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Liu L, Li Y, Li JX, Xiao X, Wan TT, Li HH, Guo SB. ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1-7)-Mas Receptor Axis. Inflammation 2024; 47:891-908. [PMID: 38240986 DOI: 10.1007/s10753-023-01949-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 06/04/2024]
Abstract
Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1-7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1-7)-Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.
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Affiliation(s)
- Lei Liu
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China
| | - Ya Li
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China
| | - Jia-Xin Li
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China
| | - Xue Xiao
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China
| | - Tian-Tian Wan
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China
| | - Hui-Hua Li
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China.
| | - Shu-Bin Guo
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker's Stadium, Chaoyang District, Beijing, 100020, China.
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Alam MJ, Rahman MH, Hossain MA, Hoque MR, Aktaruzzaman M. Bioinformatics and Systems Biology Approaches to Identify the Synergistic Effects of Alcohol Use Disorder on the Progression of Neurological Diseases. Neuroscience 2024; 543:65-82. [PMID: 38401711 DOI: 10.1016/j.neuroscience.2024.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/26/2024]
Abstract
Clinical investigations showed that individuals with Alcohol Use Disorder (AUD) have worse Neurological Disease (ND) development, pointing to possible pathogenic relationships between AUD and NDs. It remains difficult to identify risk factors that are predisposing between AUD and NDs. In order to fix these issues, we created the bioinformatics pipeline and network-based approaches for employing unbiased methods to discover genes abnormally stated in both AUD and NDs and to pinpoint some of the common molecular pathways that might underlie AUD and ND interaction. We found 100 differentially expressed genes (DEGs) in both the AUD and ND patient's tissue samples. The most important Gene Ontology (GO) terms and metabolic pathways, including positive control of cytotoxicity caused by T cells, proinflammatory responses, antigen processing and presentation, and platelet-triggered interactions with vascular and circulating cell pathways were then extracted using the overlapped DEGs. Protein-protein interaction analysis was used to identify hub proteins, including CCL2, IL1B, TH, MYCN, HLA-DRB1, SLC17A7, and HNF4A, in the pathways that have been reported as playing a function in these disorders. We determined several TFs (HNF4A, C4A, HLA-B, SNCA, HLA-DMB, SLC17A7, HLA-DRB1, HLA-C, HLA-A, and HLA-DPB1) and potential miRNAs (hsa-mir-34a-5p, hsa-mir-34c-5p, hsa-mir-449a, hsa-mir-155-5p, and hsa-mir-1-3p) were crucial for regulating the expression of AUD and ND which could serve as prospective targets for treatment. Our methodologies discovered unique putative biomarkers that point to the interaction between AUD and various neurological disorders, as well as pathways that could one day be the focus of therapeutic intervention.
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Affiliation(s)
- Md Jahangir Alam
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh; Center for Advanced Bioinformatics and Artificial Intelligence Research, Islamic University, Kushtia 7003, Bangladesh
| | - Md Habibur Rahman
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh; Center for Advanced Bioinformatics and Artificial Intelligence Research, Islamic University, Kushtia 7003, Bangladesh.
| | - Md Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh; Department of Microbiology, Primeasia University, Banani, Dhaka 1213, Bangladesh
| | - Md Robiul Hoque
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh
| | - Md Aktaruzzaman
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh
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Michalak A, Lach T, Szczygieł K, Cichoż-Lach H. COVID-19, Possible Hepatic Pathways and Alcohol Abuse-What Do We Know up to 2023? Int J Mol Sci 2024; 25:2212. [PMID: 38396888 PMCID: PMC10888568 DOI: 10.3390/ijms25042212] [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: 01/01/2024] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
The pandemic period due to coronavirus disease 2019 (COVID-19) revolutionized all possible areas of global health. Significant consequences were also related to diverse extrapulmonary manifestations of this pathology. The liver was found to be a relatively common organ, beyond the respiratory tract, affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple studies revealed the essential role of chronic liver disease (CLD) in the general outcome of coronavirus infection. Present concerns in this field are related to the direct hepatic consequences caused by COVID-19 and pre-existing liver disorders as risk factors for the severe course of the infection. Which mechanism has a key role in this phenomenon-previously existing hepatic disorder or acute liver failure due to SARS-CoV-2-is still not fully clarified. Alcoholic liver disease (ALD) constitutes another not fully elucidated context of coronavirus infection. Should the toxic effects of ethanol or already developed liver cirrhosis and its consequences be perceived as a causative or triggering factor of hepatic impairment in COVID-19 patients? In the face of these discrepancies, we decided to summarize the role of the liver in the whole picture of coronavirus infection, paying special attention to ALD and focusing on the pathological pathways related to COVID-19, ethanol toxicity and liver cirrhosis.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Karolina Szczygieł
- Clinical Dietetics Unit, Department of Bioanalytics, Medical University of Lublin, Chodźki 7, 20-093 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
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Righi FA, Vander Heide RS, Graham RP, Aubry MC, Trejo-Lopez JA, Bois MC, Roden AC, Reichard R, Maleszewski JJ, Alexander MP, Quinton RA, Jenkins SM, Hartley CP, Hagen CE. A case-control autopsy series of liver pathology associated with novel coronavirus disease (COVID-19). Ann Diagn Pathol 2024; 68:152240. [PMID: 37995413 DOI: 10.1016/j.anndiagpath.2023.152240] [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: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. METHODS Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. RESULTS 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. CONCLUSIONS The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.
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Affiliation(s)
- Fabiola A Righi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Richard S Vander Heide
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Marie Christine Aubry
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Jorge A Trejo-Lopez
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Melanie C Bois
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Anja C Roden
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Ross Reichard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Joseph J Maleszewski
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Mariam P Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Reade A Quinton
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Sarah M Jenkins
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, United States of America
| | - Christopher P Hartley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Catherine E Hagen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.
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Frank MG, Fleshner M, Maier SF. Exploring the immunogenic properties of SARS-CoV-2 structural proteins: PAMP:TLR signaling in the mediation of the neuroinflammatory and neurologic sequelae of COVID-19. Brain Behav Immun 2023; 111:259-269. [PMID: 37116592 PMCID: PMC10132835 DOI: 10.1016/j.bbi.2023.04.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/07/2023] [Accepted: 04/23/2023] [Indexed: 04/30/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces an array of neurologic and neuropsychiatric symptoms in the acute and post-acute phase of infection (PASC; post-acute sequelae of SARS-CoV-2 infection). Neuroinflammatory processes are considered key factors in the etiology of these symptoms. Several mechanisms underpinning the development of inflammatory events in the brain have been proposed including SARS-CoV-2 neurotropism and peripheral inflammatory responses (i.e., cytokine storm) to infection, which might produce neuroinflammation via immune-to-brain signaling pathways. In this review, we explore evidence in support of an alternate mechanism whereby structural proteins (e.g., spike and spike S1 subunit) derived from SARS-CoV-2 virions function as pathogen-associated molecular patterns (PAMPs) to elicit proinflammatory immune responses in the periphery and/or brain via classical Toll-Like Receptor (TLR) inflammatory pathways. We propose that SARS-CoV-2 structural proteins might directly produce inflammatory processes in brain independent of and/or in addition to peripheral proinflammatory effects, which might converge to play a causal role in the development of neurologic/neuropsychiatric symptoms in COVID-19.
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Affiliation(s)
- Matthew G Frank
- Department of Integrative Physiology, University of Colorado Boulder, Boulder CO 80301, United States.
| | - Monika Fleshner
- Department of Integrative Physiology, University of Colorado Boulder, Boulder CO 80301, United States
| | - Steven F Maier
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, Boulder CO 80301, United States
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Erickson MA, Logsdon AF, Rhea EM, Hansen KM, Holden SJ, Banks WA, Smith JL, German C, Farr SA, Morley JE, Weaver RR, Hirsch AJ, Kovac A, Kontsekova E, Baumann KK, Omer MA, Raber J. Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease. Brain Behav Immun 2023; 109:251-268. [PMID: 36682515 PMCID: PMC9867649 DOI: 10.1016/j.bbi.2023.01.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 12/19/2022] [Accepted: 01/16/2023] [Indexed: 01/22/2023] Open
Abstract
COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.
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Affiliation(s)
- Michelle A Erickson
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Aric F Logsdon
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Elizabeth M Rhea
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Kim M Hansen
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Sarah J Holden
- Department of Behavioral Neurosciences, Oregon Health and Science University, Portland, OR, USA
| | - William A Banks
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
| | - Jessica L Smith
- The Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Beaverton, OR, USA; Division of Pathobiology and Immunology Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, USA
| | - Cody German
- The Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Beaverton, OR, USA; Division of Pathobiology and Immunology Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, USA
| | - Susan A Farr
- Saint Louis Veterans Affairs Medical Center, Research Service, St. Louis, MO, USA; Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - John E Morley
- Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Riley R Weaver
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Alec J Hirsch
- The Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Beaverton, OR, USA; Division of Pathobiology and Immunology Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, USA
| | - Andrej Kovac
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Eva Kontsekova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Kristen K Baumann
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Mohamed A Omer
- Geriatrics Research Educational and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Jacob Raber
- Department of Behavioral Neurosciences, Oregon Health and Science University, Portland, OR, USA; Department of Neurology, Psychiatry, and Radiation Medicine, Division of Neuroscience, Departments of Neurology and Radiation Medicine, Oregon National Primate Research Center, Oregon Health Sciences University, Portland, OR, USA
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Liptak P, Nosakova L, Rosolanka R, Skladany L, Banovcin P. Acute-on-chronic liver failure in patients with severe acute respiratory syndrome coronavirus 2 infection. World J Hepatol 2023; 15:41-51. [PMID: 36744167 PMCID: PMC9896507 DOI: 10.4254/wjh.v15.i1.41] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/03/2022] [Accepted: 11/29/2022] [Indexed: 01/16/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on the lives of millions of people, especially those with other concomitant diseases, such as chronic liver diseases. To date, seven coronaviruses have been identified to infect humans. The main site of pathological action of these viruses is lung tissue. However, a substantial number of studies have proven that SARS-CoV-2 shows affinity towards several organs, including the gastrointestinal tract and the liver. The current state of evidence points to several proposed mechanisms of liver injury in patients with COVID-19 and their combination. Liver impairment is considered to be the result of the direct effect of the virus on the hepatic tissue cells, a systemic reaction consisting of inflammation, hypoxia and cytokine storm, drug-induced liver injury, with the possible contribution of a perturbed gut-liver axis. Reactivation of chronic hepatic disease could be another factor for liver impairment in patients with SARS-CoV-2 infection. Acute-on-chronic liver failure (ACLF) is a relatively new syndrome that occurs in 10%–30% of all hospitalized patients with chronic liver disease. It is crucial to recognize high-risk patients due to the increased morbidity and mortality in these cases. Several published studies have reported virus infection as a trigger factor for ACLF. However, to date, there are few relevant studies describing the presence of ACLF in patients with acute SARS-CoV-2 infection. In this minireview we summarize the current state of knowledge regarding the relation between ACLF and acute SARS-CoV-2 infection.
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Affiliation(s)
- Peter Liptak
- Clinic of Internal Medicine-Gastroenterology, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University, Martin 03601, Slovakia
| | - Lenka Nosakova
- Clinic of Internal Medicine-Gastroenterology, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University, Martin 03601, Slovakia
| | - Robert Rosolanka
- Clinic of Infectology and Travel Medicine, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University, Martin 03601, Slovakia
| | - Lubomir Skladany
- Department of Internal Medicine II, Division Hepatology, Gastroenterology and Liver Transplantation, FD Roosevelt University Hospital of Slovak Medical University, Banska Bystrica 97517, Slovakia
| | - Peter Banovcin
- Clinic of Internal Medicine-Gastroenterology, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University, Martin 03601, Slovakia
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Nuovo GJ, Suster D, Sawant D, Mishra A, Michaille JJ, Tili E. The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection. Ann Diagn Pathol 2022; 61:152057. [PMID: 36334414 PMCID: PMC9616485 DOI: 10.1016/j.anndiagpath.2022.152057] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 10/26/2022] [Indexed: 11/28/2022]
Abstract
Pre-existing Alzheimer's disease is a risk factor for severe/fatal COVID-19 and infection by SARS-CoV2 virus has been associated with an increased incidence of un-masked Alzheimer's disease. The molecular basis whereby SARS-CoV2 may amplify Alzheimer's disease is not well understood. This study analyzed the molecular changes in autopsy brain tissues from people with pre-existing dementia who died of COVID-19 (n = 5) which was compared to equivalent tissues of people who died of COVID-19 with no history of dementia (n = 8), Alzheimer's disease pre-COVID-19 (n = 10) and aged matched controls (n = 10) in a blinded fashion. Immunohistochemistry analyses for hyperphosphorylated tau protein, α-synuclein, and β-amyloid-42 confirmed the diagnoses of Alzheimer's disease (n = 4), and Lewy body dementia (n = 1) in the COVID-19 group. The brain tissues from patients who died of COVID-19 with no history of dementia showed a diffuse microangiopathy marked by endocytosis of spike subunit S1 and S2 in primarily CD31+ endothelia with strong co-localization with ACE2, Caspase-3, IL6, TNFα, and Complement component 6 that was not associated with SARS-CoV2 RNA. Microglial activation marked by increased TMEM119 and MCP1 protein expression closely paralleled the endocytosed spike protein. The COVID-19 tissues from people with no pre-existing dementia showed, compared to controls, 5-10× fold increases in expression of neuronal NOS and NMDAR2 as well as a marked decrease in the expression of proteins whose loss is associated with worsening Alzheimer's disease: MFSD2a, SHIP1, BCL6, BCL10, and BACH1. In COVID-19 tissues from people with dementia the widespread spike-induced microencephalitis with the concomitant microglial activation co-existed in the same areas where neurons had hyperphosphorylated tau protein suggesting that the already dysfunctional neurons were additionally stressed by the SARS-CoV2 induced microangiopathy. ACE2+ human brain endothelial cells treated with high dose (but not vaccine equivalent low dose) spike S1 protein demonstrated each of the molecular changes noted in the in vivo COVID-19 and COVID-19/Alzheimer's disease brain tissues. It is concluded that fatal COVID-19 induces a diffuse microencephalitis and microglial activation in the brain due to endocytosis of circulating viral spike protein that amplifies pre-existing dementia in at least two ways: 1) modulates the expression of proteins that may worsen Alzheimer's disease and 2) stresses the already dysfunctional neurons by causing an acute proinflammatory/hypercoagulable/hypoxic microenvironment in areas with abundant hyperphosphorylated tau protein and/or βA-42.
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Affiliation(s)
- Gerard J Nuovo
- Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; GnomeDX, Powell, OH, USA.
| | - David Suster
- Rutgers University Hospital Department of Pathology, Newark, NY, USA
| | | | | | - Jean-Jacques Michaille
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, College of Medicine, Columbus, OH, USA
| | - Esmerina Tili
- Department of Anesthesiology, The Ohio State University Wexner Medical Center, College of Medicine, Columbus, OH, USA
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9
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Hoffmann C, Gerber PA, Cavelti-Weder C, Licht L, Kotb R, Al Dweik R, Cherfane M, Bornstein SR, Perakakis N. Liver, NAFLD and COVID-19. Horm Metab Res 2022; 54:522-531. [PMID: 35468630 DOI: 10.1055/a-1834-9008] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Coronavirus disease 2019 (COVID-19) is characterized by a wide clinical spectrum that includes abnormalities in liver function indicative of liver damage. Conversely, people with liver diseases are at higher risk of severe COVID-19. In the current review, we summarize first the epidemiologic evidence describing the bidirectional relationship between COVID-19 and liver function/liver diseases. Additionally, we present the most frequent histologic findings as well as the most important direct and indirect mechanisms supporting a COVID-19 mediated liver injury. Furthermore, we focus on the most frequent liver disease in the general population, non-alcoholic or metabolic-associated fatty liver disease (NAFLD/MAFLD), and describe how COVID-19 may affect NAFLD/MAFLD development and progression and conversely how NAFLD/MAFLD may further aggravate a COVID-19 infection. Finally, we present the long-term consequences of the pandemic on the development and management of NAFLD.
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Affiliation(s)
- Carlotta Hoffmann
- University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Department of Internal Medicine III, Dresden, Germany
| | - Philipp A Gerber
- University Hospital Zurich (USZ) and University of Zurich (UZH), Switzerland, Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland
| | - Claudia Cavelti-Weder
- University Hospital Zurich (USZ) and University of Zurich (UZH), Switzerland, Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland
| | - Louisa Licht
- University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Department of Internal Medicine III, Dresden, Germany
| | - Reham Kotb
- Abu Dhabi University, Abu Dhabi, United Arab Emirates, College of Health Sciences, Abu Dhabi, United Arab Emirates
| | - Rania Al Dweik
- Abu Dhabi University, Abu Dhabi, United Arab Emirates, Department of Public Health, Abu Dhabi, United Arab Emirates
| | - Michele Cherfane
- Abu Dhabi University, Abu Dhabi, United Arab Emirates, College of Health Sciences, Abu Dhabi, United Arab Emirates
| | - Stefan R Bornstein
- University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Department of Internal Medicine III, Dresden, Germany
| | - Nikolaos Perakakis
- University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Department of Internal Medicine III, Dresden, Germany
- University Hospital and Faculty of Medicine, TU Dresden, Dresden, Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, Dresden, Germany
- Neuherberg, German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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