α4-Integrin Mediates Neutrophil-Induced Free Radical Injury to Cardiac Myocytes

Poon, Betty Y.; Ward, Christopher A.; Cooper, Conan B.; Giles, Wayne R.; Burns, Alan R.; Kubes, Paul

doi:10.1083/jcb.152.5.857

Cited by 43 publications

(39 citation statements)

References 42 publications

(51 reference statements)

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“…5, untreated neutrophils produced 0.06 Ϯ 0.03 nM/min/10 6 cells of O 2 Ϫ , and Con A-treated neutrophils produced 1.69 Ϯ 0.52 nM/min/10 6 cells. This level is comparable to that produced by murine emigrated neutrophils stimulated with zymosan-activated plasma (34) and less than half of that produced by fMLP-treated human neutrophils (35). Results obtained when Con A plus polymyxin B (10 g/ml, an endotoxin inhibitor) were given to the neutrophils were equivalent to that of Con A alone.…”

Section: Con a Stimulates Neutrophils To Produce Reactive Oxidantsmentioning

confidence: 53%

“…The shedding of L-selectin and increased expression of the ␤ 2 -integrin on neutrophils clearly indicates their activation by Con A, as does their production of reactive oxidants. The regulation of these molecules may be important, as other studies have shown that neutrophil emigration is a ␤ 2 -integrin-dependent process (45) and that oxidant release is limited from neutrophils until after they transmigrate and reach the extracellular space (34). Our results suggest that a second mechanism of action may exist wherein Con A binds directly to neutrophils, presumably via a mannose-sensitive receptor (42), and subsequently activates them independent of other leukocytes.…”

Section: Discussionmentioning

confidence: 73%

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Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Bonder¹,

Ajuebor

Zbytnuik³

et al. 2004

The Journal of Immunology

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177

166

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Leukocyte infiltration into the liver is paramount to the development of liver injury in hepatitis. Hepatitis occurring after the administration of Con A in mice is felt to be a T lymphocyte-mediated disease. In this study, we report that neutrophils are the key initiators of lymphocyte recruitment and liver injury caused by Con A. The objectives of this study were to investigate the involvement of neutrophils in Con A-induced hepatitis in vivo via intravital microscopy. After Con A administration, we observed a significant increase in leukocyte rolling flux, a decrease in rolling velocity, and an increase in leukocyte adhesion to the hepatic microvasculature. Fluorescence microscopy identified that within 4 h of Con A administration only a minority of the recruited leukocytes were T lymphocytes. Furthermore, immunohistochemistry showed a significant increase in neutrophils recruited to the liver post-Con A treatment in association with liver cell damage, as reflected by elevated serum alanine aminotransferase levels. Using flow cytometry, we observed that Con A could bind directly to neutrophils, which resulted in a shedding of L-selectin, an increase in β2-integrin expression, and the production of reactive oxidants. Following neutrophil depletion, a significant inhibition of Con A-induced CD4+ T lymphocyte recruitment to the liver resulted and complete reduction in hepatic injury, as assessed by serum alanine aminotransferase levels. In summary, the present data support the concept that neutrophils play an important and previously unrecognized role in governing Con A-induced CD4+ T cell recruitment to the liver and the subsequent development of hepatitis.

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Section: Con a Stimulates Neutrophils To Produce Reactive Oxidantsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 73%

Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Bonder¹,

Ajuebor

Zbytnuik³

et al. 2004

The Journal of Immunology

Self Cite

177

166

View full text Add to dashboard Cite

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“…For assessment of elastase release, supernatants were concentrated with microcons YM3 2-fold before being analyzed by ELISA following the manufacturer's instructions. ) by nonactivated PMNs was determined as the linear rate of superoxide dismutase-inhibitable reduction of cytochrome c as described (18,19). When indicated, PMNs were exposed to 52 nM MPO, 0.5 mg͞ml OZ, and 10 M formyl-MetLeu-Phe, respectively.…”

Section: Methodsmentioning

confidence: 99%

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins

Lau

Mollnau

Eiserich

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

388

309

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Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b͞CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NF B in PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide (O 2 •؊ ) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b͞CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease.atherosclerosis ͉ cytokine ͉ endothelium ͉ leukocyte ͉ nitric oxide

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“…18 The generation of superoxide anion by isolated human PMNs was determined as linear rate of superoxide dismutase-inhibitable reduction of cytochrome c as described. 19,20 The measurement was initiated by addition of cytochrome c (5 L, 100 mol/L) and simultaneous application of superoxide dismutase (50 L, 300 U/mL) to the samples.…”

Section: Effect Of Adma On Human Pmn Degranulation and Release Of Oxymentioning

confidence: 99%

Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase

et al. 2011

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Background-The nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and the leukocyte-derived hemoprotein myeloperoxidase (MPO) are associated with cardiovascular diseases. Activation of monocytes and polymorphonuclear neutrophils (PMNs) with concomitant release of MPO is regulated in a nitric oxide-dependent fashion. The aim of the study was to investigate a potential 2-way interaction between ADMA and MPO. Methods and Results-Ex vivo, ADMA uptake by isolated human PMNs, the principal source of MPO in humans, significantly impaired nitric oxide synthase activity determined by gas chromatography-mass spectrometry. In humans, short-term ADMA infusion (0.0125 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) significantly increased MPO plasma concentrations. Functionally, PMN exposure to ADMA enhanced leukocyte adhesion to endothelial cells, augmented NADPH oxidase activity, and stimulated PMN degranulation, resulting in release of MPO. In vivo, a 28-day ADMA infusion (250 mol ⅐ kg Ϫ1 ⅐ d Ϫ1 ) in C57Bl/6 mice significantly increased plasma MPO concentrations, whereas this ADMA effect on MPO was attenuated by human dimethylarginine dimethylaminohydrolase1 (hDDAH1) overexpression. Moreover, the MPO-derived reactive molecule hypochlorous acid impaired recombinant hDDAH1 activity in vitro. In MPO Ϫ/Ϫ mice, the lipopolysaccharide-induced increase in systemic ADMA concentrations was abrogated. Conclusions-ADMA profoundly impairs nitric oxide synthesis of PMNs, resulting in increased PMN adhesion to endothelial cells, superoxide generation, and release of MPO. In addition, MPO impairs DDAH1 activity. Our data reveal an ADMA-induced cycle of PMN activation, enhanced MPO release, and subsequent impairment of DDAH1 activity. These findings not only highlight so far unrecognized cytokine-like properties of ADMA but also identify MPO as a regulatory switch for ADMA bioavailability under inflammatory conditions. (Circulation. 2011;124:2735-2745.)

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α4-Integrin Mediates Neutrophil-Induced Free Radical Injury to Cardiac Myocytes

Cited by 43 publications

References 42 publications

Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins

Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase

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