Acute increases of O‐GlcNAcylation reduces sepsis‐associated mortality (837.8)
Vânia C. OlivonRaphael Gomes FerreiraFabíola MestrinerJosé C. Alves‐FilhoFernando Q. CunhaRita C. Tostes
0
Citation
0
Reference
10
Related Paper
Abstract:
The post‐translational modification of proteins by O ‐GlcNAcylation ( O ‐GlcNAc) is highly dynamic and modulates cell‐signaling processes. Acute increases in O ‐GlcNAc levels reduce migration of inflammatory cells and the release of pro‐inflammatory mediators, important events in sepsis caused by bacterial infection or multiple non‐infectious causes. This study tested the hypothesis that acute increases of O ‐GlcNAc levels reduce mortality and inflammatory processes in experimental models of sepsis. C57/BL6 mice were used in experimental sepsis protocols cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)‐induced severe and mild sepsis. Glucosamine treatment (300mg/Kg, i.v. 30 min. before the sepsis induction) acutely increased vascular and spleen O ‐GlcNAc levels and increased survival of mice with LPS‐induced sepsis (50%) and CLP sepsis (40%). In mice with LPS‐induced sepsis, glucosamine also reduced neutrophil migration to the peritoneal cavity (severe LPS sepsis, p <0.05; mild LPS sepsis, p <0.01), myeloperoxidase (MPO) activity of lung neutrophils (severe LPS sepsis, p <0.01; mild LPS sepsis, p <0.001) and aortic IL‐1beta mRNA expression (mild LPS sepsis, p <0.01). In the CLP model, glucosamine reduced MPO activity of lung neutrophils (p<0.05). These results show that glucosamine‐induced acute increases of O ‐GlcNAc levels increase survival in the CLP and LPS experimental models of sepsis. This study suggests that the O ‐GlcNAc pathway represents a potential target in sepsis‐related systemic inflammatory responses. Grant Funding Source : CNPq, CAPES and FAPESPHypochlorous acid
Cite
Citations (0)
The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.
Neutrophil Extracellular Traps
Eosinophil peroxidase
Cite
Citations (106)
Abstract We investigated interaction between antibodies directed against myeloperoxidase (anti‐MPO) and myeloperoxidase (MPO) with chemiluminescence. Whole serum diluted 1/10 containing circulating anti‐MPO antibodies as well as serum from normal blood donors inhibited myeloperoxidase (MPO) enzyme activity when incubated with 1.42 m̈g MPO. When further diluted the inhibitory effect was abolished. Incubation with purified human lgG fraction of anti‐MPO, did not cause any inhibition when diluted 1/10 and incubated with 1.42 m̈g MPO. When adding MPO to normal sera a rapid increase of the enzyme activity was seen above 5 m̈g, and the inhibitory effect was completely abolished when 10 m̈g was added. Both sera from healthy individuals, as well as sera from patients with circulating anti‐MPO inhibited MPO activity. The inability of pure lgG fractions from anti‐MPO sera to inhibit MPO enzyme activity, clearly indicates the presence of an inhibitory factor, unspecific or specific, in serum.
Luminol
Cite
Citations (1)
Antigenicity
Hypochlorous acid
Hypochlorite
Cite
Citations (5)
The heme-containing enzyme myeloperoxidase (MPO) is secreted from polymorphonuclear leukocytes and monocytes. It is involved in host defence and inflammation by oxidation of numerous small molecules. This review summarises our current results on the determination of redox properties of all intermediates involved in the halogenation and peroxidase cycle of MPO. The standard reduction potentials of the redox couples compound I/native MPO, compound I/compound II of MPO, and compound II/native MPO have been determined to be 1.16 V, 1.35 V, and 0.97 V, respectively, at pH 7 and 25°C. Thus, for the first time, a full description of these important thermodynamic parameters of myeloperoxidase has been performed, allowing a better understanding of its extraordinary reactivity.
Hemeprotein
Hypochlorous acid
Cite
Citations (85)
Diethanolamine
Cite
Citations (43)
Myeloperoxidase (MPO)-derived oxidants have emerged as a key contributor to tissue damage in inflammatory conditions such as cardiovascular disease. Pro-myeloperoxidase (pro-MPO), an enzymatically active precursor of myeloperoxidase (MPO), is known to be secreted from cultured bone marrow and promyelocytic leukemia cells, but evidence for the presence of pro-MPO in circulation is lacking. In the present study, we used a LC-MS/MS in addition to immunoblot analyses to show that pro-MPO is present in human blood plasma. Furthermore, we found that pro-MPO was more frequently detected in plasma from patients with myocardial infarction compared to plasma from control donors. Our study suggests that in addition to mature MPO, circulating pro-MPO may cause oxidative modifications of proteins thereby contributing to cardiovascular disease.
Cite
Citations (22)
Myeloperoxidase: New Roles for an Old Molecule Myeloperoxidase (MPO) is a member of the heme peroxidase-cyclooxygenase superfamily. It is abundantly expressed in neutrophils and monocytes. During inflammation MPO is released from leukocytes and catalyzes the formation of several reactive species and tissue damage. In this article we present state of the art knowledge on the general properties, biosynthesis and processing and trafficking of MPO. The basic functions of MPO in inflammation and oxidative stress are discussed in detail. This article also summarizes the studies that investigated the relationship between MPO and cardiovascular disease. An overview of the assays for determination of MPO, the sample type and preanalytical procedures is given. Future studies are needed before this marker is introduced into routine clinical practice.
Cite
Citations (8)
IC50
Hypochlorous acid
Cite
Citations (57)
Background : MPO is an antimicrobial enzyme in the primary granule of neutrophil. MPO exhibits MPO-I, MPO-II, MPO-III using chromatography in human peripheral leukocytes. we investigated MPO isozymes from human leukocytes of peripheral blood. Methods : Neutrophils were prepared from 58mL of peripheral blood in the group of normal persons (normal group) and the group of patients with neutrophilia (patient group). Their cells were adjusted to 2.4 cells and sonified. We got finally the crude MPO from which native PAGE was performed and treated with diaminobenzine and . Results : Normal neutrophil MPO had MPO-1 and MPO-2. The expression rates of MPO-1 and that of MPO-2 were respectively 100%, 67.5% in the normal group and 56.6%, 30.2% in the patient group (P=0.000, P=0.000). The expression rate of combined MPO-1 and MPO-2 and that of MPO-1 without MPO-2 were respectively 67.6%, 32.4% in the normal group and 28.3%, 28.3% in the patient group (P=0.000, P=0.000). The expression of MPO-2 without MPO-1 and that of no MPO isozymes were respectively 0.0%, 0.0% in the normal group and 1.9%, 41.5% in the patient group (P=0.000, P=0.000). Conclusion : Normal neutrophil MPO expresses MPO-1 and MPO-2 usig native PAGE. The main MPO isozyme is MPO-1. Expressions of MPO isozymes are variable in the patient group.
Neutrophilia
Cite
Citations (2)