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PubMed: 28716864

Title
Alpha1-antitrypsin binds hemin and prevents oxidative activation of human neutrophils: putative pathophysiological significance.
Journal
Journal of leukocyte biology
Volume
102
Issue
None
Pages
1127-1141
Date
2017-10-01
Authors
Chen R | Chorostowska-Wynimko J | Gueler F | Immenschuh S | Janciauskiene S | Madyaningrana K | Mahadeva R | Tumpara S | Vijayan V | Welte T | Wiese M | Wrenger S

Evidence e063b737e9
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As shown in Fig. 11A, in hemin-treated neutrophils, PKC activity increased by ;2.6-fold (P , 0.001) relative to controls.

a(CHEBI:heme) increases act(p(PFAM:"Pkinase_C")) View Subject | View Object

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Evidence 2a92f6148a
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Exposure of cells to hemin or hemin plus A1AT did not change TLR2/4 mRNA levels (Fig. 12).

a(CHEBI:heme) causesNoChange r(HGNC:TLR2) View Subject | View Object

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a(CHEBI:heme) causesNoChange r(HGNC:TLR4) View Subject | View Object

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complex(a(CHEBI:hemin), p(HGNC:SERPINA1)) causesNoChange r(HGNC:TLR2) View Subject | View Object

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complex(a(CHEBI:hemin), p(HGNC:SERPINA1)) causesNoChange r(HGNC:TLR4) View Subject | View Object

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Evidence abf5a4eaeb
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As expected, incubation of neutrophils with hemin resulted in a significant number of cells producing ROS (Fig. 8A and B).

a(CHEBI:heme) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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a(MESH:"Reactive Oxygen Species") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence bfe0e85469
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For instance, earlier studies have demonstrated that neutrophil elastase degrades the hemoglobin liberating free hemin that induces ROS production.

a(CHEBI:heme) increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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neutrophil
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Serum
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Malaria
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deg(p(HGNC:HBB)) increases a(CHEBI:heme) View Subject | View Object

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neutrophil
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Malaria
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p(HGNC:ELANE) increases deg(p(HGNC:HBB)) View Subject | View Object

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neutrophil
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Malaria
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Evidence 7a3f1b0fb9
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Hemin induces expression of the adhesion molecules on endothelial cells [7, 8] and enables firm neutrophil attachment to the endothelium and initiation of an inflammatory response [9, 10].

a(CHEBI:heme) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

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endothelial cell
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a(CHEBI:heme) positiveCorrelation a(MESH:"Cell Adhesion Molecules") View Subject | View Object

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endothelial cell
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a(MESH:"Cell Adhesion Molecules") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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endothelial cell
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bp(GO:"inflammatory response") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence ab4269fc6c
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As predicted, HMOX1 expression levels (means 6 SD) in hemin-treated cells were much higher (7.25 6 5.02, n = 12; P , 0.001) than in nontreated controls (0.14 6 0.18, n = 9) or A1AT-treated cells (0.09 6 0.1, n = 9).

a(CHEBI:heme) positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

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p(HGNC:HMOX1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 5d4409c878
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Based on the previous findings that hemin induces neutrophil adhesion to endothelial cells [8] and that A1AT protects endothelial cells from neutrophil adhesion induced by fMLP [27], we investigated whether A1AT, as a scavenger of hemin, can prevent hemin-induced neutrophil adhesion to HUVECs. As shown in Fig. 4, neutrophils treated with hemin or fMLP (used as a positive control) exhibited a 3-fold higher adhesion to HUVECs compared with controls. However, the adherence of neutrophils treated with hemin/A1AT did not differ from controls (Fig. 4).

a(CHEBI:heme) positiveCorrelation a(MESH:"Cell Adhesion Molecules") View Subject | View Object

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a(MESH:"Cell Adhesion Molecules") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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endothelial cell
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p(HGNC:SERPINA1) decreases a(MESH:"Cell Adhesion Molecules") View Subject | View Object

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Evidence 082438d76a
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Free hemin is a cytotoxic molecule that mediates oxidative stress, endothelial activation, and inflammation, and it is implicated in malaria pathogenesis [40] and AKI, among others [41].

a(CHEBI:heme) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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neutrophil
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a(CHEBI:heme) positiveCorrelation bp(GO:"endothelial cell activation") View Subject | View Object

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neutrophil
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Malaria
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a(CHEBI:heme) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

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neutrophil
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Malaria
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bp(GO:"endothelial cell activation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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neutrophil
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Malaria
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bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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neutrophil
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Malaria
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path(MESH:Inflammation) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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neutrophil
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Evidence 2c21cc7ad2
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With the triggering of the oxidative burst and modification of actin cytoskeleton dynamics, hemin also induces neutrophil migration [10]

a(CHEBI:heme) increases bp(GO:"neutrophil migration") View Subject | View Object

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Introduction

Evidence d1c98cdba5
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Of note, hemin significantly lowered LRP1 mRNA, whereas hemin/A1AT had no significant effect on LRP1 expression relative to controls (Supplemental Fig. 2).

a(CHEBI:heme) increases r(HGNC:LRP1) View Subject | View Object

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complex(a(CHEBI:hemin), p(HGNC:SERPINA1)) causesNoChange r(HGNC:LRP1) View Subject | View Object

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Evidence 7b6f3de087
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In contrast, hemin strongly increased the percentage of neutrophils positive for surface expression of vimentin [mean (SD) 48.8% (20) vs. 2.5% (0.8), n = 5; P , 0.001].

a(CHEBI:heme) increases p(HGNC:VIM) View Subject | View Object

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Evidence e57b0fd465
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Incubation of neutrophils with 4 mM hemin resulted in an ;2-fold increase in CXCL8 mRNA expression and in a significant increase in released and cell-associated levels of IL-8 protein compared with the nontreated controls or A1AT-treated cells (Fig. 7A–C).

a(CHEBI:heme) increases r(HGNC:CXCL8) View Subject | View Object

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a(CHEBI:heme) increases p(HGNC:CXCL8) View Subject | View Object

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Evidence 70d9ee465a
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As shown in Fig. 10, when neutrophils were incubated for 2 h with hemin, GR activity decreased by 50% (P , 0.05).

a(CHEBI:heme) decreases act(p(HGNC:NR3C1)) View Subject | View Object

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Evidence 4118e7f86d
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Under the same experimental conditions, addition of 1 mg/ ml A1AT significantly prevented hemin-induced neutrophil spreading and adhesion (Fig. 3A).

p(HGNC:SERPINA1) decreases bp(GO:"neutrophil migration") View Subject | View Object

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endothelial cell
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p(HGNC:SERPINA1) decreases bp(MESH:"Cell Adhesion") View Subject | View Object

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Evidence 87fd9102db
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In the presence of A1AT, this latter effect of hemin was significantly inhibited and did not differ from controls (Fig. 5B).

p(HGNC:SERPINA1) decreases p(HGNC:VIM) View Subject | View Object

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Evidence 23312e0db6
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In the presence of A1AT, hemin-induced release of IL-8 protein was inhibited significantly (Fig. 7B).

p(HGNC:SERPINA1) decreases p(HGNC:CXCL8) View Subject | View Object

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Evidence db2f01759c
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The ability of hemin to trigger ROS production in neutrophils was abrogated significantly in the presence of A1AT (Fig. 8).

p(HGNC:SERPINA1) decreases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Evidence 42466e2ec0
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In the presence of A1AT, hemin effect on HMOX1 expression was diminished significantly (Fig. 9A).

p(HGNC:SERPINA1) decreases p(HGNC:HMOX1) View Subject | View Object

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Evidence c3990b267d
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Under the same experimental conditions, A1AT blocked the ability of hemin to reduce GR activity (Fig. 10).

p(HGNC:SERPINA1) positiveCorrelation act(p(HGNC:NR3C1)) View Subject | View Object

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neutrophil
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act(p(HGNC:NR3C1)) positiveCorrelation p(HGNC:SERPINA1) View Subject | View Object

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Evidence 4effed19da
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However, in the presence of A1AT, hemin did not change PKC activity significantly.

p(HGNC:SERPINA1) negativeCorrelation act(p(PFAM:"Pkinase_C")) View Subject | View Object

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neutrophil
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act(p(PFAM:"Pkinase_C")) negativeCorrelation p(HGNC:SERPINA1) View Subject | View Object

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neutrophil
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Evidence 49f6aaebde
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The main function of A1AT is to inhibit neutrophil elastase and proteinase 3.

p(HGNC:SERPINA1) decreases p(HGNC:ELANE) View Subject | View Object

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neutrophil
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Malaria
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p(HGNC:SERPINA1) decreases p(HGNC:PRTN3) View Subject | View Object

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Evidence a9ac131af2
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However A1AT has broader functions [26, 27], abrogating inflammation via both enzyme-inhibitory and noninhibitory mechanisms [47].

p(HGNC:SERPINA1) decreases path(MESH:Inflammation) View Subject | View Object

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neutrophil
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Evidence c0768d91ca
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Along with this, A1AT inhibited hemin to induce PKC phosphorylation, which is an essential step for the production of ROS [9].

p(HGNC:SERPINA1) decreases p(PFAM:"Pkinase_C", pmod(Ph)) View Subject | View Object

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neutrophil
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Malaria
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Evidence 845a90b29c
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Therapy with A1AT slightly reduced serum CXCL1/KC levels (Fig. 15).

p(MGI:Serpina1a) decreases p(MGI:Cxcl1) View Subject | View Object

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