Cryopreserved human alternatively activated macrophages promote resolution of acetaminophen-induced liver injury in mouse
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ABSTRACT:
PROVIDER: PRJNA1178661 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31138550_1.fastq.gz | Fastqsanger.gz | |||
| SRR31138550_2.fastq.gz | Fastqsanger.gz | |||
| SRR31138551_1.fastq.gz | Fastqsanger.gz | |||
| SRR31138551_2.fastq.gz | Fastqsanger.gz | |||
| SRR31138552_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute liver failure (ALF) is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper we present data using cryopreserved human alternatively activated macrophages (hAAMs) - which represent a potential, rapidly available, treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for N-acetylcysteine. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established.
2025-01-29 | GSE280475 | GEO
Project description:8 and 80 week old mice treated with acetaminophen
2023-05-01 | GSE149740 | GEO
Project description:Macrophage activation must be tightly controlled to prevent overzealous responses that cause self-damage. MicroRNAs have been shown to promote classical macrophage activation by blocking concomitant anti-inflammatory signals and transcription factors, but can also place restraints on activation by preventing excessive TLR-signalling. In contrast, the microRNA profile associated with alternatively activated macrophages and their role in regulating wound-healing or anti-helminthic responses has not yet been described. Utilizing an in vivo model of alternative activation, in which adult Brugia malayi nematodes are surgically implanted in the peritoneal cavity of mice, we examined the profile of microRNA expression in these alternatively activated macrophages and compared this to alternatively activated IL-4 receptor knockout macrophages and thioglycollate elicited macrophages. Peritoneal macrophages from BALB/c wild type or IL-4 receptor knockout mice were elicited with thioglycollate or using nemtodes (peritoneal implant of Brugia malayi). The latter leads to a population of alternatively activated macrophages. Microarray analysis was used to examine the microRNA profile of WT alternatively activated macrophages (n = 4), IL-4 receptor knockout alternatively activated macrophages (n = 4), WT thioglycollate elicited macrophages (n = 3) and IL-4 receptor knockout thioglycollate elicited macrophages (n = 3).
2012-08-07 | E-GEOD-35047 | biostudies-arrayexpress
Project description:Macrophage activation must be tightly controlled to prevent overzealous responses that cause self-damage. MicroRNAs have been shown to promote classical macrophage activation by blocking concomitant anti-inflammatory signals and transcription factors, but can also place restraints on activation by preventing excessive TLR-signalling. In contrast, the microRNA profile associated with alternatively activated macrophages and their role in regulating wound-healing or anti-helminthic responses has not yet been described. Utilizing an in vivo model of alternative activation, in which adult Brugia malayi nematodes are surgically implanted in the peritoneal cavity of mice, we examined the profile of microRNA expression in these alternatively activated macrophages and compared this to alternatively activated IL-4 receptor knockout macrophages and thioglycollate elicited macrophages.
2012-08-08 | GSE35047 | GEO
Project description:Background & aimFollowing acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI).MethodsSeveral phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice.ResultsBMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings.ConclusionWe identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.Lay summaryAfter an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.
| S-EPMC7378576 | biostudies-literature
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.
2016-02-16 | GSE70786 | GEO
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.
2016-02-16 | GSE70784 | GEO
Project description:Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing and 12 genes were detected with expression profiles significantly altered within 24hrs. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. Overdosed patients admitted to the emergency room. Five male and female individuals from 19 - 59 years old were admitted to the emergency room following an overdose on acetaminophen. The patients presented 12hrs to 4 days after ingestion. ALT and AST elevated peaking beyond 400 U/I and 120 U/I. Blood was collected 2 or 5 days following ingestion.
2016-02-16 | E-GEOD-70786 | biostudies-arrayexpress
Project description:Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation upon tissue damage have remained incompletely understood. Here, we show that the transcription factor GATA3 specifically controls the IL-4-independent differentiation of pro-resolving and reparative AAMs in response to injury and the necrotic cell-derived alarmin IL-33. In macrophages, IL-33 sequentially triggered an early expression of pro-inflammatory genes as well as a subsequent differentiation into AAMs. Global analysis of involved signaling events identified an IL-33-induced GATA-3 transcriptional module that specifically orchestrated AAM differentiation. IL-4-induced AAM differentiation, in contrast, was independent of GATA-3. Conditional deletion of GATA-3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs in vitro and diminished macrophage-mediated tissue repair in vivo. Our data thus identify an IL-33-GATA3 signaling axis that controls plasticity of macrophages in response to injury and fosters resolution of inflammation.
2021-10-06 | GSE151654 | GEO