MMP-8 genotypes influence the inflammatory response in human endotoxemia.
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ABSTRACT:
SUBMITTER: Rella JM
PROVIDER: S-EPMC7101851 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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Project description:IntroductionGlycyrrhizin (GL) was recently found to suppress high-mobility group box 1 (HMGB1)-induced injury by binding directly to it. However, the effect of GL on HMGB1 expression in endotoxemia as well as its underlying molecular mechanism remained unclear.MethodsTwenty-one pigs were divided into four groups: sham group (n=3), control group (n=6), ethyl pyruvate group (n=6) and glycyrrhizin group (n=6). Pigs were anesthetized, mechanically ventilated, monitored and given a continuous intravenous infusion of lipopolysaccharide (LPS). Twelve hours after the start of the LPS infusion, ethyl pyruvate (30 mg/kg/hr) or glycyrrhizin (1 mg/kg/hr) was administered for 12 hours. Systemic and pulmonary hemodynamics, oxygen exchange, and metabolic status were measured. The concentrations of cytokines in serum and the corresponding gene and protein expressions in tissue samples from liver, lungs, kidneys, small intestine and lymph nodes were measured.ResultsGL maintained the stability of systemic hemodynamics and improved pulmonary oxygen exchange and metabolic status. GL also attenuated organ injury and decreased the serum levels of HMGB1 and other pro-inflammatory cytokines by inhibiting their gene and protein expression.ConclusionsGL improved systemic hemodynamics and protected vital organs against porcine endotoxemia through modulation of the systemic inflammatory response. By reducing the serum level and gene expression of HMGB1 and other pro-inflammatory cytokines, GL may become a potential agent for the treatment of sepsis.
| S-EPMC3672474 | biostudies-literature
Project description:In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-? (TNF-?) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-? (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.ClinicalTrials (NCT): NCT01091571.
| S-EPMC3388652 | biostudies-literature
Project description:Mitochondrial DNA (mtDNA) plays a vital role as a damage-associated molecular pattern in sepsis being able to shape the immune response. Since pathogen recognition receptors of innate immune cells are activated by demethylated DNA only, we set out to investigate the amount of DNA methyltransferase 1 (DNMT1) in mitochondria and the extent of mtDNA methylation in a human endotoxin model. Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h. Subsequently, DNMT1 protein abundance was assessed in whole cells and a mitochondrial fraction. At the same time, methylation levels of mtDNA were quantified, and cytokine expression in the supernatant was measured. Despite increased cellular expression of DNMT1 after LPS stimulation, the degree of mtDNA methylation slightly decreased. Strikingly the mitochondrial protein abundance of DNMT1 was reduced by 50% in line with the lower degree of mtDNA methylation. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. Our data may hint at a protein import problem for DNMT1 into the mitochondria under LPS stimulation and suggest a role of demethylated mtDNA in the regulation of the inflammatory immune response.
| S-EPMC7650703 | biostudies-literature
Project description:Preclinical studies have shown that the endogenous nucleoside adenosine prevents excessive tissue injury during systemic inflammation. We aimed to study whether endogenous adenosine also limits tissue injury in a human in vivo model of systemic inflammation. In addition, we studied whether subjects with the common 34C > T nonsense variant (rs17602729) of adenosine monophosphate deaminase (AMPD1), which predicts increased adenosine formation, have less inflammation-induced injury.In a randomized double-blinded design, healthy male volunteers received 2 ng/kg E. Coli LPS intravenously with (n = 10) or without (n = 10) pretreatment with the adenosine receptor antagonist caffeine (4 mg/kg body weight). In addition, lipopolysaccharide (LPS) was administered to 10 subjects heterozygous for the AMPD1 34C > T variant.The increase in adenosine levels tended to be more pronounced in the subjects heterozygous for the AMPD1 34C > T variant (71 ± 22%, P=0.04), compared to placebo- (59 ± 29%, P=0.012) and caffeine-treated (53 ± 47%, P=0.29) subjects, but this difference between groups did not reach statistical significance. Also the LPS-induced increase in circulating cytokines was similar in the LPS-placebo, LPS-caffeine and LPS-AMPD1-groups. Endotoxemia resulted in an increase in circulating plasma markers of endothelial activation [intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)], and in subclinical renal injury, measured by increased urinary excretion of tubular injury markers. The LPS-induced increase of these markers did not differ between the three groups.Human experimental endotoxemia induces an increase in circulating cytokine levels and subclinical endothelial and renal injury. Although the plasma adenosine concentration is elevated during systemic inflammation, co-administration of caffeine or the presence of the 34C > T variant of AMPD1 does not affect the observed subclinical organ damage, suggesting that adenosine does not affect the inflammatory response and subclinical endothelial and renal injury during human experimental endotoxemia.ClinicalTrials (NCT): NCT00513110.
| S-EPMC3222030 | biostudies-literature
Project description:ContextHypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk.ObjectiveTo determine whether hypoglycemia modifies subsequent innate immune system responses.Design and settingSingle-blinded, prospective study of three independent parallel groups.Participants and interventionsTwenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin.Main outcome measuresWe studied in-vivo monocyte mobilization and monocyte-platelet interactions.ResultsHypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/?L vs euglycemia 20.66 ± 3.43/?L, P < 0.01; vs sham-saline 26.20 ± 3.86/?L, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/?L vs euglycemia 12.72 ± 2.42/?L, P < 0.001; vs sham-saline 19.05 ± 3.81/?L, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/?L vs 49.32 ± 6.41/?L, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/?L vs euglycemia 4.19 ± 1.08/?L, P < 0.05; vs sham-saline 3.81± 1.42/?L, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/?L vs euglycemia 2.86 ± 0.72/?L, P < 0.01; vs sham-saline 3.08 ± 1.01/?L, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05).ConclusionsHypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.
| S-EPMC6391720 | biostudies-literature
Project description:BackgroundLittle information is available about endotoxemia in donkeys. Characterizing the systemic inflammatory response (SIRS) to lipopolysaccharide (LPS) in donkeys would provide valuable clinical and therapeutic information. The effects of meloxicam on endotoxemia have not been studied in this species.ObjectivesTo study the pathophysiology and gene expression associated with experimentally induced endotoxemia, and evaluate the effects of meloxicam on experimentally induced endotoxemia in donkeys and in equine monocyte cultures.AnimalsSix healthy adult female donkeys.MethodsEndotoxemia was induced by an IV infusion of LPS for 30 minutes. Animals either received 20 mL of saline or 0.6 mg/kg of meloxicam IV after LPS infusion. The experiments lasted 6 hours. Blood samples were collected serially for hematology, serum biochemistry, interleukin measurement, and leukocyte gene expression analysis. Vital signs were recorded throughout the study. Monocyte cultures were used to test the effects of meloxicam on LPS-activated monocytes.ResultsLipopolysaccharide induced fever, leukopenia, and neutropenia of similar magnitude in both groups, but meloxicam attenuated increases in plasma lactate, tumor necrosis factor-alpha (TNFα), and interleukin 1β concentrations compared to controls. No differences were detected between groups for cytokine mRNA expression. Furthermore, meloxicam decreased TNFα release in LPS-activated monocyte cultures.Conclusions and clinical importanceMeloxicam could be a feasible option for the treatment of endotoxemia and SIRS in donkeys. Additional studies are necessary to investigate possible meloxicam-related posttranscriptional regulation and to compare this drug with other nonsteroidal anti-inflammatory drugs (NSAIDs) in animals with endotoxemia.
| S-EPMC7379049 | biostudies-literature
Project description:Gingival fibroblast-mediated extracellular matrix remodelling is implicated in the pathogenesis of periodontitis, yet the stimuli that regulate this response are not fully understood. The immunoregulatory adipokine leptin is detectable in the gingiva, human gingival fibroblasts express functional leptin receptor mRNA and leptin is known to regulate extracellular matrix remodelling responses in cardiac fibroblasts. We therefore hypothesised that leptin would enhance matrix metalloproteinase secretion in human gingival fibroblasts.We used in vitro cell culture to investigate leptin signalling and the effect of leptin on mRNA and protein expression in human gingival fibroblasts. We confirmed human gingival fibroblasts expressed cell surface leptin receptor, found leptin increased matrix metalloproteinase-1, -3, -8 and -14 expression in human gingival fibroblasts compared to unstimulated cells, and observed that leptin stimulation activated MAPK, STAT1/3 and Akt signalling in human gingival fibroblasts. Furthermore, leptin synergised with IL-1 or the TLR2 agonist pam2CSK4 to markedly enhance matrix metalloproteinase-1 and -3 production by human gingival fibroblasts. Signalling pathway inhibition demonstrated ERK was required for leptin-stimulated matrix metalloproteinase-1 expression in human gingival fibroblasts; whilst ERK, JNK, p38 and STAT3 were required for leptin+IL-1- and leptin+pam2CSK4-induced matrix metalloproteinase-1 expression. A genome-wide expression array and gene ontology analysis confirmed genes differentially expressed in leptin+IL-1-stimulated human gingival fibroblasts (compared to unstimulated cells) were enriched for extracellular matrix organisation and disassembly, and revealed that matrix metalloproteinase-8 and -12 were also synergistically upregulated by leptin+IL-1 in human gingival fibroblasts.We conclude that leptin selectively enhances the expression and secretion of certain matrix metalloproteinases in human gingival fibroblasts, and suggest that gingival fibroblasts may have an ECM-degrading phenotype during conditions of hyperleptinaemia (e.g., obesity, type 2 diabetes mellitus, exogenous leptin therapy).
| S-EPMC4734666 | biostudies-literature
Project description:Sepsis intervention studies need better patient stratification methods, and one way to realize this is the introduction of stable biomarkers. A set of recently developed novel biomarkers, based upon precursor-fragments of short-lived hormones, was previously shown to be increased during sepsis. However, it is not known whether these biomarkers are influenced by sepsis intervention strategies. Therefore we investigated the markers in a model of human endotoxemia intervened by increasing doses of prednisolone.Prospective, open-label study in a specialized clinical research unit of a university hospital.Thirty-two healthy male volunteers.Subjects received prednisolone orally at doses of 0, 3, 10 or 30 mg (n=8 per group) at 2 h before intravenous injection of Escherichia coli lipopolysaccharide (LPS) (4 ng/kg). Blood samples were drawn during 24 h after LPS injection.LPS injection caused an increase in levels of midregional pro-adrenomedullin (MR-proADM), midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine-vasopressin (CT-proAVP) and procalcitonin (PCT). Prednisolone caused a dose dependent inhibition of MR-proADM, MR-proANP and CT-proAVP levels.These results show that a set of novel, highly stable sepsis biomarkers was increased during human endotoxemia and was dose-dependently inhibited by corticosteroid pre-treatment.
| S-EPMC2244699 | biostudies-other
Project description:In 2018, 228 million cases and 405,000 malaria-associated deaths were reported worldwide with a majority being in Africa. A wide range of factors, including parasitemia, host immunity, inflammatory responses to infection, and host hemoglobin genotype, mediate the severity of malaria. Among the hemoglobinopathies, hemoglobin S (HbS) is caused by a single amino acid substitution of Glutamic Acid replaced by Valine at the sixth position of the beta-globin chain (E6V). Hemoglobin C (HbC) on the other hand, involves a single amino acid substitution of Glutamic Acid by a Lysine (E6K), which has received the most attention. These substitutions alter the stability of Hb leading to wide-ranging hematological disorders. The homozygous state of hemoglobin S (HbSS) results in sickle cell anemia (SCA) whereas the heterozygous state (HbAS) results in sickle cell trait (SCT). Both mutations are reported to mediate the reduction in the severity and fatality of Plasmodium falciparum malaria. The mechanism underlying this protection is poorly understood. Since both malaria and sickle cell disease (SCD) are associated with the destruction of erythrocytes and widespread systemic inflammation, identifying which inflammatory factor(s) mediate susceptibility of individuals with different hemoglobin genotypes to Plasmodium infection could result in the discovery of new predictive markers and interventions against malaria or SCD severity. We hypothesized that hemoglobin genotypes modulate the inflammatory response to Plasmodium infection. We conducted a cross-sectional study in Ghana, West Africa, between 2014 and 2019 to ascertain the relationships between blood inflammatory cytokines, Plasmodium infection, and hemoglobin genotype. A total of 923 volunteers were enrolled in the study. A total of 74, age and sex-matched subjects were identified with various genotypes including HbAS, HbAC, HbSS, HbSC, HbCC, or HbAA. Complete blood counts and serum inflammatory cytokine expression levels were assessed. The results indicate that differential expression of CXCL10, TNF-α, CCL2, IL-8, and IL-6 were tightly linked to hemoglobin genotype and severity of Plasmodium infection and that these cytokine levels may be predictive for susceptibility to severe malaria or SCD severity.
| S-EPMC7786007 | biostudies-literature
Project description:Sepsis is a serious clinical condition characterized by a systemic inflammatory response, a leading cause of acute liver and kidney injury, and is associated with a high morbidity and mortality. Understanding the molecular mechanisms underlying the acute liver and kidney injury is crucial for developing an effective therapy. Golgi apparatus plays important roles and has various substrates mediating cellular stress responses. Golgi phosphoprotein 3 (GOLPH3), linking Golgi membranes to the cytoskeleton, has been identified as an important oncogenic regulator; however, its role in endotoxemia-induced acute liver and kidney injury remains elusive. Here, we found that upregulation of GOLPH3 was associated with endotoxemia-induced acute liver and kidney injury. Lipopolysaccharide (LPS) treatment increased Golgi stress and fragmentation, and associated pro-inflammatory mediator (Tnfα, IL-6, and IL-1β) production in vivo and in vitro. Interestingly, the downregulation of GOLPH3 significantly decreased LPS-induced Golgi stress and pro-inflammatory mediators (Tnfα, IL-6, Mcp1, and Nos2), and reversed apoptotic cell deaths in LPS-treated hepatocytes and renal tubular cells. GOLPH3 knockdown also reduced inflammatory response in LPS-treated macrophages. The AKT/NF-kB signaling pathway was suppressed in GOLPH3 knockdown, which may be associated with a reduction of inflammatory response and apoptosis and the recovery of Golgi morphology and function. Taken together, GOLPH3 plays a crucial role in the development and progression of acute liver and kidney injury by promoting Golgi stress and increasing inflammatory response and apoptosis, suggesting GOLPH3 as a potential therapeutic target for endotoxemia-induced tissue injury.
| S-EPMC10361983 | biostudies-literature