infection.
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Affiliation(s)
- Moira B. Hilscher
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Duan C, Kuang L, Xiang X, Zhang J, Zhu Y, Wu Y, Yan Q, Liu L, Li T. Drp1 regulates mitochondrial dysfunction and dysregulated metabolism in ischemic injury via Clec16a-, BAX-, and GSH- pathways. Cell Death Dis 2020; 11:251. [PMID: 32312970 PMCID: PMC7170874 DOI: 10.1038/s41419-020-2461-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/31/2022]
Abstract
The adaptation of mitochondrial homeostasis to ischemic injury is not fully understood. Here, we studied the role of dynamin-related protein 1 (Drp1) in this process. We found that mitochondrial morphology was altered in the early stage of ischemic injury while mitochondrial dysfunction occurred in the late stage of ischemia. Drp1 appeared to inhibit mitophagy by upregulating mito-Clec16a, which suppressed mito-Parkin recruitment and subsequently impaired the formation of autophagosomes in vascular tissues after ischemic injury. Moreover, ischemia-induced Drp1 activation enhanced apoptosis through inducing mitochondrial translocation of BAX and thereby increasing release of Cytochrome C to activate caspase-3/-9 signalling. Furthermore, Drp1 mediated metabolic disorders and inhibited the levels of mitochondrial glutathione to impair free radical scavenging, leading to further increases in ROS and the exacerbation of mitochondrial dysfunction after ischemic injury. Together, our data suggest a critical role for Drp1 in ischemic injury.
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Affiliation(s)
- Chenyang Duan
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Lei Kuang
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Xinming Xiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Jie Zhang
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Yu Zhu
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Yue Wu
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Qingguang Yan
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China
| | - Liangming Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China.
| | - Tao Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, 400042, Chongqing, P. R. China.
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Lueschow SR, McElroy SJ. The Paneth Cell: The Curator and Defender of the Immature Small Intestine. Front Immunol 2020; 11:587. [PMID: 32308658 PMCID: PMC7145889 DOI: 10.3389/fimmu.2020.00587] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/13/2020] [Indexed: 12/14/2022] Open
Abstract
Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.
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Affiliation(s)
- Shiloh R Lueschow
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States
| | - Steven J McElroy
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States.,Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, United States
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Han SJ, Lee HT. Mechanisms and therapeutic targets of ischemic acute kidney injury. Kidney Res Clin Pract 2019; 38:427-440. [PMID: 31537053 PMCID: PMC6913588 DOI: 10.23876/j.krcp.19.062] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/13/2019] [Accepted: 07/17/2019] [Indexed: 12/19/2022] Open
Abstract
Acute kidney injury (AKI) due to renal ischemia reperfusion (IR) is a major clinical problem without effective therapy and is a significant and frequent cause of morbidity and mortality during the perioperative period. Although the pathophysiology of ischemic AKI is not completely understood, several important mechanisms of renal IR-induced AKI have been studied. Renal ischemia and subsequent reperfusion injury initiates signaling cascades mediating renal cell necrosis, apoptosis, and inflammation, leading to AKI. Better understanding of the molecular and cellular pathophysiological mechanisms underlying ischemic AKI will provide more targeted approach to prevent and treat renal IR injury. In this review, we summarize important mechanisms of ischemic AKI, including renal cell death pathways and the contribution of endothelial cells, epithelial cells, and leukocytes to the inflammatory response during ischemic AKI. Additionally, we provide some updated potential therapeutic targets for the prevention or treatment of ischemic AKI, including Toll-like receptors, adenosine receptors, and peptidylarginine deiminase 4. Finally, we propose mechanisms of ischemic AKI-induced liver, intestine, and kidney dysfunction and systemic inflammation mainly mediated by Paneth cell degranulation as a potential explanation for the high mortality observed with AKI.
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Affiliation(s)
- Sang Jun Han
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
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Ansari J, Gavins FNE. Ischemia-Reperfusion Injury in Sickle Cell Disease: From Basics to Therapeutics. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:706-718. [PMID: 30904156 DOI: 10.1016/j.ajpath.2018.12.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/17/2018] [Accepted: 12/07/2018] [Indexed: 12/17/2022]
Abstract
Sickle cell disease (SCD) is one of the most common hereditary hemoglobinopathies worldwide, affecting almost 400,000 newborns globally each year. It is characterized by chronic hemolytic anemia and endothelial dysfunction, resulting in a constant state of disruption of the vascular system and leading to recurrent episodes of ischemia-reperfusion injury (I/RI) to multiple organ systems. I/RI is a fundamental vascular pathobiological paradigm and contributes to morbidity and mortality in a wide range of conditions, including myocardial infarction, stroke, acute kidney injury, and transplantation. I/RI is characterized by an initial restriction of blood supply to an organ, which can lead to ischemia, followed by the subsequent restoration of perfusion and concomitant reoxygenation. Recent advances in the pathophysiology of SCD have led to an understanding that many of the consequences of this disease can be explained by mechanisms associated with I/RI. The following review focuses on the evolving pathobiology of SCD, how various complications of SCD can be attributed to I/RI, and the role of timely therapeutic intervention(s) based on targeting mediators or pathways that influence I/R insult.
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Affiliation(s)
- Junaid Ansari
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana
| | - Felicity N E Gavins
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana.
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Han SJ, Kim M, D'Agati VD, Lee HT. Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI. Am J Physiol Renal Physiol 2019; 318:F260-F272. [PMID: 31813250 DOI: 10.1152/ajprenal.00471.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.
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Affiliation(s)
- Sang Jun Han
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - Mihwa Kim
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - Vivette Denise D'Agati
- Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
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Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice. Mucosal Immunol 2019; 12:930-944. [PMID: 31105269 PMCID: PMC6599481 DOI: 10.1038/s41385-019-0170-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/05/2019] [Accepted: 04/13/2019] [Indexed: 02/06/2023]
Abstract
Gut microbial translocation contributes to alcoholic hepatitis. Using a mouse model of alcoholic hepatitis, we investigated the effects of chronic alcohol plus binge and found increased abundance of Paneth cells and IL-17A in the proximal small intestine (PSI). Alcohol increased IL-17A production and pro-apoptotic signaling evidenced by Bax, Bim, caspase-3, and caspase-8 increases via endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) upregulation; this was prevented by the ER stress inhibitor, 4-PBA, in isolated crypts in vitro and in vivo. Mechanistically, IL-17 augmented alcohol-induced ER stress in isolated crypts. In vivo IL-17A blocking antibody administration in alcohol-treated mice attenuated ER stress-mediated apoptosis and IL-18 induction and prevented alcohol-induced impairment of tight junctions in the PSI and LPS translocation to the liver. Acute-on-chronic alcohol resulted in inflammasome activation, caspase-1 cleavage, and IL-18 production in the PSI. In vivo treatment with antibiotics or 4-PBA prevented CHOP upregulation and inflammasome activation. Our data suggest that alcohol upregulates innate immune mechanisms by increasing Paneth cell numbers and IL-17A release contributing to apoptosis amplification, inflammasome activation, and gut leakiness in the PSI. Binge alcohol-induced Paneth cell expansion, ER stress, and inflammasome activation in the PSI are modulated by the gut microbiome.
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Abstract
Inflammation is an adaptive process to the noxious stimuli that the human body is constantly exposed to. From the local inflammatory response to a full-blown systemic inflammation, a wide complex sequence of events occurs. Persistent immunosuppression and catabolism may ensue, until multiple organ failure finally sets in. And since clinically useful and specific biomarkers are lacking, diagnosis may come late. A thorough understanding of these events (how they begin, how they evolve, and how to modulate them) is imperative, but as yet poorly studied. This review aims to consolidate current knowledge of these events so that the management of these patients is not only evidence-based, but also built on an understanding of the inner workings of the human body in health and in disease.
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Affiliation(s)
- Miguel Lourenço Varela
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal.
- Intensive Care Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal.
| | - Mihail Mogildea
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
| | - Ignacio Moreno
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
| | - Ana Lopes
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
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Holly MK, Smith JG. Paneth Cells during Viral Infection and Pathogenesis. Viruses 2018; 10:v10050225. [PMID: 29701691 PMCID: PMC5977218 DOI: 10.3390/v10050225] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/17/2018] [Accepted: 04/24/2018] [Indexed: 02/07/2023] Open
Abstract
Paneth cells are major secretory cells located in the crypts of Lieberkühn in the small intestine. Our understanding of the diverse roles that Paneth cells play in homeostasis and disease has grown substantially since their discovery over a hundred years ago. Classically, Paneth cells have been characterized as a significant source of antimicrobial peptides and proteins important in host defense and shaping the composition of the commensal microbiota. More recently, Paneth cells have been shown to supply key developmental and homeostatic signals to intestinal stem cells in the crypt base. Paneth cell dysfunction leading to dysbiosis and a compromised epithelial barrier have been implicated in the etiology of Crohn’s disease and susceptibility to enteric bacterial infection. Our understanding of the impact of Paneth cells on viral infection is incomplete. Enteric α-defensins, produced by Paneth cells, can directly alter viral infection. In addition, α-defensins and other antimicrobial Paneth cell products may modulate viral infection indirectly by impacting the microbiome. Here, we discuss recent insights into Paneth cell biology, models to study their function, and the impact, both direct and indirect, of Paneth cells on enteric viral infection.
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Affiliation(s)
- Mayumi K Holly
- Department of Microbiology, University of Washington, Box 357735, 1705 NE Pacific St., Seattle, WA 98195, USA.
| | - Jason G Smith
- Department of Microbiology, University of Washington, Box 357735, 1705 NE Pacific St., Seattle, WA 98195, USA.
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Sakamoto S, Sasaki K, Uchida H, Narumoto S, Kitajima T, Irie R, Fukuda A, Yoshioka T, Kasahara M. A severely cholestatic liver graft can be successfully used in deceased donor liver transplantation. Hepatol Res 2018; 48:E367-E371. [PMID: 28834072 DOI: 10.1111/hepr.12968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/07/2017] [Accepted: 08/08/2017] [Indexed: 12/14/2022]
Abstract
The shortage of deceased organs is still a serious issue in Japan. A proactive approach to using liver grafts from extended criteria donors (ECDs) may be one way of expanding the donor pool; however, if it is recklessly attempted, a recipient receiving such a marginal graft can be at risk of mortality due to primary non-function or delayed graft function. We herein report the successful outcome of a recipient receiving a severely cholestatic graft that was considered transplantable because it lacked features characteristic of a long duration of "cholestasis" according to the precise interpretation of a donor biopsy. Plasma exchange was intentionally introduced to prevent toxic insult by hyperbilirubinemia immediately after transplant. Despite transient acute kidney injury immediately after transplant, the patient's renal impairment was well managed with a renal-sparing immunosuppressive regimen consisting of basiliximab and mycophenolate mofetil. Although the use of liver grafts from ECDs still needs to be discussed, especially regarding graft selection and allocation policies, efforts not to discard valuable grafts should be undertaken in our country.
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Affiliation(s)
- Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kengo Sasaki
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Soichi Narumoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Toshihiro Kitajima
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Rie Irie
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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Yuan X, Lee JW, Bowser JL, Neudecker V, Sridhar S, Eltzschig HK. Targeting Hypoxia Signaling for Perioperative Organ Injury. Anesth Analg 2018; 126:308-321. [PMID: 28759485 PMCID: PMC5735013 DOI: 10.1213/ane.0000000000002288] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anesthesiology, the University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Jae W. Lee
- Department of Anesthesiology, the University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Jessica L. Bowser
- Department of Anesthesiology, the University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Viola Neudecker
- Department of Anesthesiology, Clinic of the University of Munich, Munich, Germany
| | - Srikanth Sridhar
- Department of Anesthesiology, the University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Holger K. Eltzschig
- Department of Anesthesiology, the University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
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Lawrence SM, Ruoss JL, Wynn JL. IL-17 in neonatal health and disease. Am J Reprod Immunol 2017; 79:e12800. [PMID: 29243317 DOI: 10.1111/aji.12800] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022] Open
Abstract
Over the last few years, scientific interest in the cytokine IL-17A has intensified as its role in human health and disease has been elucidated. Discovered almost a quarter century ago, IL-17A is known to have poor biologic activity when acting alone, but attains robust actions when working synergistically with potent mediators of proinflammatory immune responses, such as IL-6 and IL-8. IL-17A is produced by specialized innate immune cells that protect host barriers from the outside world. Like sentries, these innate immune cells can "sound the alarm" through increased production of IL-17A, causing activation and recruitment of primed neutrophils and monocytes when pathogens escape initial host defenses. In this way, IL-17A promulgates mechanisms responsible for pathogen death and clearance. However, when IL-17A pathways are triggered during fetal development, due to chorioamnionitis or in utero inflammatory conditions, IL-17A can instigate and/or exacerbate fetal inflammatory responses that increase neonatal morbidities and mortality associated with common neonatal conditions such as sepsis, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and necrotizing enterocolitis (NEC). This review details the ontogeny of IL-17A in the fetus and newborn, discusses how derangements in its production can lead to pathology, and describes known and evolving therapies that may attenuate IL-17A-mediated human conditions.
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Affiliation(s)
- Shelley M Lawrence
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of California, San Diego, La Jolla, CA, USA.,Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Jessica Lauren Ruoss
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - James L Wynn
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
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Zuluaga M, Gueguen V, Letourneur D, Pavon-Djavid G. Astaxanthin-antioxidant impact on excessive Reactive Oxygen Species generation induced by ischemia and reperfusion injury. Chem Biol Interact 2017; 279:145-158. [PMID: 29179950 DOI: 10.1016/j.cbi.2017.11.012] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/03/2017] [Accepted: 11/21/2017] [Indexed: 01/05/2023]
Abstract
Oxidative stress induced by Reactive Oxygen Species (ROS) was shown to be involved in the pathogenesis of chronic diseases such as cardiovascular pathologies. Particularly, oxidative stress has proved to mediate abnormal platelet function and dysfunctional endothelium-dependent vasodilatation representing a key factor in the progression of ischemic injuries. Antioxidants like carotenoids have been suggested to contribute in their prevention and treatment. Astaxanthin, a xanthophyll carotenoid produced naturally and synthetically, shows interesting antioxidant and anti-inflammatory properties. In vivo studies applying different models of induced ischemia and reperfusion (I/R) injury confirm astaxanthin's protective action after oral or intravenous administration. However, some studies have shown some limitations after oral administration such as low stability, bioavailability and bioefficacy, revealing a need for the implementation of new biomaterials to act as astaxanthin vehicles in vivo. Here, a brief overview of the chemical characteristics of astaxanthin, the carrier systems developed for overcoming its delivery drawbacks and the animal studies showing its potential effect to treat I/R injury are presented.
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Affiliation(s)
- M Zuluaga
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Paris 13 University, Sorbonne Paris Cite 99, Av. Jean-Baptiste Clément, 93430 Villetaneuse, France
| | - V Gueguen
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Paris 13 University, Sorbonne Paris Cite 99, Av. Jean-Baptiste Clément, 93430 Villetaneuse, France
| | - D Letourneur
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Paris 13 University, Sorbonne Paris Cite 99, Av. Jean-Baptiste Clément, 93430 Villetaneuse, France
| | - G Pavon-Djavid
- INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Paris 13 University, Sorbonne Paris Cite 99, Av. Jean-Baptiste Clément, 93430 Villetaneuse, France.
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Kato Y, Griesemer AD, Wu A, Sondermeijer HP, Weiner JI, Duran-Struuck R, Martinez M, Slate AR, Romanov A, Lefkowitch JH, Sykes M, Kato T. Novel H-shunt Venovenous Bypass for Liver Transplantation in Cynomolgus Macaques. Comp Med 2017; 67:436-441. [PMID: 28935006 PMCID: PMC5621572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 02/05/2017] [Accepted: 04/05/2017] [Indexed: 06/07/2023]
Abstract
Cynomolgus monkeys are often used in preclinical transplantation research. Performing liver transplantation in cynomolgus monkeys is challenging because they poorly tolerate portal vein clamping during the anhepatic phase. Finding an alternative to portal vein clamping is necessary before preclinical liver transplant models can be performed with reliable outcomes. We used 3 different techniques to perform 5 liver transplants in male cynomolgus macaques (weight, 7.4-10.8 kg; mismatched for MHC I and II; matched for ABO). In procedure A, we clamped the portal vein briefly, as in human transplants, as well as the superior mesentery artery to minimize congestion at the expense of temporary ischemia (n = 2). In procedure B, we performed a temporary portocaval shunt with extracorporeal venovenous bypass (n = 1). For procedure C, we developed an H-shunt system (modified portocaval shunt) with extracorporeal bypass (n = 2). Postoperative immunosuppression comprised cyclosporine A, mycophenolate mofetil, and steroids. Recipients in procedure A developed hemodynamic instability and were euthanized within 2 d. The recipient that underwent procedure B was euthanized within 11 d due to inferior vena caval thrombosis. The H-shunt in procedure C led to minimal PV congestion during the anhepatic phase, and both recipients reached the 21-d survival endpoint with good graft function. Our novel H-shunt bypass system resulted in successful liver transplantation in cynomolgus macaques, with long-term posttransplant survival possible. This technical innovation makes possible the use of cynomolgus monkeys for preclinical liver transplant tolerance models.
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Affiliation(s)
- Yojiro Kato
- Departments of Surgery, Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Adam D Griesemer
- Departments of Surgery, Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Anette Wu
- Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Hugo P Sondermeijer
- Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Joshua I Weiner
- Departments of Surgery, Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Raimon Duran-Struuck
- Departments of Surgery, Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Mercedes Martinez
- Departments of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Andrea R Slate
- Institute of Comparative Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Alexander Romanov
- Institute of Comparative Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jay H Lefkowitch
- Departments of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Megan Sykes
- Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Tomoaki Kato
- Departments of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York;,
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Stengel S, Messner B, Falk-Paulsen M, Sommer N, Rosenstiel P. Regulated proteolysis as an element of ER stress and autophagy: Implications for intestinal inflammation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:2183-2190. [PMID: 28736290 DOI: 10.1016/j.bbamcr.2017.07.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/17/2017] [Accepted: 07/19/2017] [Indexed: 02/07/2023]
Abstract
Endoplasmic reticulum (ER) stress and autophagy are tightly controlled cellular processes, which are responsible for maintaining protein homeostasis in a cell. Impairment of the interlinking pathways have been implicated in a number of human diseases, prominently in inflammatory bowel disease, where genetic variants in several independent autophagy and ER stress related loci have been associated to increased disease risk. Autophagy is a selective quality control process, which governs the integrity of the cell by removal of aged organelles and proteins via the lysosome, but recently has been shown to actively license the outcome of other signaling pathways by guiding the proteolytic removal of signaling protein complexes (adaptophagy). In this review, we summarize our knowledge on regulated proteolytic events involved in ER stress responses and autophagy, their interplay and potential regulatory effects with a particular focus on intestinal inflammation. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
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Affiliation(s)
- Stephanie Stengel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany
| | - Berith Messner
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany
| | - Maren Falk-Paulsen
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany
| | - Nina Sommer
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany.
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Abstract
Recent developments in our understanding of the pathogenesis of kidney disease in the setting of liver failure have highlighted that kidney injury, rather than occurring in isolation, is a marker of systemic disease and poor prognosis. The differential diagnosis of kidney disease associated with liver failure is broader than formerly described and new biopsy data, along with better acute kidney injury classification tools, have increased appreciation for distinct pathophysiological mechanisms. Evidence suggests that acute kidney injury contributes to worsening hepatic failure by directly injuring hepatic cells and by imposing restrictions on therapeutic strategies for portal hypertension. Furthermore, kidney injury limits the use of various therapeutic agents and increases their toxicity due to altered pharmacodynamics. A greater appreciation of CKD in this population is also overdue because management decisions are affected and increased vigilance may avoid further kidney injury. A multidisciplinary approach to kidney injury in the setting of liver failure will enable targeted therapeutic strategies that are safe and effective and serve to guide further research, while limiting clinical potential for harm. Finally, new hepatitis C antiviral therapies promise to change the landscape of liver failure, and a discussion of kidney risk factors and antiviral therapy of patients with kidney disease and hepatitis C is worthwhile.
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Ma G, Chen C, Jiang H, Qiu Y, Li Y, Li X, Zhang X, Liu J, Zhu T. Ribonuclease attenuates hepatic ischemia reperfusion induced cognitive impairment through the inhibition of inflammatory cytokines in aged mice. Biomed Pharmacother 2017; 90:62-68. [PMID: 28343072 DOI: 10.1016/j.biopha.2017.02.094] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Revised: 02/24/2017] [Accepted: 02/24/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Elderly patients undergoing major surgery often develop cognitive dysfunction, and no optimum treatment exists for this postoperative complication. Ribonuclease, the counterpart of ribonucleic acid, has mostly been reported in terms of its use as a potential modality in anticancer therapy, and recent studies have demonstrated that ribonuclease can exert organ-protective effects in several pathological conditions. Our study also demonstrated that ribonuclease protects the liver against ischemia reperfusion injury. Nevertheless, it is unknown whether ribonuclease can attenuate the cognitive dysfunction that is induced by liver ischemia reperfusion. In this study, we aimed to evaluate the effect of ribonuclease on cognitive function after liver ischemia reperfusion. METHODS Aged mice underwent sham surgery or 60min of hepatic ischemia reperfusion, vehicle or ribonuclease, which were administered subcutaneously. The primary observation endpoint was the Morris water maze; following 24h, 3days, and 7days of reperfusion, the levels of serum and hippocampus proinflammatory cytokines were measured to reveal the underlying mechanism. RESULTS A probe test was conducted on day 3 and a reversal probe test was conducted on day 7 after surgery; the results demonstrated a reduction in cognitive function after liver ischemia reperfusion and that ribonuclease treatment attenuated cognitive impairment. The levels of serum and hippocampus proinflammatory cytokines (interleukin-6 and interleukin-1β) and extracellular ribonucleic acid were significantly increased at 24h after reperfusion, but ribonuclease treatment markedly reduced the proinflammatory cytokine increase. CONCLUSION The results of the study suggested that hepatic ischemia reperfusion leads to cognitive impairment in aged mice and an increase in inflammatory cytokine expression in both serum and the hippocampus; more importantly, ribonuclease showed protective effects against cognitive impairment through inhibiting the release of inflammatory cytokines.
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Affiliation(s)
- Gang Ma
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China; Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chan Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Haixia Jiang
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yanhua Qiu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Yansong Li
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Xiaoqiang Li
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Xiyang Zhang
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Jin Liu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China
| | - Tao Zhu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 China.
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