ABSTRACT
BACKGROUND AND AIMS: The majority of indeterminate pediatric acute liver failure (PALF) cases are secondary to immune dysregulation, labeled activated T-cell hepatitis (TCHep). We aimed to describe a cohort of children with acute severe hepatitis and PALF and define how clinical immune labs may help identify the TCHep group. METHODS: Retrospective review of children with acute hepatitis and PALF between March 2020 and August 2022. Patients were classified as known diagnosis, indeterminate hepatitis (IND-Hep), or TCHep (defined by liver biopsy with predominant CD8 T-cell inflammation or development of aplastic anemia). RESULTS: 124 patients were identified: 83 with known diagnoses, 16 with TCHep, and 25 with IND-Hep. Patients with TCHep had significantly increased median total bilirubin levels (7.5 mg/dL (IQR 6.8-8.9) vs 1.5 mg/dL (IQR 1.0-3.6), p < 0.0001), soluble interleukin-2 receptor levels (4512 IU/mL (IQR 4073-5771) vs 2997 IU/mL (IQR 1957-3237), p = 0.02), and percent of CD8+ T-cells expressing perforin (14.5 % (IQR 8.0-20.0) vs 1.0 % (IQR 0.8-1.0), p = 0.004) and granzyme (37.5 % (IQR 15.8-54.8) vs 4.0 % (IQR 2.5-5.5), p = 0.004) compared to IND-Hep patients. Clinical flow cytometry showed that TCHep patients had significantly increased percent CD8+ T cells (29.0 % (IQR 24.5-33.5) vs 23.6 % (IQR 19.8-25.8), p = 0.04) and HLA-DR+ (16.0 % (IQR 14.5-24.5) vs 2.7 (1.8-5.3), p < 0.001) compared to IND-Hep patients indicative of increase in CD8+ T cells that are activated. CONCLUSIONS: Peripheral blood clinical immune studies demonstrate increased markers of CD8 T-cell activation, proliferation, and cytotoxic function for TCHep patients. These readily available immune function labs can be used to help distinguish patients with TCHep from those with other causes. This provides a non-invasive tool for early detection of potential TCHep before progression to liver failure.
Subject(s)
CD8-Positive T-Lymphocytes , Humans , Retrospective Studies , Child , Male , Female , Child, Preschool , CD8-Positive T-Lymphocytes/immunology , Liver Failure, Acute/immunology , Liver Failure, Acute/blood , Adolescent , Hepatitis/immunology , Hepatitis/blood , Lymphocyte Activation , Infant , Receptors, Interleukin-2/blood , Granzymes/bloodABSTRACT
Hepatitis E virus (HEV) infection in pregnant women is associated with a wide spectrum of adverse consequences for both mother and fetus. The high mortality in this population appears to be associated with hormonal changes and consequent immunological changes. This study conducted an analysis of immune responses in pregnant women infected with HEV manifesting varying severity. Data mining analysis of the GSE79197 was utilized to examine differentially biological functions in pregnant women with HEV infection (P-HEV) versus without HEV infection (P-nHEV), P-HEV progressing to ALF (P-ALF) versus P-HEV, and P-HEV versus non-pregnant women with HEV infection (nP-HEV). We found cellular response to interleukin and immune response-regulating signalings were activated in P-HEV compared with P-nHEV. However, there was a significant decrease of immune responses, such as T cell activation, leukocyte cell-cell adhesion, regulation of lymphocyte activation, and immune response-regulating signaling pathway in P-ALF patient than P-HEV patient. Compared with nP-HEV, MHC protein complex binding function was inhibited in P-HEV. Further microRNA enrichment analysis showed that MAPK and T cell receptor signaling pathways were inhibited in P-HEV compared with nP-HEV. In summary, immune responses were activated during HEV infection while being suppressed when developing ALF during pregnancy, heightening the importance of immune mediation in the pathogenesis of severe outcome in HEV infected pregnant women.
Subject(s)
Hepatitis E virus , Hepatitis E , Pregnancy Complications, Infectious , Humans , Female , Pregnancy , Hepatitis E/immunology , Hepatitis E/virology , Pregnancy Complications, Infectious/virology , Pregnancy Complications, Infectious/immunology , Hepatitis E virus/immunology , Signal Transduction , Liver Failure, Acute/immunology , Liver Failure, Acute/virology , MicroRNAs/genetics , AdultABSTRACT
Acute liver failure (ALF) is a potentially fatal disorder characterized by extensive hepatocyte necrosis and rapid decline in liver function. Numerous factors, including oxidative stress, cell death, and inflammatory responses, are associated with its pathogenesis. Endotoxin tolerance (ET) refers to the phenomenon in which the body or cells exhibit low or no response to high-dose lipopolysaccharide (LPS) stimulation after pre-stimulation with low-dose LPS. However, the specific mechanism through which ET regulates LPS/D-galactosamine (D-GalN)-induced ALF remains unclear. An ALF mouse model was established by intraperitoneal injection of D-GalN (400 mg/kg) and LPS (10 mg/kg). A low dose of LPS (0.1 mg/kg/d) was continuously administered to mice for 5 d before modeling to assess the protective effect of ET. The data from this study showed that ET alleviated the inflammatory response in mice with LPS/D-GalN-induced ALF. ET inhibited LPS-induced oxidative damage and pyroptosis in macrophages in vitro. RNA sequencing analysis showed that the NF-κB/NLRP3 pathway was linked to the anti-inflammatory and antioxidative effects of ET. Furthermore, using western blot, RT-qPCR, and immunofluorescence, we verified that ET inhibited the NF-κB/NLRP3 pathway and triggered the Nrf2/HO-1 signaling pathway to attenuate oxidative stress and cell pyroptosis. Sirt1 knockdown reversed this protective effect. In summary, our research elucidates that ET prevents ALF advancement by upregulating Sirt1 levels, triggering the Nrf2/HO-1 signaling axis, and suppressing the NF-κB/NLRP3 signaling cascade to inhibit oxidative stress and cell pyroptosis. Our results provide a mechanistic explanation for the protective effect of ET against ALF.
Subject(s)
Galactosamine , Lipopolysaccharides , Liver Failure, Acute , Signal Transduction , Animals , Male , Mice , Disease Models, Animal , Endotoxins/toxicity , Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Immune Tolerance/drug effects , Liver/drug effects , Liver/pathology , Liver/metabolism , Liver/immunology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/immunology , Liver Failure, Acute/metabolism , Liver Failure, Acute/drug therapy , Macrophages/drug effects , Macrophages/immunology , Membrane Proteins/metabolism , Membrane Proteins/genetics , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress/drug effects , Pyroptosis/drug effects , Signal Transduction/drug effects , Sirtuin 1/metabolism , Sirtuin 1/geneticsABSTRACT
The complement system (CS) is part of the human immune system, consisting of more than 30 proteins that play a vital role in the protection against various pathogens and diseases, including viral diseases. Activated via three pathways, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP), the complement system leads to the formation of a membrane attack complex (MAC) that disrupts the membrane of target cells, leading to cell lysis and death. Due to the increasing number of reports on its role in viral diseases, which may have implications for research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this review aims to highlight significant progress in understanding and defining the role of the complement system in four groups of diseases of viral etiology: (1) respiratory diseases; (2) acute liver failure (ALF); (3) disseminated intravascular coagulation (DIC); and (4) vector-borne diseases (VBDs). Some of these diseases already present a serious global health problem, while others are a matter of concern and require the collaboration of relevant national services and scientists with the World Health Organization (WHO) to avoid their spread.
Subject(s)
Complement System Proteins , Virus Diseases/etiology , Animals , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Humans , Liver Failure, Acute/immunology , Liver Failure, Acute/virology , Respiratory Tract Diseases/immunology , Respiratory Tract Diseases/virology , Vector Borne Diseases/immunology , Vector Borne Diseases/virologyABSTRACT
The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/- ) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Inducible T-Cell Co-Stimulator Protein/metabolism , Liver Failure, Acute/immunology , Liver Regeneration/immunology , Macrophages/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , Carbon Tetrachloride/administration & dosage , Carbon Tetrachloride/toxicity , Cell Communication/immunology , Disease Models, Animal , Humans , Inducible T-Cell Co-Stimulator Ligand/metabolism , Inducible T-Cell Co-Stimulator Protein/genetics , Liver/cytology , Liver/drug effects , Liver/immunology , Liver/pathology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/pathology , Macrophages/metabolism , Male , Mice , Mice, Knockout , Signal Transduction/immunologyABSTRACT
Acute liver failure (ALF) is a dramatic liver disease characterized by large areas of inflammation. However, there are no available effective targeted drugs for ALF treatment. In the study, serum biochemical index and H&E were used to explore the amelioration of the liver histopathological changes. The oxidative stress kits, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to elucidate the mechanisms underlying isoliquiritigenin (ISL) protection. The results showed that ISL significantly improved the liver pathological changes. Furthermore, ISL reduced oxidative stress by altering the expression of PGC-1α, Nrf2, HO-1, NQO1, Keap1, GCLC, and GCLM in damaged hepatocytes. Moreover, the levels of inflammation-related genes including NLRP3 inflammasome, IL-1ß, IL-6, TNF-α, iNOS, and Mip-2 were repressed by ISL. In addition, ISL alleviated LPS/D-GalN-induced hepatocytes apoptosis by increasing the Bcl-2/Bax ratio and suppressing the expression of cleaved caspase-3. Further in vivo and in vitro evidence proved the involvement of the PGC-1α/Nrf2 signaling pathway in ISL protection. In conclusion, ISL improves the ability of anti-oxidative stress, alleviates inflammatory reaction, apoptosis, and inhibits NLRP3 inflammasome to protect lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF through activating the PGC-1α/Nrf2 pathway, which provides the possibility for the treatment of ALF.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Chalcones/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Inflammation Mediators/metabolism , Liver Failure, Acute/prevention & control , Liver/drug effects , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cells, Cultured , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Galactosamine , Inflammasomes/genetics , Inflammasomes/metabolism , Lipopolysaccharides , Liver/immunology , Liver/metabolism , Liver/pathology , Liver Failure, Acute/immunology , Liver Failure, Acute/metabolism , Liver Failure, Acute/pathology , Male , Mice, Inbred C57BL , NF-E2-Related Factor 2/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Signal TransductionABSTRACT
Massive cellular necrosis in acute liver failure (ALF) is dominantly immune mediated and innate immune cells are major pathophysiological determinants in liver damage. In fifty ALF and fifteen healthy, immune cells phenotyping by flow-cytometry, DAMPs using ELISA were analysed and correlated with clinical and biochemical parameters. ALF patients (aged 27 ± 9 yr, 56% males, 78% viral aetiology) showed no difference in neutrophils and classical monocytes, but significantly increased intermediate monocytes (CD14+CD16+) (p < 0.01), decreased non-classical monocytes (CD14-CD16+) and CD3-veCD16+CD56+ NK cells compared to HC. ALF patients who survived, showed higher NK cells (9.28 vs. 5.1%, p < 0.001) among lymphocytes and lower serum lactate levels (6.1 vs. 28, Odds ratio 2.23, CI 1.27-3.94) than non- survivors had higher. Logistic regression model predicted the combination of lactate levels with NK cell percentage at admission for survival. In conclusion, Combination of NK cell frequency among lymphocytes and lactate levels at admission can reliably predict survival of ALF patients.
Subject(s)
Killer Cells, Natural/immunology , Lactic Acid/blood , Liver Failure, Acute/blood , Liver Failure, Acute/immunology , Adult , Female , Humans , Liver Failure, Acute/virology , Male , Middle Aged , Prognosis , Virus Diseases/complicationsABSTRACT
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an AIRE gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an AIRE gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and AIRE gene mutations.
Subject(s)
Adrenal Cortex Hormones/administration & dosage , Autoimmune Diseases/drug therapy , Liver Failure, Acute/drug therapy , Methylprednisolone/administration & dosage , Mutation , Polyendocrinopathies, Autoimmune/drug therapy , Retinal Diseases/drug therapy , Transcription Factors/genetics , Administration, Intravenous , Autoantibodies/blood , Autoimmune Diseases/diagnosis , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Azathioprine/administration & dosage , Child, Preschool , Drug Therapy, Combination , Female , Genetic Predisposition to Disease , Humans , Immunosuppressive Agents/administration & dosage , Liver Failure, Acute/diagnosis , Liver Failure, Acute/genetics , Liver Failure, Acute/immunology , Phenotype , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Pulse Therapy, Drug , Recoverin/immunology , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Diseases/immunology , Treatment Outcome , AIRE ProteinABSTRACT
Alcoholism represents a predisposing factor for liver-related morbidity and mortality worldwide. Pogostemon cablin has been widely used in China for the treatment of digestive system diseases. Patchouli oil, the major active fraction of Pogostemon cablin, can ameliorate alcohol-induced acute liver injury (ALI). However, patchouli alcohol (PA),a principal bioactive ingredient of PO, exerts a protection against ALI remains elusive. Thepresentwork focused on the hepatoprotection of PA against acute ethanol-induced hepatotoxicity in rats. In this study, male Wistar rats orally received PA (10, 20, or 40 mg/kg), PO (400 mg/kg) and silymarin (200 mg/kg) for ten days. On the 8th day, the rats orally received 65% ethanol (10 mL/kg, 6.5 g/kg) every 12 h for 3 days. Results showed that PA wasfound to reduce alcohol-induced ALI, as evidenced bysignificantly alleviated histopathologicalalterations, decreased the elevation ofALT and AST levels, and enhancedthe alcoholdehydrogenase(ADH) andaldehyde dehydrogenase (ALDH) activities. Additionally, PA markedly suppressed ROS levels and increased antioxidant enzyme activities via the CYP2E1/ROS/Nrf2/HO-1 pathway. PA regulated lipid accumulation by markedly inhibiting the expression of lipogenesis-related genes and stimulating that of lipolysis-relatedgenes, which were associated with the activation of theAMPKpathway. What's more, PA pretreatment also restored acute alcohol-inducedalterationsin gut barrier function, colonic histopathology, and gut microbiota richness and evenness. PA pretreatment alleviated gut-origin LPS-inducedinflammation by inhibiting the MyD88/TLR4/NF-κB signal pathway. In general, PA ameliorates ethanol-induced ALI via restoration of CYP2E1/ROS/Nrf2/HO-1-mediatedoxidativestressand AMPK-mediated fat accumulation, as well as alleviation of gut-LPS-leakage-induced inflammation regulated by the MyD88/TLR4/NF-κB signaling pathway.
Subject(s)
Gastrointestinal Microbiome/immunology , Intestinal Mucosa/drug effects , Liver Failure, Acute/drug therapy , Liver/drug effects , Sesquiterpenes/pharmacology , Animals , Disease Models, Animal , Humans , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Lipogenesis/drug effects , Lipogenesis/immunology , Lipolysis/drug effects , Lipolysis/immunology , Lipopolysaccharides/immunology , Lipopolysaccharides/metabolism , Liver/immunology , Liver/pathology , Liver Failure, Acute/immunology , Liver Failure, Acute/pathology , Male , Oxidative Stress/drug effects , Oxidative Stress/immunology , Rats , Reactive Oxygen Species/metabolism , Sesquiterpenes/isolation & purification , Sesquiterpenes/therapeutic use , Signal Transduction/drug effects , Signal Transduction/immunologySubject(s)
Hepatic Encephalopathy/complications , Liver Failure, Acute/complications , Liver Failure, Acute/immunology , Multiple Organ Failure/complications , Sepsis/complications , Alarmins/metabolism , Critical Care/methods , Hepatocytes/metabolism , Humans , Liver Failure, Acute/metabolism , Liver Failure, Acute/therapy , Liver Transplantation/methods , Monocytes/immunology , Multiple Organ Failure/mortality , Neutrophils/immunology , Sepsis/mortality , Treatment OutcomeABSTRACT
Clinically, severe bacterial infection can cause septicemia and multiple organ dysfunction syndrome, especially liver injury. CD38 is closely related to many inflammatory pathways, but its role in liver injury caused by bacterial infection remains unclear. The purpose of this study is to discuss the specific role of CD38 in bacterial liver injury. Eight-week-old male C57BL/6 mice (WT, CD38-/- and CD38-/-TLR4mut) were used and stimulated with Escherichia coli (ATCC25922) or PBS, intraperitoneally. After 3 hours of bacterial stimulation, serum was collected to detect ALT and AST concentration, and liver tissue was harvested for hematoxylin and eosin staining and bacterial culture. The mRNA expressions of TLR4, NLRP3, IL-1ß, IL-18, and GSDMD were quantitatively determined by RT-qPCR. The expressions of TLR4, MyD88, TRIF, NF-κB p65, NLRP3, GSDMD, and cytokines were detected by Western blot. The expression and localization of ERK1/2 were detected by immunohistochemistry and Western blot. The results showed that bacterial stimulation could upregulate the expression of inflammatory cytokines, leading to hepatic dysfunction. Moreover, bacterial stimulation of CD38-deficient mice can aggravate the inflammatory response, the expressions of TLR4, NF-κB, and ERK1/2 were significantly increased, and the biomarkers related to pyroptosis also manifested more obvious pyroptosis. However, TLR4 mutation significantly alleviated inflammation and pyroptosis in the liver caused by bacteria, on the basis of CD38 deficiency. Overall, CD38 knockout exacerbates bacteria-induced liver damage through TLR4-NLRP3-GSDMD-mediated pyroptosis.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Liver Failure, Acute/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/metabolism , Sepsis/complications , Toll-Like Receptor 4/metabolism , ADP-ribosyl Cyclase 1/genetics , Animals , Disease Models, Animal , Escherichia coli/immunology , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Liver/immunology , Liver/microbiology , Liver/pathology , Liver Failure, Acute/microbiology , Liver Failure, Acute/pathology , MAP Kinase Signaling System/genetics , MAP Kinase Signaling System/immunology , Male , Membrane Glycoproteins/genetics , Mice , Mice, Knockout , Pyroptosis/immunology , Sepsis/immunology , Sepsis/microbiology , Sepsis/pathologyABSTRACT
BACKGROUND AND AIM: Acute liver failure (ALF) poses a serious public health issue. The menstrual blood-derived mesenchymal stem cells (MenSCs) have been applied to cure various liver-related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF. METHODS: We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d-galactosamine (d-GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin-eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells. RESULTS: The MenSCs can decrease the lipid polysaccharide-induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated-NF-kBp65 (p-NF-kBp65), PI3K, and p-AKT, p-mTOR and p-IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes. CONCLUSIONS: The MenSCs can attenuate the ALF-induced liver injury via inhibition of TLR4-mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p-NF-κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above-mentioned effects.
Subject(s)
Adenosine A2 Receptor Agonists , Liver Failure, Acute , Menstruation , Mesenchymal Stem Cells , Adenosine A2 Receptor Agonists/immunology , Adenosine A2 Receptor Agonists/pharmacology , Animals , Cytokines/immunology , Disease Models, Animal , Inflammation/immunology , Inflammation/therapy , Liver Failure, Acute/chemically induced , Liver Failure, Acute/immunology , Liver Failure, Acute/mortality , Liver Failure, Acute/therapy , Mesenchymal Stem Cells/immunology , Mice , Mice, Inbred C57BLABSTRACT
Increasing evidence indicates that signal transducer and activator of transcription 3 (STAT3), a vital transcription factor, plays crucial roles in the regulation of inflammation. STAT3 has become a novel therapeutic target for intervention in inflammation-related disorders. However, it remains unclear whether STAT3 plays a part in acute hepatic damage. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated. The results showed that Stattic mitigated the hepatic morphologic abnormalities and decreased the level of aminotransferase in LPS/D-GalN-insulted mice. The results also indicated that Stattic decreased the levels of TNF-α and IL-6, prevented the activation of the caspase cascade, suppressed cleavage of PARP, and decreased the quantity of TUNEL-positive cells. These results suggest that Stattic provided protective benefits in LPS/d-GalN-induced hepatic damage, and the protective effects might be associated with its anti-inflammatory and anti-apoptotic effects. Therefore, STAT3 might become a novel target for intervening in inflammation-based and apoptosis-based hepatic disorders.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cyclic S-Oxides/therapeutic use , Liver Failure, Acute/drug therapy , Liver/pathology , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis , Caspases/metabolism , Cyclic S-Oxides/pharmacology , Disease Models, Animal , Galactosamine/metabolism , Humans , Interleukin-6/metabolism , Lipopolysaccharides/metabolism , Liver/immunology , Liver Failure, Acute/immunology , Male , Mice , Mice, Inbred BALB C , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Background: Severe hepatitis is a common cause of chronic or acute liver disease and autophagy might play an important role in cellular response to inflammation and injury. It has been reported that Ginsenoside-Rg1 (G-Rg1) has strong hepatoprotective effects for acute liver injury, but its protective mechanisms have not yet been elucidated. This study aims to explore the detailed molecular mechanisms of G-Rg1 on acute liver injury via autophagy. Methods: The role of G-Rg1 by autophagic induction was studied in the mouse model of acute liver injury which induced by carbon tetrachloride (CCl4). Liver function, inflammatory reaction and apoptosis were detected when autophagy has been inhibited by 3-MA or stimulated by RPA. MCC950 and ATP were applied to investigate the role of NLRP3 inflammasome in acute liver injury. The differential expression of NF-κB, NLRP3 inflammasome, caspase 1, caspase 3, IL-1ß, IL-18, LC3-I, LC3-II, Beclin-1, PINK1 and Parkin have been detected by the quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Results: G-Rg1 could decrease ALT, AST, TNF-α, IL-1ß and IL-6 in mice with CCl4-induced acute liver injury. The change of autophagy and apoptosis after the treatment of 3-MA or RPA demonstrated that the autophagy played a key role in the protective effect of G-Rg1 in acute liver injury. The enhancement of G-Rg1 promoted-autophagy resulted in the significant decrease in NF-κB, NLRP3 inflammasome, caspase 1, caspase 3, IL-1ß and IL-18, which suggesting that NF-κB/NLRP3 inflammasome signaling pathway was associated with the autophagy induced by G-Rg1 in acute liver injury. Conclusion: G-Rg1 ameliorated acute liver injury via the autophagy, which may be related to NF-κB/NLRP3 inflammasome signaling pathway.
Subject(s)
Autophagy/drug effects , Ginsenosides/pharmacology , Inflammasomes/antagonists & inhibitors , Liver Failure, Acute/drug therapy , Protective Agents/pharmacology , Animals , Carbon Tetrachloride/administration & dosage , Carbon Tetrachloride/toxicity , Disease Models, Animal , Ginsenosides/therapeutic use , Humans , Inflammasomes/metabolism , Liver/drug effects , Liver/immunology , Liver/pathology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/immunology , Liver Failure, Acute/pathology , Male , Mice , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Protective Agents/therapeutic use , Signal Transduction/drug effectsABSTRACT
The nucleotide-binding domain and leucine-rich repeat-containing family pyrin domain containing 3 (NLRP3) inflammasome is involved in various acute and chronic liver diseases, however, it is not clear whether NLRP3 contributes to d-Galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced acute liver failure (ALF). This study aims to investigate the role of NLRP3 inflammasome in D-GalN/LPS-induced fatal hepatitis. We found that Nlrp3-/- and WT mice showed similar mortality against a lethal dose of D-GalN/LPS treatment. Serum ALT and AST levels, as well as liver necrosis area and hepatocyte apoptosis, were not significantly different between Nlrp3-/- and WT mice at 6 h after D-GalN/LPS injection. Moreover, the numbers of intrahepatic F4/80+ cells and Ly6G+ cells were comparable in two genotype mice following D-GalN/LPS treatment. Besides, Nlrp3-/- mice had reduced IL-1ß levels but similar TNF-α, IL-6, and MCP-1 levels compared with WT mice upon D-GalN/LPS administration. Our findings revealed that NLRP3 ablation does not protect mice from D-GalN/LPS-induced fatal hepatitis and has a marginal effect on intrahepatic inflammatory response upon D-GalN/LPS treatment. This suggests that NLRP3 inflammasome does not appear to be a major contributor to D-GalN/LPS-induced ALF.
Subject(s)
Liver Failure, Acute/etiology , NLR Family, Pyrin Domain-Containing 3 Protein/physiology , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Galactosamine , Inflammasomes/metabolism , Inflammasomes/physiology , Interleukin-1beta/blood , Lipopolysaccharides , Liver Failure, Acute/chemically induced , Liver Failure, Acute/immunology , Liver Failure, Acute/metabolism , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Tumor Necrosis Factor-alpha/bloodABSTRACT
BACKGROUND AND OBJECTIVE: Acute liver failure (ALF) is a type of disease with high mortality and rapid progression with no specific treatment methods currently available. Glucocorticoids exert beneficial clinical effects on therapy for ALF. However, the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to determine. The purpose of this study was to investigate the specific immunological mechanism of dexamethasone (Dex) on treatment of ALF induced by lipopolysaccharide (LPS)/D-galactosamine (D-GaIN) in mice. METHODS: Male C57BL/6 mice were given LPS and D-GaIN by intraperitoneal injection to establish an animal model of ALF. Dex was administrated to these mice and its therapeutic effect was observed. Hematoxylin and eosin (H&E) staining was used to determine liver pathology. Multicolor flow cytometry, cytometric bead array (CBA) method, and next-generation sequencing were performed to detect changes of messenger RNA (mRNA) in immune cells, cytokines, and Kupffer cells, respectively. RESULTS: A mouse model of ALF can be constructed successfully using LPS/D-GaIN, which causes a cytokine storm in early disease progression. Innate immune cells change markedly with progression of liver failure. Earlier use of Dex, at 0 h rather than 1 h, could significantly improve the progression of ALF induced by LPS/D-GaIN in mice. Numbers of innate immune cells, especially Kupffer cells and neutrophils, increased significantly in the Dex-treated group. In vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor (Gr). Sequencing of Kupffer cells revealed that Dex could increase mRNA transcription level of nuclear receptor subfamily 4 group A member 1 (Nr4a1), and that this effect disappeared after Gr inhibition. CONCLUSIONS: In LPS/D-GaIN-induced ALF mice, early administration of Dex improved ALF by increasing the numbers of innate immune cells, especially Kupffer cells and neutrophils. Gr-dependent Nr4a1 upregulation in Kupffer cells may be an important ALF effect regulated by Dex in this process.
Subject(s)
Dexamethasone/pharmacology , Kupffer Cells/drug effects , Liver Failure, Acute/drug therapy , Nuclear Receptor Subfamily 4, Group A, Member 1/physiology , Receptors, Glucocorticoid/physiology , Animals , Dexamethasone/therapeutic use , Disease Models, Animal , Kupffer Cells/physiology , Liver Failure, Acute/immunology , Liver Failure, Acute/pathology , Male , Mice , Mice, Inbred C57BL , Nuclear Receptor Subfamily 4, Group A, Member 1/analysisABSTRACT
OBJECTIVES: Amphiregulin (Areg), a glycoprotein from the epidermal growth factor receptor (EGFR) ligand family, has a well-documented protective role against tissue injury; however, its effects on immune-mediated liver injury are still unclear. Here, we used a concanavalin A (ConA)-induced acute liver hepatitis model to explore the effects of Areg on immune-mediated acute liver injury. MATERIALS AND METHODS: Some C57BL/6 mice were administered ConA at a dose of 20 mg/kg (model mice), and some received 5 µg of Areg (treated mice). Then, their survival rates over 36 h were analyzed. After 5 h of treatment, liver function, hepatic histology, and apoptosis in liver tissue were investigated, and cytokine expression and neutrophil infiltration and activity in the liver were detected. Moreover, the protective effects of Areg were also evaluated without IL-22 in vivo. RESULTS: Our results showed that Areg administration increased acute liver failure (ALF) mouse survival, restored liver function, and alleviated liver damage. Interestingly, Areg administration increased IL-22 production in hepatic T cells and upregulated IL-22 concentrations in the serum and liver, whereas IL-22 neutralization completely abolished the therapeutic effect of Areg. Meanwhile, Areg administration was concomitant with increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, which are important in the hepatoprotective mechanism of IL-22. CONCLUSIONS: Areg showed direct protective effects against ConA-induced acute liver injury, which suggests the potential therapeutic application of Areg in immune-mediated ALF.
Subject(s)
Amphiregulin/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Interleukins/metabolism , Liver Failure, Acute/prevention & control , Liver/drug effects , T-Lymphocytes/drug effects , Animals , Apoptosis/drug effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Concanavalin A , Disease Models, Animal , Liver/immunology , Liver/metabolism , Liver/pathology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/immunology , Liver Failure, Acute/metabolism , Mice, Inbred C57BL , Phosphorylation , Proto-Oncogene Proteins c-bcl-2/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , bcl-X Protein/metabolism , Interleukin-22ABSTRACT
A 79-year-old man with liver failure, hypertension and hyperlipidemia presented with a 1.5-month history of progressive nasal crusting and pain on the inside of the nose, advancing into a necrotic columella and philtrum. On rigid endoscopy, debris extended to middle and inferior turbinate to midway posteriorly. Initial culture swabs and CT were negative. The patient underwent endoscopic biopsy of the lesion, with histopathological findings revealing abundant acute inflammation and minute fragments of atypical squamous epithelium, favouring reactive atypia. Non-invasive fungal hyphae were identified. Bacterial cultures revealed Staphylococcus epidermidis, Corynebacterium accolens, Curvularia species and Pseudomonas putida A current literature search failed to find other published cases of P. putida nasal infections. P. putida is generally difficult to isolate on swab culture as the surrounding tissue is necrosed; this case highlights the importance of reconsidering bacterial infection and obtaining a tissue biopsy in the case of non-healing necrotic-appearing tissue with negative culture swab and CT without evidence of mass.
Subject(s)
Immunocompromised Host , Liver Failure, Acute/immunology , Necrosis/microbiology , Nose/microbiology , Pseudomonas Infections/diagnosis , Pseudomonas putida/isolation & purification , Aged , Anti-Bacterial Agents/therapeutic use , Diagnosis, Differential , Humans , Male , Nose/pathology , Pseudomonas Infections/complications , Pseudomonas Infections/drug therapy , Pseudomonas Infections/pathologyABSTRACT
Acute liver failure (ALF) caused by hepatitis B virus (HBV) is common type of liver failure in the world, with high morbidity and mortality rates. However, the prevalence, genetic background and factors determining the development of HBV-related ALF are rarely studied. In this study, we examined three Gene Expression Omnibus (GEO) data sets by bioinformatics analysis to identify differentially expressed genes (DEGs), key biological processes and pathways. Immune infiltration analysis showed high immune cells infiltration in HBV-related ALF tissue. We then confirmed natural killer cells and macrophages infiltration in clinical samples by immunohistochemistry assay, implying these cells play a significant role in HBV-ALF. We found 1277 genes were co-up-regulated and that 1082 genes were co-down-regulated in the 3 data sets. Inflammation-related pathways were enriched in the co-up-regulated genes and synthetic metabolic pathways were enriched in the co-down-regulated genes. WGCNA also revealed a key module enriching in immune inflammation response and identified 10 hub genes, differentially expressed in an independent data set. In conclusion, we identified fierce immune inflammatory response to elucidate the immune-driven mechanism of HBV-ALF and 10 hub genes based on gene expression profiles.
Subject(s)
Hepatitis B virus/immunology , Hepatitis B/immunology , Immunity/genetics , Liver Failure, Acute/immunology , Computational Biology , Female , Gene Expression Profiling , Gene Expression Regulation/immunology , Gene Ontology , Hepatitis B/complications , Hepatitis B/genetics , Hepatitis B/virology , Hepatitis B virus/genetics , Hepatitis B virus/pathogenicity , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/virology , Liver Failure, Acute/complications , Liver Failure, Acute/genetics , Liver Failure, Acute/virology , Male , Protein Interaction Maps/geneticsABSTRACT
Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus D-galactosamine (D-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/D-Galn- and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells.