Phagocytic Activity and Oxidative Burst of Granulocytes in Persons with Myeloperoxidase Deficiency

Gerber, Claudia E.; Kuçi, Selim; Zipfel, Matthias; Niethammer, D.; Bruchelt, Gernot

doi:10.1515/cclm.1996.34.11.901

Cited by 28 publications

(24 citation statements)

References 23 publications

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“…Thus, the role of H 2 O 2 as a primary oxidant or as simply the catalyst for MPO activity had been indefinable. The converse is not true; MPO is a significant consumer of H 2 O 2 and MPO deficiency elevates H 2 O 2 levels from zebrafish to humans (Gerber et al, 1996;Pase et al, 2012). Except for PF-1355 reported here, the only MPO-specific inhibitors were just recently described (Tidén et al, 2011) and now offer the potential to elucidate the role of MPO activity in physiology and disease.…”

Section: Discussionmentioning

confidence: 79%

PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis

Zheng

Warner

Ruggeri

et al. 2015

J Pharmacol Exp Ther

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Small vessel vasculitis is a life-threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been associated with vasculitis, disseminated vascular inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to vascular injury by 1) catabolizing nitric oxide, impairing vasomotor function; 2) causing oxidative damage to lipoproteins and endothelial cells, leading to atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and thrombosis. Here we report a selective 2-thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) and demonstrate that MPO is a critical mediator of vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti-glomerular basement membrane disease, formerly known as Goodpasture disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases.

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Section: Discussionmentioning

confidence: 79%

PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis

Zheng

Warner

Ruggeri

et al. 2015

J Pharmacol Exp Ther

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“…The level of reactive oxygen generated by phagocytes was assayed by CL measurements using lucigenin or luminol. Lucigenin-amplified CL predominantly monitors the initial O 2 Ϫ production, whereas luminol is a suitable substrate to measure reactions linked to the release of lysosomal MPO into the surrounding medium (2,19,23,43). Porin-treated PMN showed a reduction in luminol-enhanced CL when they were stimulated with zymosan, latex particles, gonococci, or cytochalasin B plus FMLP (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This CL reaction can be amplified by addition of the indicators luminol or lucigenin (4,14). These indicators measure different stages of the reaction since lucigenin reacts directly with O 2 Ϫ , whereas luminol-enhanced light emission is due to oxidation of luminol by oxygen derivatives resulting primarily from MPO-catalyzed reactions (16,19,23,43).…”

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confidence: 99%

Neisseria gonorrhoeaePorin Modifies the Oxidative Burst of Human Professional Phagocytes

et al. 2000

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A hallmark of infection with the gram-negative bacterium Neisseria gonorrhoeae is the local infiltration and subsequent activation of polymorphonuclear neutrophils. Several gonococcal outer membrane proteins are involved in the interaction with and the activation of these phagocytes, including gonococcal porin, the most abundant protein in the outer membrane. Previous work suggests that this porin plays a role in various cellular processes, including inhibiting neutrophils activation and phagosome maturation in professional phagocytes. Here we investigated the ability of porin to modify the oxidative metabolism of human peripheral blood neutrophils and monocytes in response to particulate stimuli (including live gonococci) and soluble agents. The activation of the oxidative metabolism was determined by chemiluminescence amplified with either luminol or lucigenin. We found that treatment of the phagocytes with porin inhibits the release of reactive oxygen species measured as luminol-enhanced chemiluminescence in response to zymosan, latex particles, and gonococci. The engulfment of these particles was not, however, affected by porin treatment. Similar effects of porin on the chemiluminescence response were observed in cytochalasin B-treated neutrophils exposed to the soluble chemotactic peptide N-formylmethionyl-leucyl-phenylalanine. This indicates that porin selectively inhibits granule fusion with those cellular membranes that are in direct contact with porin, namely, the phagosomal and plasma membranes. This porin-induced downregulation of oxidative metabolism may be a potent mechanism by which gonococci modulate oxygen-dependent reactions by activated phagocytes at inflammation sites.Professional phagocytes such as polymorphonuclear neutrophils (PMN) and peripheral blood monocytes play a crucial role in the host defense against infection with microorganisms.

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“…ROS production was measured by luminol-enhanced chemiluminescence as described by Gerber (18). Chemiluminescence assay was performed on a Biolumat (LB 9505; Berthold, Wildbad, Germany).…”

Section: Methodsmentioning

confidence: 99%

Diminished Phagocytosis-Induced Cell Death (PICD) in Neonatal Monocytes upon Infection with Escherichia coli

et al. 2008

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An imbalance in apoptosis or survival of immune cells plays an essential role in the pathophysiology of sepsis. Phagocytosis-induced cell death (PICD) is a common result of the pathogenhost cell interaction mediated by reactive oxygen species (ROS). Neonatal sepsis is frequently characterized by hyperinflammation. Cord blood monocytes (CBMO) are equivalent to monocytes of adults [peripheral blood monocytes (PBMO)], both in terms of phagocytosis and killing of Escherichia coli. We investigated whether CBMO are less sensitive toward PICD compared with PBMO. Monocytes were infected with green fluorescent protein (GFP)-labeled E. coli. Phagocytic activity, cell-count, Annexin V staining, hypoploid DNA content, CD95 and CD95L expression, and caspase-8 and -9 activities were analyzed by flow cytometry, ROS production by chemiluminescence, and CD95L mRNA expression by reverse-transcriptase polymerase chain reaction. With equal phagocytic activity and ROS production, PBMO cell count was decreased by 82 Ϯ 6% versus 28 Ϯ 8% for CBMO after infection. Annexin V binding was enhanced fivefold on PBMO; 56 Ϯ 15% of PBMO showed a hypodiploid DNA content compared with 9 Ϯ 6% of CBMO. Caspases CD95L and CD95L mRNA were up-regulated in PBMO. Our results indicate that CBMO are less sensitive toward E. coli-mediated PICD than PBMO. Modifying monocyte apoptosis may be a target for future interventions in sepsis. (Pediatr Res 63: [33][34][35][36][37][38] 2008)

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Phagocytic Activity and Oxidative Burst of Granulocytes in Persons with Myeloperoxidase Deficiency

Cited by 28 publications

References 23 publications

PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis

PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis

Neisseria gonorrhoeaePorin Modifies the Oxidative Burst of Human Professional Phagocytes

Diminished Phagocytosis-Induced Cell Death (PICD) in Neonatal Monocytes upon Infection with Escherichia coli

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