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Nyquist P, Bhende B. The Mellow Dampening of Febrile Insanity. Crit Care Med 2025:00003246-990000000-00511. [PMID: 40207987 DOI: 10.1097/ccm.0000000000006674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Affiliation(s)
- Paul Nyquist
- Department of Neurology, Anesthesia and Critical Care Medicine, General Internal Medicine, and Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD
| | - Bhagyashri Bhende
- Division of Neurosciences Critical Care, Department of Anesthesiology and Critical Care Medicine, Neurology and Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD
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2
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Denver P, Cunningham C. Microglial activation and neuroinflammation in acute and chronic cognitive deficits in sepsis. Neuropharmacology 2025; 267:110285. [PMID: 39746541 DOI: 10.1016/j.neuropharm.2024.110285] [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: 09/20/2024] [Revised: 12/11/2024] [Accepted: 12/26/2024] [Indexed: 01/04/2025]
Abstract
Sepsis is characterised by dysregulated immune responses to infection, leading to multi-organ dysfunction and high rates of mortality. With increasing survival rates in recent years long-term neurological and psychiatric consequences have become more apparent in survivors. Many patients develop sepsis associated encephalopathy (SAE) which encompasses the profound but usually transient neuropsychiatric syndrome delirium but also new brain injury that emerges in the months and years post-sepsis. It is now clear that systemic inflammatory signals reach the brain during sepsis and that very significant neuroinflammation ensues. The major brain resident immune cell population, the microglia, has been implicated in acute and chronic cognitive dysfunction in animal models of sepsis based on a growing number of studies using bacterial endotoxin and in polymicrobial sepsis models such as cecal ligation and puncture. The current review explores the effects of sepsis on the brain, focussing on how systemic insults translate to microglial activation and neuroinflammation and how this disrupts neuronal function and integrity. We examine what has been demonstrated specifically with respect to microglial activation, revealing robust evidence for a role for neuroinflammation in sepsis-induced brain sequelae but less clear information on the extent of the specific microglial contribution to this, arising from findings using global knockout mice, non-selective drugs and treatments that equally target peripheral and central compartments. There is, nonetheless, clear evidence that microglia do become activated and do contribute to brain consequences of sepsis thus arguing for improved understanding of these neuroinflammatory processes toward the prevention and treatment of sepsis-induced brain dysfunction.
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Affiliation(s)
- Paul Denver
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland
| | - Colm Cunningham
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
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Liu H, Zhang T, Zhang L, Zhong Y. Neuroinflammatory Mechanisms of Adult Sepsis-Associated Encephalopathy: Implications for Blood-Brain Barrier Disruption and Oxidative Stress. Diagnostics (Basel) 2025; 15:873. [PMID: 40218223 PMCID: PMC11988331 DOI: 10.3390/diagnostics15070873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/28/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025] Open
Abstract
Sepsis is a syndrome of life-threatening acute organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) refers to the diffuse brain dysfunction observed in sepsis cases, clinically characterized by a spectrum of neuropsychiatric manifestations ranging from delirium to coma. SAE is independently associated with increased short-term mortality and long-term neurological abnormalities, with currently no effective preventive or treatment strategies. The pathogenesis is intricate, involving disruptions in neurotransmitters, blood-brain barrier (BBB) breakdown, abnormal brain signal transmission, and oxidative stress, among others. These mechanisms interact or act in conjunction, contributing to the complexity of SAE. Scholars worldwide have made significant strides in understanding the pathogenesis of SAE, offering new perspectives for diagnosis and treatment. This review synthesizes recent mechanistic breakthroughs and clinical evidence to guide future research directions, particularly in targeting BBB restoration and oxidative stress.
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Affiliation(s)
- Hao Liu
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China; (H.L.); (T.Z.)
| | - Ting Zhang
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China; (H.L.); (T.Z.)
| | - Lixiao Zhang
- Xiangya School of Medicine, Central South University, Changsha 410013, China;
| | - Yanjun Zhong
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China; (H.L.); (T.Z.)
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Zhang N, Ma Y, Li Y, Wang Y, Zhang L, Zheng M, Tian Y, Zhang R, Yang K, Li J, Yan F, Liu H, Zhang Y, Xu J, Yu C, Xu J. Paeonol prevents sepsis-associated encephalopathy via regulating the HIF1A pathway in microglia. Int Immunopharmacol 2024; 143:113287. [PMID: 39362015 DOI: 10.1016/j.intimp.2024.113287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/22/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
Paeonol, a phenolic acid compound extracted from the Cortex Moutan, exhibits significant anti-inflammatory, antioxidant, and anti-apoptotic properties. This study aimed to investigate the effects of paeonol on neuroinflammation and depressive-like symptoms, and the underlying mechanisms in a mouse model of sepsis-associated encephalopathy (SAE) induced by lipopolysaccharide (LPS). To assess the therapeutic potential of paeonol in mice treated with LPS, behavioral assessments were conducted using the open-field test (OFT), tail suspension test (TST), and forced swimming test (FST), and quantitative PCR (qPCR), Western blot, and immunofluorescent staining were utilized to determine the expression levels of inflammatory molecules in the hippocampus in vivo and microglial cells in vitro. Our results revealed that paeonol significantly alleviated anxiety and depressive-like symptoms, as evidenced by improved activity in OFT, reduced immobility time in TST and FST, and decreased levels of inflammatory markers such as IL6, TNFα, and PFKFB3. Further in vitro experiments confirmed that paeonol downregulated the expression of pro-inflammatory molecules. A network pharmacology-based strategy combined with molecular docking and cellular thermal shift assay highlighted HIF1A as a potential target for paeonol. Similar anti-inflammatory effects of a HIF1A inhibitor were also observed in microglia treated with LPS. Furthermore, these effects were reversed by CoCl2, a HIF1A agonist, indicating the critical role of the HIF1A signaling pathway in mediating the therapeutic effects of paeonol. These findings highlight the potential of paeonol in modulating the HIF1A pathway, offering a promising therapeutic strategy for neuroinflammation in SAE.
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Affiliation(s)
- Ning Zhang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Yongjie Ma
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Yuqing Li
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Yiqi Wang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Lisheng Zhang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Mincheng Zheng
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Yu Tian
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Ruiying Zhang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Kanlin Yang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Jieyuan Li
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Fuman Yan
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Haimei Liu
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China; Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Yaxing Zhang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China; Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Jinwen Xu
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China; Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China.
| | - Cong Yu
- Department of Neonatology, Jiangxi Provincial Children's Hospital, Nanchang, China.
| | - Jiean Xu
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China; Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China.
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Rump K, Adamzik M. Aquaporins in sepsis- an update. Front Immunol 2024; 15:1495206. [PMID: 39544938 PMCID: PMC11560437 DOI: 10.3389/fimmu.2024.1495206] [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: 09/12/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024] Open
Abstract
Aquaporins (AQPs), a family of membrane proteins that facilitate the transport of water and small solutes, have garnered increasing attention for their role in sepsis, not only in fluid balance but also in immune modulation and metabolic regulation. Sepsis, characterized by an excessive and dysregulated immune response to infection, leads to widespread organ dysfunction and significant mortality. This review focuses on the emerging roles of aquaporins in immune metabolism and their potential as therapeutic targets in sepsis, with particular attention to the modulation of inflammatory responses and organ protection. Additionally, it explores the diverse roles of aquaporins across various organ systems, highlighting their contributions to renal function, pulmonary gas exchange, cardiac protection, and gastrointestinal barrier integrity in the context of sepsis. Recent studies suggest that AQPs, particularly aquaglyceroporins like AQP3, AQP7, AQP9, and AQP10, play pivotal roles in immune cell metabolism and offer new therapeutic avenues for sepsis treatment. In the context of sepsis, immune cells undergo metabolic shifts to meet the heightened energy demands of the inflammatory response. A key adaptation is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, where pyruvate is converted to lactate, enabling faster ATP production. AQPs, particularly aquaglyceroporins, may facilitate this process by transporting glycerol, a substrate that fuels glycolysis. AQP3, for example, enhances glucose metabolism by transporting glycerol and complementing glucose uptake via GLUT1, while also regulating O-GlcNAcylation, a post-translational modification that boosts glycolytic flux. AQP7 could further contributes to immune cell energy production by influencing lipid metabolism and promoting glycolysis through p38 signaling. These mechanisms could be crucial for maintaining the energy supply needed for an effective immune response during sepsis. Beyond metabolism, AQPs also regulate key immune functions. AQP9, highly expressed in septic patients, is essential for neutrophil migration and activation, both of which are critical for controlling infection. AQP3, on the other hand, modulates inflammation through the Toll-like receptor 4 (TLR4) pathway, while AQP1 plays a role in immune responses by activating the PI3K pathway, promoting macrophage polarization, and protecting against lipopolysaccharide (LPS)-induced acute kidney injury (AKI). These insights into the immunoregulatory roles of AQPs suggest their potential as therapeutic targets to modulate inflammation in sepsis. Therapeutically, AQPs present promising targets for reducing organ damage and improving survival in sepsis. For instance, inhibition of AQP9 with compounds like HTS13286 or RG100204 has been shown to reduce inflammation and improve survival by modulating NF-κB signaling and decreasing oxidative stress in animal models. AQP5 inhibition with methazolamide and furosemide has demonstrated efficacy in reducing immune cell migration and lung injury, suggesting its potential in treating acute lung injury (ALI) in sepsis. Additionally, the regulation of AQP1 through non-coding RNAs (lncRNAs and miRNAs) may offer new strategies to mitigate organ damage and inflammatory responses. Moreover, AQPs have emerged as potential biomarkers for sepsis progression and outcomes. Altered expression of AQPs, such as AQP1, AQP3, and AQP5, correlates with sepsis severity, and polymorphisms in AQP5 have been linked to better survival rates and improved outcomes in sepsis-related acute respiratory distress syndrome (ARDS). This suggests that AQP expression could be used to stratify patients and tailor treatments based on individual AQP profiles. In conclusion, AQPs play a multifaceted role in the pathophysiology of sepsis, extending beyond fluid balance to crucial involvement in immune metabolism and inflammation. Targeting AQPs offers novel therapeutic strategies to mitigate sepsis-induced organ damage and improve patient survival. Continued research into the metabolic and immune functions of AQPs will be essential for developing targeted therapies that can be translated into clinical practice.
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Affiliation(s)
- Katharina Rump
- Klinik für Anästhesiologie Intensivmedizin und Schmerztherapie Universitätsklinikum Knappschaftskrankenhaus Bochum, University Clinic of Ruhr University Bochum, Bochum, Germany
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Peng S, Sun T, Yang D, Zhao H, Lin L, Xia B, Li M, Piao M, Shi Z, Tuo Q. Dipsacoside B ameliorates cognitive impairment in sepsis-associated encephalopathy by reducing Th17 cell infiltration and neuroinflammation. Biochem Pharmacol 2024; 227:116428. [PMID: 39009096 DOI: 10.1016/j.bcp.2024.116428] [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: 04/16/2024] [Revised: 06/24/2024] [Accepted: 07/12/2024] [Indexed: 07/17/2024]
Abstract
Sepsis-associated encephalopathy (SAE) is the main cause of cognitive impairment in patients with sepsis. The infiltration of inflammatory signals into the central nervous system (CNS) via the compromised blood-brain barrier (BBB) represents a crucial step in the pathological progression of SAE. In particular, T-helper 17 cell (Th17 cells) has been suggested to be highly correlated with the activation of central immune responses. Thus, preventing Th17 cell infiltration into the CNS may be a possible strategy to alleviate cognitive decline in SAE. Dipsacoside B (DB) is one of the primary active components in Chuan Xu Duan (Dipsacus asper Wall). We speculate that DB may be a potential candidate for the treatment of SAE-related cognitive deficits. In the present study, we demonstrated that DB could effectively alleviate cognitive impairment in SAE mice. DB significantly suppressed the central inflammatory response induced by repeated lipopolysaccharide (LPS) injection. The mechanism underlying its therapeutic effect should be attributed to the reduction of BBB impairment and pathogenic Th17 cell infiltration into the CNS by inhibition of vascular endothelial growth factor A (VEGFA)/ Vascular endothelial growth factor receptor 2(VEGFR2)/ Endothelial nitric oxide synthase (eNOS) signaling. Our findings suggest that DB is a potential candidate for the treatment of SAE-related cognitive dysfunction.
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Affiliation(s)
- Sha Peng
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Taoli Sun
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Dongmei Yang
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Basic Research Center of Integrated Chinese and Western medicine on prevention and treatment of vascular diseases, Medical School, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Hongqing Zhao
- Science & Technology Innovation Center, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Limei Lin
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Bohou Xia
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Minjie Li
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Meihong Piao
- Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Basic Research Center of Integrated Chinese and Western medicine on prevention and treatment of vascular diseases, Medical School, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China
| | - Zhe Shi
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China.
| | - Qinhui Tuo
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China; Basic Research Center of Integrated Chinese and Western medicine on prevention and treatment of vascular diseases, Medical School, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China.
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Sriram S, Carstens K, Dewing W, Fiacco TA. Astrocyte regulation of extracellular space parameters across the sleep-wake cycle. Front Cell Neurosci 2024; 18:1401698. [PMID: 38988660 PMCID: PMC11233815 DOI: 10.3389/fncel.2024.1401698] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/07/2024] [Indexed: 07/12/2024] Open
Abstract
Multiple subfields of neuroscience research are beginning to incorporate astrocytes into current frameworks of understanding overall brain physiology, neuronal circuitry, and disease etiology that underlie sleep and sleep-related disorders. Astrocytes have emerged as a dynamic regulator of neuronal activity through control of extracellular space (ECS) volume and composition, both of which can vary dramatically during different levels of sleep and arousal. Astrocytes are also an attractive target of sleep research due to their prominent role in the glymphatic system, a method by which toxic metabolites generated during wakefulness are cleared away. In this review we assess the literature surrounding glial influences on fluctuations in ECS volume and composition across the sleep-wake cycle. We also examine mechanisms of astrocyte volume regulation in glymphatic solute clearance and their role in sleep and wake states. Overall, findings highlight the importance of astrocytes in sleep and sleep research.
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Affiliation(s)
- Sandhya Sriram
- Interdepartmental Graduate Program in Neuroscience, University of California, Riverside, Riverside, CA, United States
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
| | - Kaira Carstens
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
| | - Wayne Dewing
- Undergraduate Major in Neuroscience, University of California, Riverside, Riverside, CA, United States
| | - Todd A Fiacco
- Interdepartmental Graduate Program in Neuroscience, University of California, Riverside, Riverside, CA, United States
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
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Mao Y, Zhang A, Yang H, Zhang C. Identification of IL-8 in CSF as a potential biomarker in sepsis-associated encephalopathy. Cytokine 2023; 172:156390. [PMID: 37812997 DOI: 10.1016/j.cyto.2023.156390] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Sepsis-associated encephalopathy (SAE) is frequently present at the acute and chronic phase of sepsis, which is characterized by delirium, coma, and cognitive dysfunction. Despite the increased morbidity and mortality of SAE, the pathogenesis of SAE remains unclear. This study aims to discover the potential biomarkers, so as to clear the pathogenesis potentially contributing to the development of SAE and provide new therapeutic strategies for the treatment of SAE. METHODS The GSE135838 dataset was obtained from the Gene Expression Omnibus (GEO) database and utilized for analysis the differentially expressed genes (DEGs). The DEGs were analyzed by limma package of R language and the extracellular protein-differentially expressed genes (EP-DEGs) were screened by the Human Protein Atlas (HPA) and UniProt database. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out to analyze the function and pathway of EP-DEGs. STRING, Cytoscape, MCODE and Cytohubba were used to construct a protein-protein interaction (PPI) network and screen key EP-DEGs. Key EP-DEGs levels were detected in the cerebrospinal fluid (CSF) of SAE patients and non-sepsis patients with critical illness. ROC curve was used to evaluate the diagnostic of SAE. RESULTS We screened 82 EP-DEGs from DEGs. EP-DEGs were enriched in cytokine-cytokine receptor interaction, IL-17 signaling pathway and NOD-like receptor signaling pathway. We identified 2 key extracellular proteins IL-1B and IL-8. We clinically verified that IL-6 and IL-8 levels were increased in CSF of SAE patients and CSF IL-8 (AUC = 0.882, 95 % CI = 0.775-0.988) had a higher accuracy in the diagnosis of SAE than CSF IL-6 (AUC = 0.824, 95 % CI = 0.686-0.961). Furthermore, we found that the IL-8 levels in CSF might not associated with Glasgow Coma Scale (GCS) scores of SAE patients. CONCLUSION IL-8 may be the key extracellular cytokine in the pathogenesis of SAE. Bioinformatics methods were used to explore the biomarkers of SAE and validated the results in clinical samples. Our findings indicate that the IL-8 in CSF might be the potential diagnostic biomarker and therapeutic target in SAE.
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Affiliation(s)
- Yingying Mao
- Department of General Practice, Liaocheng People's Hospital, No.67 West Dongchang Road, Liaocheng 252000, Shandong Province, China
| | - Amin Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan 250012, Shandong Province, China
| | - Haitao Yang
- Department of General Practice, Liaocheng People's Hospital, No.67 West Dongchang Road, Liaocheng 252000, Shandong Province, China
| | - Chen Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan 250012, Shandong Province, China.
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Bozkurt A, Halici H, Yayla M. Aquaporins: Potential Targets in Inflammatory Diseases. Eurasian J Med 2023; 55:106-113. [PMID: 39128069 PMCID: PMC11075024 DOI: 10.5152/eurasianjmed.2023.23357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 12/26/2023] [Indexed: 08/13/2024] Open
Abstract
Inflammation involves a long chain of molecular reactions and cellular activity designed to repair tissue damaged by various causes. The inflammatory process and its complex mechanisms have recently become a focus of interest for many researchers. After the onset of inflammation, various adverse conditions that initiate the inflammatory response need to be addressed; however, failure to limit the inflammatory reaction may result in the damage or destruction of host cells. Therefore, inflammatory reactions play a role in many diferent diseases. Aquaporins (AQPs), commonly referred to as water channels, are protein channels responsible for forming pores in the membranes of biological cells. Their main function is to aid in the movement of water between cells. Aquaporins not only regulate transepithelial fluid transport across membranes but also play a role in regulating essential events crucial for the inflammatory response. Aquaporins have been shown in many studies to have important roles in inflammatory diseases. This clearly indicates that AQPs may be potential targets for inflammatory diseases. This review summarizes the research to date on the structure and function of AQPs and provides an update on the relationship between AQPs and various human inflammatory diseases.
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Affiliation(s)
- Ayse Bozkurt
- Department of Pharmacology, Van Yüzüncü Yıl University Faculty of Pharmacy, Van, Turkey
| | - Hamza Halici
- Department of Pharmacology, Atatürk University Hınıs Vocational College, Erzurum, Turkey
| | - Muhammed Yayla
- Department of Pharmacology, Kafkas University Faculty of Medicine, Kars, Turkey
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Yu L, Liu Y, Cao C, Yang L, Liu H, Wang C. Andrographolide Attenuates Inflammation Due to Intra-Abdominal Sepsis by Enhancing Bacterial Clearance in Mice. J Inflamm Res 2023; 16:4413-4423. [PMID: 37822531 PMCID: PMC10564118 DOI: 10.2147/jir.s422342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/03/2023] [Indexed: 10/13/2023] Open
Abstract
Purpose Intra-abdominal infection is a complex pathophysiological process involving multiple systems and organs of the body. Abdominal infections complicated by severe sepsis or septic shock have a high mortality rate of 30-50%. Therefore, novel strategies to treat sepsis are urgently needed. Methods Andrographolide (AD), the main active ingredient of Andrographis paniculata, reportedly exerts beneficial effects on mice with sepsis. However, its exact mechanism of action in attenuating inflammation due to intra-abdominal sepsis remains unclear to date. Hence, this study aimed to examine the therapeutic effects of AD on cecal ligation and puncture (CLP)-induced sepsis and elucidate the underlying mechanisms. Results Results showed that AD therapy could significantly improve the 7-day survival rate and alleviate pathological organ injury in mice with CLP. In addition, AD treatment decreased the levels of proinflammatory factors, such as tumor necrosis factor-α and interleukin (IL)-6 in the peritoneal cavity fluid and blood and increased the level of anti-inflammatory factor IL-10 in the peritoneal cavity fluid of mice with CLP. Moreover, bacterial counts in the blood and peritoneal lavage fluid were lower in the mice treated with AD than in those untreated. Mechanistically, AD treatment increased the percentage and phagocytic activity of macrophages in the peritoneal cavity. Conclusion These data showed that AD can improve the survival of mice with intra-abdominal sepsis by enhancing bacterial clearance, as evidenced by the increased percentages and phagocytic activity of macrophages in the peritoneal cavity. This study is the first to demonstrate the protective effects of AD against intra-abdominal sepsis.
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Affiliation(s)
- Lechang Yu
- Department of Geriatrics, Tianjin Medical University General Hospital; Tianjin Geriatrics Institute, Tianjin, 300052, People’s Republic of China
| | - Ying Liu
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China
| | - Chao Cao
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China
| | - Liheng Yang
- Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Haijing Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China
| | - Chunli Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China
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Sawoo R, Dey R, Ghosh R, Bishayi B. Exogenous IL-10 posttreatment along with TLR4 and TNFR1 blockade improves tissue antioxidant status by modulating sepsis-induced macrophage polarization. J Appl Toxicol 2023; 43:1549-1572. [PMID: 37177863 DOI: 10.1002/jat.4496] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/10/2023] [Accepted: 05/10/2023] [Indexed: 05/15/2023]
Abstract
Multi-organ dysfunction is one of the major reasons behind the high mortality of sepsis throughout the world. With the pathophysiology of sepsis remaining largely unknown, the uncontrolled reactive oxygen species (ROS) production along with the decreased antioxidants contributes to the progression toward septic shock. Being the effector cells of the innate immunity system, macrophages secrete both pro-inflammatory and anti-inflammatory mediators during inflammation. Lipopolysaccharide (LPS) binding to toll-like receptor 4 (TLR4) releases TNF-α, which initiates pro-inflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling. However, it is counteracted by the anti-inflammatory interleukin 10 (IL-10) causing decreased oxidative stress. Our study thus aimed to assess the effects of exogenous IL-10 treatment post-neutralization of TLR4 and TNFR1 (by anti-TLR4 antibody and anti-TNFR1 antibody, respectively) in an in vivo murine model of LPS-sepsis. We have also examined the tissue-specific antioxidant status in the spleen, liver, and lungs along with the serum cytokine levels in adult male Swiss albino mice to determine the functional association with the disease. The results showed that administration of recombinant IL-10 post-neutralization of the receptors was beneficial in shifting the macrophage polarization to the anti-inflammatory M2 phenotype. IL-10 treatment significantly downregulated the free radicals production resulting in diminished lipid peroxidase (LPO) levels. The increased antioxidant activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GRX ) conferred protection against LPS-induced sepsis. Western blot data further confirmed diminished expressions of TLR4 and TNFR1 along with suppressed stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) and increased SOD and CAT expressions, which altogether indicated that neutralization of TLR4 and TNFR1 along with IL-10 posttreatment might be a potential therapeutic measure for the treatment of sepsis.
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Affiliation(s)
- Ritasha Sawoo
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, India
| | - Rajen Dey
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, India
| | - Rituparna Ghosh
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, India
| | - Biswadev Bishayi
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, Calcutta, India
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12
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Zhong Y, Guan J, Ma Y, Xu M, Cheng Y, Xu L, Lin Y, Zhang X, Wu R. Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy. ACS Chem Neurosci 2023; 14:2172-2182. [PMID: 37216423 PMCID: PMC10252850 DOI: 10.1021/acschemneuro.3c00180] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/04/2023] [Indexed: 05/24/2023] Open
Abstract
Sepsis-associated encephalopathy is a severe systemic infection complication. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in early disease stages using magnetic resonance imaging (MRI). N-Acetylcysteine, an antioxidant and precursor of glutathione, regulates neurotransmitter glutamate metabolism and participates in neuroinflammation. We investigated the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitored changes in brain using magnetic resonance (MR) molecular imaging. Bacterial lipopolysaccharide was injected intraperitoneally to induce a sepsis-associated encephalopathy model. Behavioral performance was assessed using the open-field test. Tumor necrosis factor α and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expression, cellular damage, and changes in blood-brain barrier permeability were assessed using western blotting, pathological staining, and Evans blue staining, respectively. Lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. MR molecular imaging can identify pathological processes at different disease stages. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumor necrosis factor α, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signaling pathway. Finally, n-acetylcysteine-treated rats showed reduced cellular damage by pathology and reduced extravasation of their blood-brain barrier by Evans Blue staining. Thus, n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, noninvasive "dynamic visual monitoring" of physiological and pathological changes related to sepsis-associated encephalopathy was achieved using MR molecular imaging for the first time, providing a more sensitive imaging basis for early diagnosis, identification, and prognosis.
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Affiliation(s)
- Yazhi Zhong
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
- Department
of Radiology, Huizhou Central People’s
Hospital, Huizhou 516001 Guangdong, China
| | - Jitian Guan
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
| | - Yunfeng Ma
- Department
of Emergency, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
| | - Meiling Xu
- Department
of Emergency, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
| | - Yan Cheng
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
- Department
of Radiology, The Second Hospital of Shandong
University, Jinan 250033 Shandong, China
| | - Liang Xu
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
- Department
of Radiology, The Seventh Affiliated Hospital,
Sun Yat-sen University, Shenzhen 518100 Guangdong, China
| | - Yan Lin
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
| | - Xiaolei Zhang
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
| | - Renhua Wu
- Department
of Radiology, The Second Affiliated Hospital,
Shantou University Medical College, Shantou 515041 Guangdong, China
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13
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Dumbuya JS, Li S, Liang L, Zeng Q. Paediatric sepsis-associated encephalopathy (SAE): a comprehensive review. Mol Med 2023; 29:27. [PMID: 36823611 PMCID: PMC9951490 DOI: 10.1186/s10020-023-00621-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
Sepsis-associated encephalopathy (SAE) is one of the most common types of organ dysfunction without overt central nervous system (CNS) infection. It is associated with higher mortality, low quality of life, and long-term neurological sequelae, its mortality in patients diagnosed with sepsis, progressing to SAE, is 9% to 76%. The pathophysiology of SAE is still unknown, but its mechanisms are well elaborated, including oxidative stress, increased cytokines and proinflammatory factors levels, disturbances in the cerebral circulation, changes in blood-brain barrier permeability, injury to the brain's vascular endothelium, altered levels of neurotransmitters, changes in amino acid levels, dysfunction of cerebral microvascular cells, mitochondria dysfunction, activation of microglia and astrocytes, and neuronal death. The diagnosis of SAE involves excluding direct CNS infection or other types of encephalopathies, which might hinder its early detection and appropriate implementation of management protocols, especially in paediatric patients where only a few cases have been reported in the literature. The most commonly applied diagnostic tools include electroencephalography, neurological imaging, and biomarker detection. SAE treatment mainly focuses on managing underlying conditions and using antibiotics and supportive therapy. In contrast, sedative medication is used judiciously to treat those showing features such as agitation. The most widely used medication is dexmedetomidine which is neuroprotective by inhibiting neuronal apoptosis and reducing a sepsis-associated inflammatory response, resulting in improved short-term mortality and shorter time on a ventilator. Other agents, such as dexamethasone, melatonin, and magnesium, are also being explored in vivo and ex vivo with encouraging results. Managing modifiable factors associated with SAE is crucial in improving generalised neurological outcomes. From those mentioned above, there are still only a few experimentation models of paediatric SAE and its treatment strategies. Extrapolation of adult SAE models is challenging because of the evolving brain and technical complexity of the model being investigated. Here, we reviewed the current understanding of paediatric SAE, its pathophysiological mechanisms, diagnostic methods, therapeutic interventions, and potential emerging neuroprotective agents.
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Affiliation(s)
- John Sieh Dumbuya
- Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Siqi Li
- Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Lili Liang
- Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Qiyi Zeng
- Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People's Republic of China.
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14
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Nishikawa Y, Choudhury ME, Mikami K, Matsuura T, Kubo M, Nagai M, Yamagishi S, Doi T, Hisai M, Yamamoto H, Yajima C, Nishihara T, Abe N, Yano H, Yorozuya T, Tanaka J. Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model. Neurochem Int 2023; 163:105479. [PMID: 36608872 DOI: 10.1016/j.neuint.2023.105479] [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: 10/26/2022] [Revised: 12/25/2022] [Accepted: 01/02/2023] [Indexed: 01/05/2023]
Abstract
Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1β (IL-1β) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1β and TNFα in the PFC. DA levels were increased in the PFC 21 h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1β expression, was abruptly decreased 21 h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1β and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium.
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Affiliation(s)
- Yuki Nishikawa
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan; Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Mohammed E Choudhury
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Kanta Mikami
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Taisei Matsuura
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Madoka Kubo
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Satoru Yamagishi
- Optical Neuroanatomy, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan
| | - Tomomi Doi
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Manami Hisai
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Haruto Yamamoto
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Chisato Yajima
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Tasuku Nishihara
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Naoki Abe
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Hajime Yano
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Toshihiro Yorozuya
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Junya Tanaka
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
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15
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Zhong Y, Guan J, Ma Y, Xu M, Cheng Y, Xu L, Lin Y, Zhang X, wu R. Role of imaging modalities and N-acetylcysteine treatment in sepsis-associated encephalopathy.. [DOI: 10.21203/rs.3.rs-2459747/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Abstract
Background
Sepsis-associated encephalopathy is a severe complication due to systemic infection. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in the early stage of the disease by MRI. N-acetylcysteine, an antioxidant and precursor of glutathione, regulates the metabolism of the neurotransmitter glutamate and participates in neuroinflammation. We aimed to investigate the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitor changes in the brain using magnetic resonance molecular imaging.
Methods
Bacterial lipopolysaccharide was injected intraperitoneally into the rats to induce a sepsis-associated encephalopathy model. The behavioural performance was assessed using the open field test. Tumour necrosis factor alpha and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expressions and cellular damage were assessed by western blotting and pathological staining, respectively. We also evaluated changes in the blood-brain barrier permeability by the Evans blue staining.
Results
The lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. Magnetic resonance molecular imaging can identify pathological processes at different stages of the disease. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumour necrosis factor alpha, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed a reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signalling pathway. Finally, n-acetylcysteine treated rats also showed reduced cellular damage by pathology and reduced extravasation of their blood-brain barrier by Evan Blue staining.
Conclusion
This study showed that n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, non-invasive ‘dynamic visual monitoring’ of the physiological and pathological changes related to sepsis-associated encephalopathy was achieved for the first time using magnetic resonance molecular imaging, which provides a more sensitive imaging basis for early clinical diagnosis, identification, and prognosis.
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Affiliation(s)
| | - Jitian Guan
- Second Affiliated Hospital of Shantou University Medical College
| | - Yunfeng Ma
- Second Affiliated Hospital of Shantou University Medical College
| | - Meiling Xu
- Second Affiliated Hospital of Shantou University Medical College
| | - Yan Cheng
- Second Affiliated Hospital of Shantou University Medical College
| | - Liang Xu
- The Seventh Affiliated Hospital of Sun Yat-sen University
| | - Yan Lin
- The Second Hospital of Shandong University
| | - Xiaolei Zhang
- Second Affiliated Hospital of Shantou University Medical College
| | - renhua wu
- Second Affiliated Hospital of Shantou University Medical College
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16
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Xin Y, Tian M, Deng S, Li J, Yang M, Gao J, Pei X, Wang Y, Tan J, Zhao F, Gao Y, Gong Y. The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation. Mol Neurobiol 2023; 60:1369-1390. [PMID: 36445634 PMCID: PMC9899199 DOI: 10.1007/s12035-022-03148-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/21/2022] [Indexed: 12/03/2022]
Abstract
Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.
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Affiliation(s)
- Yuewen Xin
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Mi Tian
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Shuixiang Deng
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Jiaying Li
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Miaoxian Yang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Jianpeng Gao
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Xu Pei
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yao Wang
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Jiaying Tan
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Feng Zhao
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yanqin Gao
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China.
| | - Ye Gong
- Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China.
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Dumbuya JS, Li S, Liang L, Chen Y, Du J, Zeng Q. Effects of hydrogen-rich saline in neuroinflammation and mitochondrial dysfunction in rat model of sepsis-associated encephalopathy. J Transl Med 2022; 20:546. [DOI: 10.1186/s12967-022-03746-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/31/2022] [Indexed: 11/28/2022] Open
Abstract
Abstract
Background
Sepsis-associated encephalopathy (SAE) is one of the most common types of sepsis-related organ dysfunction without overt central nervous system (CNS) infection. It is associated with higher mortality, low quality of life, and long-term neurological sequelae in suspected patients. At present there is no specific treatment for SAE rather than supportive therapy and judicious use of antibiotics, which are sometimes associated with adverse effects. Molecular hydrogen (H2) has been reported to play crucial role in regulating inflammatory responses, neuronal injury, apoptosis and mitochondrial dysfunction in adult models of SAE. Here we report the protective effect of hydrogen-rich saline in juvenile SAE rat model and its possible underling mechanism(s).
Materials and methods
Rats were challenged with lipopolysaccharide (LPS) at a dose of 8 mg/kg injected intraperitoneally to induce sepsis and hydrogen-rich saline (HRS) administered 1 h following LPS induction at a dose of 5 ml/kg. Rats were divided into: sham, sham + HRS, LPS and LPS + HRS. At 48 h, rats were sacrificed and Nissl staining for neuronal injury, TUNEL assay for apoptotic cells detection, immunohistochemistry, and ELISA protocol for inflammatory cytokines determination, mitochondrial dysfunction parameters, electron microscopy and western blot analysis were studied to examine the effect of HRS in LPS-induced septic rats.
Results
Rats treated with HRS improved neuronal injury, improvement in rats’ survival rate. ELISA analysis showed decreased TNF-α and IL-1β and increased IL-10 expression levels in the HRS-treated group. Apoptotic cells were decreased after HRS administration in septic rats. The numbers of GFAP and IBA-1positive cells were attenuated in the HRS-treated group when compared to the LPS group. Subsequently, GFAP and IBA-1 immunoreactivity were decreased after HRS treatment. Mitochondrial membrane potential detected by JC-1 dye and ATP content were decreased in septic rats, which were improved after HRS treatment, while release of ROS was increased in the LPS group reverted by HRS treatment, ameliorating mitochondrial dysfunction. Further analysis by transmission electron microscopy showed decreased number of mitochondria and synapses, and disrupted mitochondrial membrane ultrastructure in the LPS group, while HRS administration increased mitochondria and synapses number.
Conclusion
These data demonstrated that HRS can improve survival rate, attenuate neuroinflammation, astrocyte and microglial activation, neuronal injury and mitochondrial dysfunction in juvenile SAE rat model, making it a potential therapeutic candidate in treating paediatric SAE.
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Martinez-Orengo N, Tahmazian S, Lai J, Wang Z, Sinharay S, Schreiber-Stainthorp W, Basuli F, Maric D, Reid W, Shah S, Hammoud DA. Assessing organ-level immunoreactivity in a rat model of sepsis using TSPO PET imaging. Front Immunol 2022; 13:1010263. [PMID: 36439175 PMCID: PMC9685400 DOI: 10.3389/fimmu.2022.1010263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022] Open
Abstract
There is current need for new approaches to assess/measure organ-level immunoreactivity and ensuing dysfunction in systemic inflammatory response syndrome (SIRS) and sepsis, in order to protect or recover organ function. Using a rat model of systemic sterile inflammatory shock (intravenous LPS administration), we performed PET imaging with a translocator protein (TSPO) tracer, [18F]DPA-714, as a biomarker for reactive immunoreactive changes in the brain and peripheral organs. In vivo dynamic PET/CT scans showed increased [18F]DPA-714 binding in the brain, lungs, liver and bone marrow, 4 hours after LPS injection. Post-LPS mean standard uptake values (SUVmean) at equilibrium were significantly higher in those organs compared to baseline. Changes in spleen [18F]DPA-714 binding were variable but generally decreased after LPS. SUVmean values in all organs, except the spleen, positively correlated with several serum cytokines/chemokines. In vitro measures of TSPO expression and immunofluorescent staining validated the imaging results. Noninvasive molecular imaging with [18F]DPA-714 PET in a rat model of systemic sterile inflammatory shock, along with in vitro measures of TSPO expression, showed brain, liver and lung inflammation, spleen monocytic efflux/lymphocytic activation and suggested increased bone marrow hematopoiesis. TSPO PET imaging can potentially be used to quantify SIRS and sepsis-associated organ-level immunoreactivity and assess the effectiveness of therapeutic and preventative approaches for associated organ failures, in vivo.
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Affiliation(s)
- Neysha Martinez-Orengo
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Sarine Tahmazian
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Jianhao Lai
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Zeping Wang
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Sanhita Sinharay
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - William Schreiber-Stainthorp
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Falguni Basuli
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD, United States
| | - Dragan Maric
- Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - William Reid
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Swati Shah
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Dima A. Hammoud
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Dima A. Hammoud,
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19
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Danielski LG, Giustina AD, Gava FF, Barichello T, Petronilho F. The Many Faces of Astrocytes in the Septic Brain. Mol Neurobiol 2022; 59:7229-7235. [PMID: 36136265 DOI: 10.1007/s12035-022-03027-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/31/2022] [Indexed: 10/14/2022]
Abstract
Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Surviving patients have cognitive and memory damage that started during sepsis. These neurologic damages have been associated with increased BBB permeability and microglial activation. However, a few discrete studies have seen over the years pointing to the potential role of astrocytes in the pathophysiology of neurological damage after sepsis. The purpose of this article is to review information on the potential role of astrocytes during sepsis, as well as to provoke further studies in this area. These published articles show astrocytic activation after sepsis; they also evidence the release of inflammatory mediators by these cells. In this sense, the role of astrocytes should be better elucidated during sepsis progression.
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Affiliation(s)
- Lucinéia Gainski Danielski
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of South Santa Catarina, Tubarao, SC, Brazil.,Laboratory of Experimental Neurology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil
| | - Amanda Della Giustina
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
| | - Fernanda Frederico Gava
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil
| | - Tatiana Barichello
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil.,Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, Translational Psychiatry Program, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, 77054, USA
| | - Fabricia Petronilho
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil.
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20
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Smith RJ, Lachner C, Singh VP, Trivedi S, Khatua B, Cartin-Ceba R. Cytokine profiles in intensive care unit delirium. Acute Crit Care 2022; 37:415-428. [PMID: 35791660 PMCID: PMC9475146 DOI: 10.4266/acc.2021.01508] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 12/13/2021] [Indexed: 12/13/2022] Open
Abstract
Background Neuroinflammation causing disruption of the blood-brain barrier and immune cell extravasation into the brain parenchyma may cause delirium; however, knowledge of the exact pathophysiologic mechanism remains incomplete. The purpose of our study was to determine whether cytokine profiles differ depending on whether delirium occurs in the setting of sepsis, coronavirus disease 2019 (COVID-19), or recent surgery. Methods This prospective observational cohort study involved 119 critically ill patients admitted to a multidisciplinary intensive care unit (ICU) during 2019 and 2020. Delirium was identified using the validated confusion assessment method for the ICU. Multiple delirium risk factors were collected daily including clinical characteristics, hospital course, lab values, vital signs, surgical exposure, drug exposure, and COVID-19 characteristics. Serums samples were collected within 12 hours of ICU admission and cytokine levels were measured. Results: The following proinflammatory cytokines were elevated in our delirium population: tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-18, C-C motif ligand (CCL) 2, CCL3, C-X-C motif chemokine ligand (CXCL)1, CXCL10, IL-8, IL-1 receptor antagonist, and IL-10. Analysis of relative cytokine levels in those patients that developed delirium in the setting of sepsis, COVID-19, and recent surgery showed elevations of CCL2, CXCL10, and TNF-α in both the sepsis and COVID-19 group in comparison to the postsurgical population. In the postsurgical group, granulocyte colony-stimulating factor was elevated and CXCL10 was decreased relative to the opposing groups. Conclusions We identify several cytokines and precipitating factors known to be associated with delirium. However, our study suggests that the cytokine profile associated with delirium is variable and contingent upon delirium precipitating factors.
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21
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Sepsis-Induced Brain Dysfunction: Pathogenesis, Diagnosis, and Treatment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1328729. [PMID: 36062193 PMCID: PMC9433216 DOI: 10.1155/2022/1328729] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/30/2022] [Accepted: 06/28/2022] [Indexed: 11/18/2022]
Abstract
Dysregulated host response to infection, which cause life-threatening organ dysfunction, was defined as sepsis. Sepsis can cause acute and long-term brain dysfunction, namely, sepsis-associated encephalopathy (SAE) and cognitive impairment. SAE refers to changes in consciousness without direct evidence of central nervous system infection. It is highly prevalent and may cause poor outcomes in sepsis patients. Cognitive impairment seriously affects the life quality of sepsis patients and increases the medical burden. The pathogenesis of sepsis-induced brain dysfunction is mainly characterized by the interaction of systemic inflammation, blood-brain barrier (BBB) dysfunction, neuroinflammation, microcirculation dysfunction, and brain dysfunction. Currently, the diagnosis of sepsis-induced brain dysfunction is based on clinical manifestation of altered consciousness along with neuropathological examination, and the treatment is mainly involves controlling sepsis. Although treatments for sepsis-induced brain dysfunction have been tested in animals, clinical treat sepsis-induced brain dysfunction is still difficult. Therefore, we review the underlying mechanisms of sepsis-induced brain injury, which mainly focus on the influence of systemic inflammation on BBB, neuroinflammation, brain microcirculation, and the brain function, which want to bring new mechanism-based directions for future basic and clinical research aimed at preventing or ameliorating brain dysfunction.
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22
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Ziaka M, Exadaktylos A. ARDS associated acute brain injury: from the lung to the brain. Eur J Med Res 2022; 27:150. [PMID: 35964069 PMCID: PMC9375183 DOI: 10.1186/s40001-022-00780-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/29/2022] [Indexed: 01/10/2023] Open
Abstract
A complex interrelation between lung and brain in patients with acute lung injury (ALI) has been established by experimental and clinical studies during the last decades. Although, acute brain injury represents one of the most common insufficiencies in patients with ALI and acute respiratory distress syndrome (ARDS), the underlying pathophysiology of the observed crosstalk remains poorly understood due to its complexity. Specifically, it involves numerous pathophysiological parameters such as hypoxemia, neurological adverse events of lung protective ventilation, hypotension, disruption of the BBB, and neuroinflammation in such a manner that the brain of ARDS patients-especially hippocampus-becomes very vulnerable to develop secondary lung-mediated acute brain injury. A protective ventilator strategy could reduce or even minimize further systemic release of inflammatory mediators and thus maintain brain homeostasis. On the other hand, mechanical ventilation with low tidal volumes may lead to self-inflicted lung injury, hypercapnia and subsequent cerebral vasodilatation, increased cerebral blood flow, and intracranial hypertension. Therefore, by describing the pathophysiology of ARDS-associated acute brain injury we aim to highlight and discuss the possible influence of mechanical ventilation on ALI-associated acute brain injury.
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Affiliation(s)
- Mairi Ziaka
- Department of Internal Medicine, Thun General Hospital, Thun, Switzerland
| | - Aristomenis Exadaktylos
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland
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23
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Yan X, Yang K, Xiao Q, Hou R, Pan X, Zhu X. Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy. Front Immunol 2022; 13:929316. [PMID: 35958583 PMCID: PMC9361477 DOI: 10.3389/fimmu.2022.929316] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/22/2022] [Indexed: 11/20/2022] Open
Abstract
Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.
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Affiliation(s)
- Xiaoqian Yan
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kaiying Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qi Xiao
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Rongyao Hou
- Department of Neurology, The Affiliated Hiser Hospital of Qingdao University, Qingdao, China
- *Correspondence: Rongyao Hou, ; Xudong Pan, ; Xiaoyan Zhu,
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Rongyao Hou, ; Xudong Pan, ; Xiaoyan Zhu,
| | - Xiaoyan Zhu
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Rongyao Hou, ; Xudong Pan, ; Xiaoyan Zhu,
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24
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Liu F, Liu J, Xiang H, Sun Z, Li Y, Li X, Liu Y, Liu J. Dihydroartemisinin protects blood-brain barrier permeability during sepsis by inhibiting the transcription factor SNAI1. Clin Exp Pharmacol Physiol 2022; 49:979-987. [PMID: 35651290 PMCID: PMC9543489 DOI: 10.1111/1440-1681.13683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 04/07/2022] [Accepted: 05/30/2022] [Indexed: 11/28/2022]
Abstract
Blood–brain barrier (BBB) injury is involved in the pathogenesis of sepsis‐associated encephalopathy. In this study, we used dihydroartemisinin (DHA), a derivative of artemisinin, to treat a cecal ligation and puncture (CLP)‐induced mouse sepsis model and a tumour necrosis factor α (TNF‐α)‐stimulated human cerebral microvessel endothelial cells (hCMEC)/D3 cell line. We found that DHA decreased BBB permeability and increased the expression of the tight junction protein occludin (OCLN) in the CLP model. In hCMEC/D3 cells, DHA decreased TNF‐α‐induced hyperpermeability and increased the expression of OCLN. DHA also repressed SNAI1 expression in the CLP mouse model and in TNF‐α‐stimulated hCMEC/D3 cells. These data suggest that DHA protects BBB permeability during sepsis by stimulating the expression of OCLN, by downregulating the expression of the SNAI1 transcription factor.
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Affiliation(s)
- Fuhong Liu
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan, Shandong, China
| | - Jing Liu
- Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan, Shandong, China
| | - Hongjie Xiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan, Shandong, China
| | - Zongguo Sun
- Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan, Shandong, China
| | - Yan Li
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao Li
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanjun Liu
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ju Liu
- Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan, Shandong, China
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25
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Hiengrach P, Visitchanakun P, Tongchairawewat P, Tangsirisatian P, Jungteerapanich T, Ritprajak P, Wannigama DL, Tangtanatakul P, Leelahavanichkul A. Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice. Int J Mol Sci 2022; 23:5445. [PMID: 35628259 PMCID: PMC9141734 DOI: 10.3390/ijms23105445] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood-brain barrier (BBB) damage (Evan's blue dye and the presence of green fluorescent E. coli in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (iNOS and IL-1β) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation.
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Affiliation(s)
- Pratsanee Hiengrach
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand; (P.H.); (P.V.)
| | - Peerapat Visitchanakun
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand; (P.H.); (P.V.)
| | - Pakteema Tongchairawewat
- Chulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (P.T.); (P.T.); (T.J.)
| | - Ponphisudti Tangsirisatian
- Chulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (P.T.); (P.T.); (T.J.)
| | - Thitiphat Jungteerapanich
- Chulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (P.T.); (P.T.); (T.J.)
| | - Patcharee Ritprajak
- Research Unit in Integrative Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Dhammika Leshan Wannigama
- Antimicrobial Resistance and Stewardship Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand;
- School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Pattarin Tangtanatakul
- Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Immunology and Immune-Mediated Disease, Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand; (P.H.); (P.V.)
- Nephrology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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26
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Leitão RA, Fontes-Ribeiro CA, Silva AP. The effect of parthenolide on methamphetamine-induced blood-brain barrier and astrocyte alterations. Eur J Clin Invest 2022; 52:e13694. [PMID: 34694635 DOI: 10.1111/eci.13694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/23/2021] [Accepted: 10/11/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Methamphetamine abuse is a worldwide concern with long-term health complications. Its impact on neurons has been extensively investigated, and it is currently known that glial cells, including astrocytes, are involved in drug-induced outcomes. Importantly, METH also causes blood-brain barrier (BBB) disruption and astrocytes are critical for BBB (dys)function. Therefore, we aimed to clarify the involvement of neuroinflammation mediated by astrocytes in BBB permeability and brain oedema induced by METH. Further, we aimed to identify a new approach to counteract METH effects. METHODS Mice were administered with a METH binge regimen (4 × 10 mg/kg) alone or in combination with parthenolide (PTL; 4 × 1 mg/kg), and hippocampi were analysed. For in vitro studies, mouse primary cultures of astrocytes were exposed to 250 µM METH, alone or co-treated with 10 µM PTL. RESULTS We observed a neuroinflammatory response characterized by astrocytic morphological changes and increased TNF-α, iNOS and ICAM-1 protein levels (213.62%, 205.76% and 191.47% of control, respectively). Additionally, brain oedema and BBB disruption were identified by increased water content (81.30% of tissue weight) and albumin (224.40% of control) in the hippocampal tissue, as well as a significant decrease in vessel coverage by astrocytes after METH exposure. Regarding astrocyte cultures, we further identified TNF-α as a key player in METH-induced cell swelling. Importantly, PTL (present in feverfew plant) prevented both animal and in vitro effects induced by METH. CONCLUSIONS We provided important insights on brain dysfunction induced by METH, and we also suggest a new approach to counteract such negative effects.
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Affiliation(s)
- Ricardo A Leitão
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Carlos A Fontes-Ribeiro
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Ana Paula Silva
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
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27
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Joshi L, Plastira I, Bernhart E, Reicher H, Koshenov Z, Graier WF, Vujic N, Kratky D, Rivera R, Chun J, Sattler W. Lysophosphatidic Acid Receptor 5 (LPA 5) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro. Cells 2022; 11:cells11071071. [PMID: 35406635 PMCID: PMC8998093 DOI: 10.3390/cells11071071] [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: 02/24/2022] [Revised: 03/14/2022] [Accepted: 03/20/2022] [Indexed: 12/02/2022] Open
Abstract
Systemic inflammation induces alterations in the finely tuned micromilieu of the brain that is continuously monitored by microglia. In the CNS, these changes include increased synthesis of the bioactive lipid lysophosphatidic acid (LPA), a ligand for the six members of the LPA receptor family (LPA1-6). In mouse and human microglia, LPA5 belongs to a set of receptors that cooperatively detect danger signals in the brain. Engagement of LPA5 by LPA polarizes microglia toward a pro-inflammatory phenotype. Therefore, we studied the consequences of global LPA5 knockout (-/-) on neuroinflammatory parameters in a mouse endotoxemia model and in primary microglia exposed to LPA in vitro. A single endotoxin injection (5 mg/kg body weight) resulted in lower circulating concentrations of TNFα and IL-1β and significantly reduced gene expression of IL-6 and CXCL2 in the brain of LPS-injected LPA5-/- mice. LPA5 deficiency improved sickness behavior and energy deficits produced by low-dose (1.4 mg LPS/kg body weight) chronic LPS treatment. LPA5-/- microglia secreted lower concentrations of pro-inflammatory cyto-/chemokines in response to LPA and showed higher maximal mitochondrial respiration under basal and LPA-activated conditions, further accompanied by lower lactate release, decreased NADPH and GSH synthesis, and inhibited NO production. Collectively, our data suggest that LPA5 promotes neuroinflammation by transmiting pro-inflammatory signals during endotoxemia through microglial activation induced by LPA.
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Affiliation(s)
- Lisha Joshi
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Ioanna Plastira
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Eva Bernhart
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Helga Reicher
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Zhanat Koshenov
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Wolfgang F. Graier
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Nemanja Vujic
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
| | - Dagmar Kratky
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Richard Rivera
- Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; (R.R.); (J.C.)
| | - Jerold Chun
- Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; (R.R.); (J.C.)
| | - Wolfgang Sattler
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.); (Z.K.); (W.F.G.); (N.V.); (D.K.)
- BioTechMed-Graz, 8010 Graz, Austria
- Correspondence: ; Tel.: +43-316-385-71950
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28
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Becker AE, Teixeira SR, Lunig NA, Mondal A, Fitzgerald JC, Topjian AA, Weiss SL, Griffis H, Schramm SE, Traynor DM, Vossough A, Kirschen MP. Sepsis-Related Brain MRI Abnormalities Are Associated With Mortality and Poor Neurological Outcome in Pediatric Sepsis. Pediatr Neurol 2022; 128:1-8. [PMID: 34992035 PMCID: PMC9685598 DOI: 10.1016/j.pediatrneurol.2021.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/28/2021] [Accepted: 12/02/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND It is not known whether brain magnetic resonance imaging (MRI) abnormalities in pediatric sepsis are associated with clinical outcomes. Study objectives were to (1) determine the prevalence and type of sepsis-related neuroimaging abnormalities evident on clinically indicated brain MRI in children with sepsis and (2) test the association of these abnormalities with mortality, new disability, length of stay (LOS), and MRI indication. METHODS Retrospective cohort study of 140 pediatric patients with sepsis and a clinically indicated brain MRI obtained within 60 days of sepsis onset at a single, large academic pediatric intensive care unit (PICU). Two radiologists systematically reviewed the first post-sepsis brain MRI and determined which abnormalities were sepsis-related. Outcomes compared in patients with versus without sepsis-related MRI abnormalities. RESULTS PICU mortality was 7%. Thirty patients had one or more sepsis-related MRI abnormality, yielding a prevalence of 21% (95% confidence interval 15%, 28%). Among those, 53% (16 of 30) had sepsis-related white matter signal abnormalities; 53% (16 of 30) sepsis-related ischemia, infarction, or thrombosis; and 27% (eight of 30) sepsis-related posterior reversible encephalopathy. Patients with one or more sepsis-related MRI abnormality had increased mortality (17% vs 5%; P = 0.04), new neurological disability at PICU discharge (32% vs 11%; P = 0.03), and longer PICU LOS (median 18 vs 11 days; P = 0.04) compared with patients without. CONCLUSIONS In children with sepsis and a clinically indicated brain MRI, 21% had a sepsis-related MRI abnormality. Sepsis-related MRI abnormalities were associated with increased mortality, new neurological disability, and longer PICU LOS.
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Affiliation(s)
- Andrew E. Becker
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Sara R. Teixeira
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Nicholas A. Lunig
- Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Antara Mondal
- Department of Biomedical & Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Julie C. Fitzgerald
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,CHOP Pediatric Sepsis Program, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Alexis A. Topjian
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Scott L. Weiss
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,CHOP Pediatric Sepsis Program, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Heather Griffis
- Department of Biomedical & Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Stephanie E. Schramm
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Danielle M. Traynor
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Arastoo Vossough
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Matthew P. Kirschen
- Department of Anesthesiology & Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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Peng X, Luo Z, He S, Zhang L, Li Y. Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy. Front Cell Infect Microbiol 2021; 11:768108. [PMID: 34804998 PMCID: PMC8599158 DOI: 10.3389/fcimb.2021.768108] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/14/2021] [Indexed: 12/29/2022] Open
Abstract
As a complex multicellular structure of the vascular system at the central nervous system (CNS), the blood-brain barrier (BBB) separates the CNS from the system circulation and regulates the influx and efflux of substances to maintain the steady-state environment of the CNS. Lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, can damage the barrier function of BBB and further promote the occurrence and development of sepsis-associated encephalopathy (SAE). Here, we conduct a literature review of the direct and indirect damage mechanisms of LPS to BBB and the relationship between these processes and SAE. We believe that after LPS destroys BBB, a large number of inflammatory factors and neurotoxins will enter and damage the brain tissue, which will activate brain immune cells to mediate inflammatory response and in turn further destroys BBB. This vicious circle will ultimately lead to the progression of SAE. Finally, we present a succinct overview of the treatment of SAE by restoring the BBB barrier function and summarize novel opportunities in controlling the progression of SAE by targeting the BBB.
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Affiliation(s)
- Xiaoyao Peng
- Department of Clinical Medicine, School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Zhixuan Luo
- Department of Clinical Medicine, School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Shuang He
- Department of Clinical Medicine, School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Luhua Zhang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Ying Li
- Department of Immunology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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30
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Shaheryar ZA, Khan MA, Adnan CS, Zaidi AA, Hänggi D, Muhammad S. Neuroinflammatory Triangle Presenting Novel Pharmacological Targets for Ischemic Brain Injury. Front Immunol 2021; 12:748663. [PMID: 34691061 PMCID: PMC8529160 DOI: 10.3389/fimmu.2021.748663] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/15/2021] [Indexed: 12/20/2022] Open
Abstract
Ischemic stroke is one of the leading causes of morbidity and mortality globally. Hundreds of clinical trials have proven ineffective in bringing forth a definitive and effective treatment for ischemic stroke, except a myopic class of thrombolytic drugs. That, too, has little to do with treating long-term post-stroke disabilities. These studies proposed diverse options to treat stroke, ranging from neurotropic interpolation to venting antioxidant activity, from blocking specific receptors to obstructing functional capacity of ion channels, and more recently the utilization of neuroprotective substances. However, state of the art knowledge suggests that more pragmatic focus in finding effective therapeutic remedy for stroke might be targeting intricate intracellular signaling pathways of the 'neuroinflammatory triangle': ROS burst, inflammatory cytokines, and BBB disruption. Experimental evidence reviewed here supports the notion that allowing neuroprotective mechanisms to advance, while limiting neuroinflammatory cascades, will help confine post-stroke damage and disabilities.
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Affiliation(s)
- Zaib A. Shaheryar
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
- Faculty of Pharmacy, University of Lahore, Lahore, Pakistan
| | - Mahtab A. Khan
- Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan
| | | | - Awais Ali Zaidi
- Faculty of Pharmacy, University of Lahore, Lahore, Pakistan
- Imran Idrees College of Pharmacy, Lahore, Pakistan
| | - Daniel Hänggi
- Department of Neurosurgery, Faculty of Medicine and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Sajjad Muhammad
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Neurosurgery, Faculty of Medicine and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
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31
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You L, Jiang H. Cabergoline possesses a beneficial effect on blood-brain barrier (BBB) integrity against lipopolysaccharide (LPS). Bioengineered 2021; 12:8358-8369. [PMID: 34592907 PMCID: PMC8806944 DOI: 10.1080/21655979.2021.1987066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Sepsis is a disease induced by severe systemic inflammation and contributes to multiple acute organic dysfunctions. It is reported that disrupted blood-brain barrier (BBB) integrity is involved in sepsis-associated encephalopathy (SAE), which can be alleviated by repairing the damaged tight junction structure. Cabergoline is a specific dopamine D2 receptor agonist developed to treat Parkinson’s disease and hyperprolactinemia and is reported to exert promising anti-inflammatory properties. The present study aimed to explore the beneficial effect of Cabergoline for the treatment of sepsis. In the animal experiments, mice were separated into 4 groups: sham, LPS (5 mg/kg), Cabergoline (0.1 mg/kg/day), and Cabergoline+LPS. We found that the increased neurological deficits, disrupted BBB integrity, elevated production of inflammatory factors, and declined expression level of zonula occludens-1 (ZO-1) were observed in lipopolysaccharide (LPS)-treated mice, all of which were significantly reversed by the administration of Cabergoline. In the in vitro model, human brain microvascular endothelial cells (HBMECs) were challenged with 1 µg/mL LPS in the presence or absence of Cabergoline (10, 20 μM) for 24 hours. The elevated cell permeability Papp value of fluorescein disodium across the HBMECs monolayer and declined trans-endothelial electrical resistance (TEER) in the LPS-treated HBMECs were significantly alleviated by Cabergoline, accompanied by the upregulation of ZO-1. In addition, wnt1 and β-catenin were found downregulated, which was reversed by Cabergoline. Importantly, the protective benefits of Cabergoline were all abolished by the overexpression of Dickkopf 3 (DKK3). Taken together, our data reveal that Cabergoline possessed a protective effect on BBB integrity against LPS.
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Affiliation(s)
- Lina You
- Department of Gerontology, Traditional Chinese medicine hospital of Jiulongpo District in Chongqing, Chongqing, 400080, China
| | - Haidong Jiang
- Chongqing Infectious Disease Medical Center, Chongqing, 400080, China
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32
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Ren C, Yao RQ, Wang LX, Li JC, Chen KW, Wu Y, Dong N, Feng YW, Yao YM. Antagonism of Cerebral High Mobility Group Box 1 Ameliorates Dendritic Cell Dysfunction in Sepsis. Front Pharmacol 2021; 12:665579. [PMID: 34512319 PMCID: PMC8427508 DOI: 10.3389/fphar.2021.665579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis has emerged as a global health issue, and accounts for millions of deaths in intensive care units. Dysregulation of the immune response reportedly contributes to the pathogenesis and progression of this lethal condition, which involves both the dysfunction of immune cells and incompetent immunomodulatory mechanisms. High mobility group box 1 (HMGB1) is known as a later inflammatory mediator and is critically involved in the severity and prognosis of sepsis by inducing intractable inflammation and dysfunction of various immune cells. In the present study, we found that intracerebroventricular (ICV) injection of Box A, a specific antagonist of HMGB1, restored the dysregulated response of splenic dendritic cells (DCs) in septic mice by enhancing the expression of surface molecules, including CD80, CD86, and MHC-II, as well as improving DC priming of T lymphocytes. Cerebral HMGB1 was also confirmed to have potent inhibitory effects on DC functions when administrated by ICV injection in normal mice. The brain cholinergic system was found to mediate the immunomodulatory effects of central HMGB1, as it exhibited enhanced activity with persistent HMGB1 exposure. Furthermore, the inhibitory effects of cerebral HMGB1 on the response of peripheral DCs were also blocked by α7nAchR gene knockout. These findings provide novel insight into the relationship between cerebral HMGB1 and splenic DC dysfunction during sepsis, which is, at least in part, dependent on cholinergic system activity.
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Affiliation(s)
- Chao Ren
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Ren-Qi Yao
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China.,Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Li-Xue Wang
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Jun-Cong Li
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Kun-Wei Chen
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Yao Wu
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Ning Dong
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China
| | - Yong-Wen Feng
- Department of Critical Care Medicine, The Second People's Hospital of Shenzhen, Shenzhen, China
| | - Yong-Ming Yao
- Trauma Research Center, Fourth Medical Center and Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, China.,State Key Laboratory of Kidney Disease, The Chinese PLA General Hospital, Beijing, China
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Early Axonal Injury and Delayed Cytotoxic Cerebral Edema are Associated with Microglial Activation in a Mouse Model of Sepsis. Shock 2021; 54:256-264. [PMID: 31513049 DOI: 10.1097/shk.0000000000001446] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in preclinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI) to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP). Sepsis was induced in 6-10-week-old male C57/BL6 mice by CLP. We used immunohistochemistry (IHC) to define neuropathology in a mouse model of sepsis along with parallel studies using MRI, focusing on cerebral edema, blood-brain barrier (BBB) disruption, and microglial activation on days 1 and 4 days after CLP. We demonstrate that septic mice had evidence of early axonal injury, inflammation, and robust microglial activation on day 1 followed by cytotoxic edema on day 4 in the cortex, thalamus, and hippocampus in the absence of BBB disruption. We note the superiority of the MRI to detect subtle brain injury and cytotoxic cerebral edema in comparison with the traditional gold standard assessment, i.e., percent brain water (wet-dry weight method). We conclude that inflammatory changes in the septic brain can be detected in real time, and further studies are needed to understand axonal injury and the impact of inhibition of microglial activation on the development of cerebral edema.
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Plasma miR-370-3P as a Biomarker of Sepsis-Associated Encephalopathy, the Transcriptomic Profiling Analysis of Microrna-Arrays From Mouse Brains. Shock 2021; 54:347-357. [PMID: 31743302 DOI: 10.1097/shk.0000000000001473] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The diagnosis of sepsis-associated encephalopathy (SAE), an alteration of conscious from sepsis, is difficult due to the similarity to altered states of conscious that occur from other causes. Transcriptomic analyses between mouse brains at 24 h after cecal ligation and puncture (CLP) (SAE brain as evaluated by SHIRPA score) and at 120 h post-CLP (survivor) were performed to discover the SAE biomarker. Then, candidate microRNAs were validated in mouse and patient samples.As such, increased miR-370-3p in SAE mouse-brains (compared with recovery phase) was demonstrated by transcriptomic miR-profiling and was highly expressed in brain (but not other organs) of 24 h post-CLP mice. Plasma miR-370-3p also increased in CLP but was non-detectable in bilateral-nephrectomy (BiNx, a representative model of acute uremic encephalopathy) despite blood brain barrier permeability defect (determined by plasma s100β and Evan blue dye assay) in both conditions. In parallel, high plasma miR-370-3p was demonstrated in patients with SAE (but not sepsis alone or uremia) suggesting the specificity toward SAE. The association among TNF-α, miR-370-3p and brain apoptosis was demonstrated by high serum TNF-α and increased brain apoptosis in SAE mice, TNF-α (but not other cytokines) activated miR-370-3p expression in PC-12 neuron cell, and increased cell apoptosis in miR-370-3p transfected PC-12 after incubation with TNF-α.In conclusion, miR-370-3p increased in brain and plasma of SAE mice but not uremic encephalopathy. Perhaps, TNF-α enhances cell susceptibility toward brain apoptosis in SAE, in part, through miR-370-3p induction in neuron. Our pilot results in patients with SAE supported the possibility that plasma miR-370-3p is an interesting SAE biomarker candidate. Further studies are warranted.
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Osca-Verdegal R, Beltrán-García J, Pallardó FV, García-Giménez JL. Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy. Mol Neurobiol 2021; 58:4682-4693. [PMID: 34160774 PMCID: PMC8220114 DOI: 10.1007/s12035-021-02445-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/06/2021] [Indexed: 12/29/2022]
Abstract
Sepsis-associated encephalopathy (SAE) is a neurological complication of sepsis, characterized by brain dysfunction without any direct central nervous system infection. The diagnosis of SAE is currently a challenge. In fact, problems in making a diagnosis of SAE cause a great variability of incidence that can reach up to 70% of all septic patients. Even more, despite SAE is the most frequent type of encephalopathy occurring in critically ill patients, the molecular mechanisms that guide its progression have not been completely elucidated. On the other hand, miRNAs have proven to be excellent biomarkers for both diagnosis and prognosis, especially in brain pathologies because of their small size they can cross the blood–brain barrier easier than other biomolecules. The identification of new miRNAs as biomarkers may help to improve SAE diagnosis and prognosis and also to design new therapies for this clinical manifestation that produces diffuse cerebral dysfunction. This review is focused on SAE physiopathology and the need to have clear criteria for its diagnosis; thus, this work postulates some miRNA candidates to be used for SAE biomarkers because of their role in both, neurological damage and sepsis.
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Affiliation(s)
- Rebeca Osca-Verdegal
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
| | - Jesús Beltrán-García
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - Federico V. Pallardó
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - José Luis García-Giménez
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
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The furin-S2' site in avian coronavirus plays a key role in central nervous system damage progression. J Virol 2021; 95:JVI.02447-20. [PMID: 33727330 PMCID: PMC8139701 DOI: 10.1128/jvi.02447-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The furin cleavage site plays an important role in virus pathogenicity. The spike protein of SARS-CoV-2 harbors a furin cleavage site insertion in contrast to SARS-CoV, which may be related to its stronger communicability. An avian coronavirus with an extra furin cleavage site upstream of the fusion peptide (S2' site) infected monocyte cells and neuron cells leading to viremia or encephalitis, respectively. Immunohistochemistry and real-time quantitative polymerase chain reaction were used to follow disease progression and demonstrated differences between the parent avian coronavirus and mutated avian coronavirus with a furin-S2' site. Magnetic resonance imaging and biological dye to evaluate the blood-brain barrier permeability showed that avian coronavirus with a furin-S2' site had increased permeability compared with parent avian coronavirus. Immunohistochemistry of brains after intracerebral injection of avian coronavirus and immunofluorescence staining of primary neuron cells demonstrated the furin-S2' site expanded the cell tropism of the mutant avian coronavirus to neuron cells. TNF-α, which has a key role in blood-brain barrier permeability, was highly induced by avian coronavirus with a furin-S2' site compared with the parent avian coronavirus. We demonstrated the process involved in mutant avian coronavirus-induced disease and that the addition of a furin-S2' site changed the virus cell tropism.IMPORTANCECoronaviruses have broken out three times in two decades. Spike (S) protein plays a key role in the process of infection. To clarify importance of furin cleavage site in spike protein for coronavirus, we investigated the pathogenesis of neurotropic avian coronavirus whose spike protein contains an extra furin cleavage site (furin-S2' site). By combining real-time quantitative polymerase chain reaction and immunohistochemistry we demonstrated that infectious bronchitis virus (IBV) infects brain instead of trachea when its S protein contains furin-S2' site. Moreover, the virus was shown to increase the permeability of blood-brain barrier, infect neuron cells and induce high expression of TNF-α. Based on these results we further show that furin cleavage site in S protein plays an important role in coronavirus pathogenicity and cell tropism. Our study extends previous publications on function of S protein of coronavirus, increasing the understanding of researchers to coronavirus.
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Moraes CA, Zaverucha-do-Valle C, Fleurance R, Sharshar T, Bozza FA, d’Avila JC. Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation. Pharmaceuticals (Basel) 2021; 14:ph14050416. [PMID: 34062710 PMCID: PMC8147235 DOI: 10.3390/ph14050416] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/11/2022] Open
Abstract
Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.
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Affiliation(s)
- Carolina Araújo Moraes
- Immunopharmacology Lab, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil;
| | - Camila Zaverucha-do-Valle
- National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Ministry of Health, Rio de Janeiro 21040-360, Brazil; (C.Z.-d.-V.); (F.A.B.)
| | - Renaud Fleurance
- UCB Biopharma SRL, 1420 Braine L’Alleud, Belgium;
- Experimental Neuropathology, Infection, and Epidemiology Department, Institut Pasteur, 75015 Paris, France;
- Université de Paris Sciences et Lettres, 75006 Paris Paris, France
| | - Tarek Sharshar
- Experimental Neuropathology, Infection, and Epidemiology Department, Institut Pasteur, 75015 Paris, France;
- Neuro-Anesthesiology and Intensive Care Medicine, Sainte-Anne Hospital, Paris-Descartes University, 75015 Paris, France
| | - Fernando Augusto Bozza
- National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Ministry of Health, Rio de Janeiro 21040-360, Brazil; (C.Z.-d.-V.); (F.A.B.)
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil
| | - Joana Costa d’Avila
- Immunopharmacology Lab, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil;
- School of Medicine, Universidade Iguaçu, Rio de Janeiro 26260-045, Brazil
- Correspondence:
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Lu B, Wu C, Azami NLB, Xie D, Zhao C, Xu W, Hui D, Chen X, Sun R, Song J, An Y, Li K, Wang H, Ye G, Sun M. Babao Dan improves neurocognitive function by inhibiting inflammation in clinical minimal hepatic encephalopathy. Biomed Pharmacother 2021; 135:111084. [PMID: 33383371 DOI: 10.1016/j.biopha.2020.111084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/22/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Inflammation has been considered a precipitating event that contributes to neurocognitive dysfunction in minimal hepatic encephalopathy (MHE). Inhibition TLR-4 related inflammation can effectively improve neurocognitive dysfunction of MHE. Our previous study showed that Babao Dan (BBD) effectively inhibited inflammation and ameliorated neurocognitive function in rats with acute hepatic encephalopathy (HE) and chronic HE. The mechanism may lie in the regulation of TLR4 signaling pathway. Therefore, this study aimed to evaluate the role of BBD in the treatment of MHE patients with cirrhosis and to elucidate the underlying mechanism by which BBD regulated TLR4 pathway to alleviate inflammation. METHODS A randomized controlled trial (n = 62) was conducted to evaluate the clinical efficacy between BBD plus lactulose (n = 31) and lactulose alone (n = 31) in MHE patients by testing neurocognitive function (NCT-A and DST), blood ammonia, liver function (ALT, AST and TBIL) and blood inflammation (IL-1β, IL-6 and TNF-α). Afterward, we detected NO, inflammatory cytokines (IL-1β, IL-6 and TNF-α) and the phosphorylation of P65, JNK, ERK as well as P38 in LPS-activated rat primary bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs), and mouse primary BMDMs/PMs/microglia/astrocytes, to investigate the underlying mechanism of BBD inhibiting inflammation through TLR4 pathway. Also, the survival rate of mice, liver function (ALT, AST), blood inflammation (IL-1β, IL-6 and TNF-α), inflammatory cytokines (IL-1β, IL-6 and TNF-α) and histopathological changes in the liver, brain and lung were measured to assess the anti-inflammatory effect of BBD on neurocognitive function in endotoxin shock/endotoxemia mice. RESULTS BBD combined with lactulose significantly ameliorated neurocognitive function by decreasing NCT-A (p＜0.001) and increasing DST (p＜0.001); inhibited systemic inflammation by decreasing IL-1β (p＜0.001), IL-6(p＜0.001) and TNF-α (p＜0.001); reduced ammonia level (p = 0.005), and improved liver function by decreasing ALT(p = 0.043), AST(p = 0.003) and TBIL (p = 0.026) in MHE patients. Furthermore, BBD inhibited gene and protein expression of IL-1β, IL-6 and TNF-α as well as NO in rat primary BMDMs/PMs, and mouse primary BMDMs/PMs/microglia/astrocytes in a dose-dependent manner. BBD inhibited the activation of mouse primary BMDMs/PMs/microglia/astrocytes by regulating TLR4 pathway involving the phosphorylation of P65, JNK, ERK and P38. Also, BBD reduced the mortality of mice with endotoxin shock/endotoxemia; serum levels of ALT, AST, IL-1β, IL-6 and TNF-α; gene expression of IL-1β, IL-6 and TNF-α in the liver, brain and lung, and tissue damage in the liver and lung. CONCLUSION Our study provided for the first time clinical and experimental evidence supporting the use of BBD in MHE, and revealed that BBD could play a crucial role in targeting and regulating TLR4 inflammatory pathway to improve neurocognitive function in MHE patients.
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Affiliation(s)
- Bingjie Lu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Chao Wu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Nisma Lena Bahaji Azami
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Dong Xie
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Changqing Zhao
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wan Xu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Dengcheng Hui
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xi Chen
- Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200082, China.
| | - Runfei Sun
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jingru Song
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yongtong An
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China.
| | - Kun Li
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Huijun Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Guan Ye
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China.
| | - Mingyu Sun
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Baris E, Simsek O, Efe H, Oncu S, Gelal A, Hamurtekin E, Tosun M, Ozbal S, Yuce Z, Arici M. Effects of CDP-Choline and Choline on COX Pathway in LPS-Induced Inflammatory Response in Rats. INT J PHARMACOL 2021. [DOI: 10.3923/ijp.2021.84.96] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Catarina AV, Branchini G, Bettoni L, De Oliveira JR, Nunes FB. Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies. Mol Neurobiol 2021; 58:2770-2779. [PMID: 33495934 DOI: 10.1007/s12035-021-02303-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 01/18/2021] [Indexed: 12/14/2022]
Abstract
Sepsis is an organ dysfunction caused by an uncontrolled inflammatory response from the host to an infection. Sepsis is the main cause of morbidity and mortality in intensive care units (ICU) worldwide. One of the first organs to suffer from injuries resulting from sepsis is the brain. The central nervous system (CNS) is particularly vulnerable to damage, mediated by inflammatory and oxidative processes, which can cause the sepsis-associated encephalopathy (SAE), being reported in up to 70% of septic patients. This review aims to bring a summary of the main pathophysiological changes and dysfunctions in SAE, and the main focuses of current experimental studies for new treatments and therapies. The pathophysiology of SAE is complex and multifactorial, combining intertwined processes, and is promoted by countless alterations and dysfunctions resulting from sepsis, such as inflammation, neuroinflammation, oxidative stress, reduced brain metabolism, and injuries to the integrity of the blood-brain barrier (BBB). The treatment is limited once its cause is not completely understood. The patient's sedation is far to provide an adequate treatment to this complex condition. Studies and experimental advances are important for a better understanding of its pathophysiology and for the development of new treatments, medicines, and therapies for the treatment of SAE and to reduce its effects during and after sepsis.
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Affiliation(s)
- Anderson Velasque Catarina
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS, 90050-170, Brazil.
| | - Gisele Branchini
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS, 90050-170, Brazil
| | - Lais Bettoni
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS, 90050-170, Brazil
| | - Jarbas Rodrigues De Oliveira
- Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Porto Alegre, Brazil
| | - Fernanda Bordignon Nunes
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS, 90050-170, Brazil.,Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Porto Alegre, Brazil
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Aquaporin-1 and aquaporin-9 gene variations in sudden infant death syndrome. Int J Legal Med 2021; 135:719-725. [PMID: 33462668 PMCID: PMC8036210 DOI: 10.1007/s00414-020-02493-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 12/17/2020] [Indexed: 11/09/2022]
Abstract
Several studies have indicated that a vulnerability in the development and regulation of brain function is involved in sudden infant death syndrome (SIDS). The aim of this study was to investigate the genes encoding the brain aquaporins (AQPs) AQP1 and AQP9 in SIDS. The hypothesis was that specific variants of these genes are part of the genetic vulnerability predisposing infants to sudden unexpected death. The study included 168 SIDS cases with a median age of 15.5 (range 2–52) weeks and 372 adolescent/adult deceased controls with a median age of 44 (range 11–91) years. In the AQP1 gene, the rs17159702 CC/CT genotypes were found to be associated with SIDS (p = 0.02). In the AQP9 gene, the combination of a TT genotype of rs8042354, rs2292711 and rs13329178 was more frequent in SIDS cases than in controls (p = 0.03). In the SIDS group, an association was found between genetic variations in the AQP1 gene and maternal smoking and between the 3xTT combination in the AQP9 gene and being found lifeless in a prone position. In conclusion, this study adds further evidence to the involvement of brain aquaporins in SIDS, suggesting that specific variants of AQP genes constitute a genetic predisposition, making the infant vulnerable to sudden death together with external risk factors and probably other genetic factors.
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Zhang L, Zhang X, Wu T, Pan X, Wang Z. Isoflurane reduces septic neuron injury by HO‑1‑mediated abatement of inflammation and apoptosis. Mol Med Rep 2020; 23:155. [PMID: 33355378 PMCID: PMC7789092 DOI: 10.3892/mmr.2020.11794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 11/27/2020] [Indexed: 12/29/2022] Open
Abstract
Sepsis-associated encephalopathy (SAE) frequently occurs in critically ill patients with severe systemic infections. Subanesthetic isoflurane (0.7% ISO) possesses anti-inflammatory, antioxidant and anti-apoptotic properties against a number of human diseases, including brain injury. The activation of heme oxygenase-1 (HO-1) impedes inflammation, oxidation and apoptosis, thus alleviating sepsis-induced brain damage. However, whether 0.7% ISO affords protection against septic neuronal injury involving HO-1 activation is unclear. The present study aimed to investigate the neuroprotective effects of 0.7% ISO and its potential underlying mechanisms in SAE using a mouse model established by cecal ligation and puncture (CLP). The results indicated that the expression and activity of HO-1 in the mouse hippocampus were increased by CLP, and further enhanced by ISO. ISO reduced the death rate, brain water content and blood-brain barrier disruption, but improved the learning and memory functions of CLP-treated mice. ISO significantly decreased the production of pro-inflammatory cytokines and the levels of oxidative indictors in the serum and hippocampus, as well as the number of apoptotic neurons and the expression of pro-apoptotic proteins in the hippocampus. Inversely, anti-inflammatory factors, antioxidative enzymes and anti-apoptotic proteins were markedly increased by ISO administration. However, the neuroprotective effects of ISO were abolished by a HO-1 inhibitor. Overall, these findings suggested that 0.7% ISO alleviated SAE via its anti-inflammatory, antioxidative and anti-apoptotic properties, which involved the activated form of HO-1.
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Affiliation(s)
- Lina Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xuece Zhang
- Digestive Department, The Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Ting Wu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xu Pan
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Zhi Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Keskey R, Cone JT, DeFazio JR, Alverdy JC. The use of fecal microbiota transplant in sepsis. Transl Res 2020; 226:12-25. [PMID: 32649987 PMCID: PMC7572598 DOI: 10.1016/j.trsl.2020.07.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/30/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022]
Abstract
Sepsis is defined as a dysregulated inflammatory response, which ultimately results from a perturbed interaction of both an altered immune system and the biomass and virulence of involved pathogens. This response has been tied to the intestinal microbiota, as the microbiota and its associated metabolites play an essential role in regulating the host immune response to infection. In turn, critical illness as well as necessary health care treatments result in a collapse of the intestinal microbiota diversity and a subsequent loss of health-promoting short chain fatty acids, such as butyrate, leading to the development of a maladaptive pathobiome. These perturbations of the microbiota contribute to the dysregulated immune response and organ failure associated with sepsis. Several case series have reported the ability of fecal microbiota transplant (FMT) to restore the host immune response and aid in recovery of septic patients. Additionally, animal studies have revealed the mechanism of FMT rescue in sepsis is likely related to the ability of FMT to restore butyrate producing bacteria and alter the innate immune response aiding in pathogen clearance. However, several studies have reported lethal complications associated with FMT, including bacteremia. Therefore, FMT in the treatment of sepsis is and should remain investigational until a more detailed mechanism of how FMT restores the host immune response in sepsis is determined, allowing for the development of more fine-tuned microbiota therapies.
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Affiliation(s)
- Robert Keskey
- Section of General Surgery, Department of Surgery, University of Chicago, Chicago, Illinois
| | - Jennifer T Cone
- Section of Trauma and Acute Care Surgery, Department of Surgery, University of Chicago, Chicago, Illinois
| | - Jennifer R DeFazio
- Division of Pediatric Surgery, New York-Presbyterian Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, New York
| | - John C Alverdy
- Section of General Surgery, Department of Surgery, University of Chicago, Chicago, Illinois.
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Hu J, Zhang YM, Miao YF, Zhu L, Yi XL, Chen H, Yang XJ, Wan MH, Tang WF. Effects of Yue-Bi-Tang on water metabolism in severe acute pancreatitis rats with acute lung-kidney injury. World J Gastroenterol 2020; 26:6810-6821. [PMID: 33268963 PMCID: PMC7684462 DOI: 10.3748/wjg.v26.i43.6810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The complications acute lung injury and acute kidney injury caused by severe inflammation are the main reasons of high mortality of severe acute pancreatitis (SAP). These two complications can both lead to water metabolism and acid-base balance disorders, which could act as additional critical factors affecting the disease trend. Aquaporins (AQPs), which can regulate the transmembrane water transport, have been proved to participate in the pathophysiological process of SAP and the associated complications, such as acute lung injury and acute kidney injury. Thus, exploring herbs that can effectively regulate the expression of AQP in SAP could benefit the prognosis of this disease.
AIM To determine whether Yue-Bi-Tang (YBT) can regulate the water metabolism in rats with severe acute pancreatitis via regulating the expression of aquaporins.
METHODS Sprague-Dawley rats were randomly divided into three groups, sham operation group (SOG), model group (MG), and treatment group (TG). SAP was induced with 3.5% sodium taurocholate in the MG and TG. Rats in the TG were administered with YBT while SOG and MG rats were given the same volume of saline. Blood and tissue samples were harvested to detect serum inflammatory cytokines, histopathological changes, malondialdehyde and superoxide dismutase in the lung, and protein and mRNA expression of kidney injury molecule-1, α-smooth muscle actin, and vimentin in the kidney, and AQP1 and 4 in the lung, pancreas, and kidney.
RESULTS The serum interleukin-10, tumor necrosis factor α, and creatinine levels were higher in the MG than in the SOG. Tumor necrosis factor α level in the TG was lower than that in the MG. Malondialdehyde level in lung tissues was higher than in the SOG. The pathological scores and edema scores of the pancreas, lung, and kidney tissues in the MG were all higher than those in the SOG and TG. The protein expression of AQP4 in lung tissues and AQP1 in kidney tissues in the MG were higher than those in the SOG and TG. The expression of vimentin was significantly higher in the MG than in the SOG. The expression of AQP1 mRNA in the lung and kidney, and AQP4 mRNA in the kidney was up-regulated in the MG compared to the SOG.
CONCLUSION YBT might regulate water metabolism to reduce lung and kidney edema of SAP rats via decreasing AQP expression, and alleviate the tissue inflammatory injury.
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Affiliation(s)
- Jing Hu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Mei Zhang
- Department of Traditional Chinese Medicine, Xiang’an Hospital of Xiamen University, Xiamen 361101, Fujian Province, China
| | - Yi-Fan Miao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Lin Yi
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xi-Jing Yang
- Animal Experiment Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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van der Slikke EC, An AY, Hancock REW, Bouma HR. Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities. EBioMedicine 2020; 61:103044. [PMID: 33039713 PMCID: PMC7544455 DOI: 10.1016/j.ebiom.2020.103044] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/09/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022] Open
Abstract
Sepsis is a major health problem worldwide. As the number of sepsis cases increases, so does the number of sepsis survivors who suffer from “post-sepsis syndrome” after hospital discharge. This syndrome involves deficits in multiple systems, including the immune, cognitive, psychiatric, cardiovascular, and renal systems. Combined, these detrimental consequences lead to rehospitalizations, poorer quality of life, and increased mortality. Understanding the pathophysiology of these issues is crucial to develop new therapeutic opportunities to improve survival rate and quality of life of sepsis survivors. Such novel strategies include modulating the immune system and addressing mitochondrial dysfunction. A sepsis follow-up clinic may be useful to identify long-term health issues associated with post-sepsis syndrome and evaluate existing and novel strategies to improve the lives of sepsis survivors.
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Affiliation(s)
- Elisabeth C van der Slikke
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, , P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands
| | - Andy Y An
- Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Robert E W Hancock
- Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Hjalmar R Bouma
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, , P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Tang S, Gao P, Chen H, Zhou X, Ou Y, He Y. The Role of Iron, Its Metabolism and Ferroptosis in Traumatic Brain Injury. Front Cell Neurosci 2020; 14:590789. [PMID: 33100976 PMCID: PMC7545318 DOI: 10.3389/fncel.2020.590789] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/04/2020] [Indexed: 12/29/2022] Open
Abstract
Traumatic brain injury (TBI) is a structural and physiological disruption of brain function caused by external forces. It is a major cause of death and disability for patients worldwide. TBI includes both primary and secondary impairments. Iron overload and ferroptosis highly involved in the pathophysiological process of secondary brain injury. Ferroptosis is a form of regulatory cell death, as increased iron accumulation in the brain leads to lipid peroxidation, reactive oxygen species (ROS) production, mitochondrial dysfunction and neuroinflammatory responses, resulting in cellular and neuronal damage. For this reason, eliminating factors like iron deposition and inhibiting lipid peroxidation may be a promising therapy. Iron chelators can be used to eliminate excess iron and to alleviate some of the clinical manifestations of TBI. In this review we will focus on the mechanisms of iron and ferroptosis involving the manifestations of TBI, broaden our understanding of the use of iron chelators for TBI. Through this review, we were able to better find novel clinical therapeutic directions for further TBI study.
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Affiliation(s)
- Sicheng Tang
- Medical Clinic and Polyclinic IV, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
| | - Pan Gao
- Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Hanmin Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyue Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yibo Ou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wu F, Chen X, Zhai L, Wang H, Sun M, Song C, Wang T, Qian Z. CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation. Biochem Biophys Res Commun 2020; 529:839-845. [PMID: 32616311 DOI: 10.1016/j.bbrc.2020.05.124] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 05/17/2020] [Indexed: 10/24/2022]
Abstract
Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis with intolerable high motility. SAE is accompanied with brain vascular injury, endothelial hyperpermeability, and neutrophil infiltration into the brain tissue, key inflammatory processes leading to further brain edema and neuronal cell apoptosis. Recent studies from us and others suggest that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is crucial for neutrophil recruitment during SAE. Here we use CXCR2 antagonist SB225002 to characterize the role of CXCR2 in brain infiltration of neutrophil in a murine model of SAE. Systemic administration of high-dose LPS (10 mg/kg) induced evident neutrophil infiltration into the cerebral cortex in wild-type mice. However, CXCR2 antagonist SB225002 markedly attenuated neutrophil infiltration into brain. The CXCR2 expression on neutrophils in the peripheral circulation was dramatically downregulated in response to this LPS dose, and endothelial CXCR2 was significantly upregulated, suggesting endothelial but not neutrophil CXCR2 plays a more important role in neutrophil infiltration into brain. Strikingly, although these CXCR2 antagonist SB225002 treated mice displayed reduced neutrophil infiltration, no change in neutrophil rolling and adhesion was observed. Furthermore, we confirmed that CXCR2 agonist CXCL1 induced a marked increase in actin stress fiber synthesis and paracellular gap formation in cultured cerebral endothelial cells, which is attenuated by SB225002. Thus, these results demonstrate a selective role for endothelial CXCR2 to regulate cerebral vascular permeability and neutrophil transmigration in high-dose LPS induced neuroinflammation, and also suggest a therapeutic potential of CXCR2 antagonist SB225002 in SAE.
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Affiliation(s)
- Fengjiao Wu
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Xiaofen Chen
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Liqian Zhai
- Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Hongtao Wang
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Meiqun Sun
- Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Chuanwang Song
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Ting Wang
- Department of Internal Medicine, University of Arizona, Phoenix, AZ, 85004, USA.
| | - Zhongqing Qian
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China.
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Ferlini L, Su F, Creteur J, Taccone FS, Gaspard N. Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study. Intensive Care Med Exp 2020; 8:44. [PMID: 32797301 PMCID: PMC7426896 DOI: 10.1186/s40635-020-00332-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Background Alteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE. Methods Thirty-six anesthetized, mechanically ventilated female sheep were randomized to sham procedures (sham, n = 15), sepsis (n = 14), or septic shock (n = 7). Blood pressure, CBF, and electrocorticography were continuously recorded. Pearson’s correlation coefficient Lxa and transfer function analysis were used to estimate dCA. NVC was assessed by the analysis of CBF variations induced by cortical gamma activity (Eγ) peaks and by the magnitude-squared coherence (MSC) between the spontaneous fluctuations of CBF and Eγ. Cortical function was estimated by the alpha-delta ratio. Wilcoxon signed rank and rank sum tests, Friedman tests, and RMANOVA test were used as appropriate. Results Sepsis and sham animals did not differ neither in dCA nor in NVC parameters. A significant impairment of dCA occurred only after septic shock (Lxa, p = 0.03, TFA gain p = 0.03, phase p = 0.01). Similarly, NVC was altered during septic shock, as indicated by a lower MSC in the frequency band 0.03–0.06 Hz (p < 0.001). dCA and NVC impairments were associated with cortical dysfunction (reduction in the alpha-delta ratio (p = 0.03)). Conclusions A progressive loss of dCA and NVC occurs during septic shock and is associated with cortical dysfunction. These findings indicate that the alteration of mechanisms controlling cortical perfusion plays a late role in the pathophysiology of SAE and suggest that alterations of CBF regulation mechanisms in less severe phases of sepsis reported in clinical studies might be due to patients’ comorbidities or other confounders. Furthermore, a mean arterial pressure targeting therapy aiming to optimize dCA might not be sufficient to prevent neuronal dysfunction in sepsis since it would not improve NVC.
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Affiliation(s)
- Lorenzo Ferlini
- Department of Neurology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Bruxelles, Belgium.
| | - Fuhong Su
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Jacques Creteur
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Fabio Silvio Taccone
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Nicolas Gaspard
- Department of Neurology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Bruxelles, Belgium
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Ismail Hassan F, Didari T, Baeeri M, Gholami M, Haghi-Aminjan H, Khalid M, Navaei-Nigjeh M, Rahimifard M, Solgi S, Abdollahi M, Mojtahedzadeh M. Metformin Attenuates Brain Injury by Inhibiting Inflammation and Regulating Tight Junction Proteins in Septic Rats. CELL JOURNAL 2020; 22:29-37. [PMID: 32779431 PMCID: PMC7481907 DOI: 10.22074/cellj.2020.7046] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/01/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Metformin has a potent inhibitory activity against inflammation and oxidative stress, which inevitably occur in sepsis-associated encephalopathy (SAE). The precise mechanisms underlying neuroprotective effects of metformin in SAE, are still unclear. In the present work, the protective effect of metformin on SAE using cecal ligation and puncture (CLP) model of sepsis, was assessed. MATERIALS AND METHODS In this experimental study, CLP procedure was performed in Wistar rats and 50 mg/kg metformin was administered immediately. Specific markers of sepsis severity, inflammation, blood brain barrier (BBB) dysfunction, and brain injury, were investigated. Specific assay kits and real-time polymerase chain reaction (RT-PCR) were used. Histopathological assessment was also carried out. RESULTS Treatment with metformin decreased murine sepsis score (MSS), lactate, platelet lymphocyte ratio (PLR), and high mobility group box (HMGB1) levels. The expression levels of claudin 3 (Cldn3) and claudin 5 (Cldn5) were increased following treatment with metformin. Metformin decreased the expression of S100b, neuron specific enolase (Nse), and glial fibrillary acidic protein (Gfap). CONCLUSION Our study suggests that metformin may inhibit inflammation and increase tight junction protein expressions which may improve BBB function and attenuate CLP-induced brain injury. Hence, the potential beneficial effects of metformin in sepsis, should be considered in future.
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Affiliation(s)
- Fatima Ismail Hassan
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Tina Didari
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Baeeri
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Gholami
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Madiha Khalid
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mona Navaei-Nigjeh
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mahban Rahimifard
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Solgi
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. Electronic Address:
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Mojtahedzadeh
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. Electronic Address:
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Jin SC, Kim MH, Jo SY, Yoon Choi L, Lee H, Yang WM. Soshiho-tang protects LPS-induced acute liver injury by attenuating inflammatory response. J Nat Med 2020; 74:788-795. [PMID: 32533386 DOI: 10.1007/s11418-020-01421-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 06/03/2020] [Indexed: 10/24/2022]
Abstract
Soshiho-tang (SSHT) has traditionally been used to treat gastrointestinal disorders. In this experiment, we investigated the protective effect of SSHT on inflammatory liver injury in lipopolysaccharide (LPS)-sensitized mice. Male C57BL/6J mice aged 6 weeks were randomly placed in 6 groups (n = 5): normal mice (CTR), LPS-sensitized mice (LPS), LPS-sensitized mice treated with dexamethasone (DEX) and LPS-sensitized mice treated with 0.05, 0.55, and 5.55 g/kg of SSHT (SSHT 0.05, SSHT 0.55, and SSHT 5.55). Various doses of SSHT was given once a day for 7 days. After 2 h of LPS injection, the liver tissue was collected. SSHT pretreatment recovered hemorrhage of liver tissues in LPS-induced acute liver injury. The expressions of MAP Kinase, NF-κB, IκBα, p-IκBα, COX-2, and iNOS protein levels were markedly decreased by SSHT-treated liver tissues. Additionally, SSHT pretreatment significantly regulated the expressions of MCP-1, TNF-α, and IL-6 cytokines. These results suggest the potential of SSHT on the protection of acute liver injury.
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Affiliation(s)
- Seong Chul Jin
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Mi Hye Kim
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Si Yeon Jo
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - La Yoon Choi
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Haesu Lee
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Woong Mo Yang
- Department of Convergence Korean Medical Science, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
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