Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly.

DeLeo, Frank R.; Renee, Jan; McCormick, Sally; Nakamura, Michio; Apicella, Michael A.; Weiss, Jerrold; Nauseef, William M.

doi:10.1172/jci949

Cited by 288 publications

(252 citation statements)

References 51 publications

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“…Endotoxin not only is a priming agent 6 but has been reported to fully activate neutrophils 12,13 by up-regulating the NADPH oxidase assembly. 32 The highest levels of endotoxin reported in patients with liver disease are found in portal venous blood, 33,34 highlighting the importance of the bowel and altered gut permeability as a possible source of endotoxin. 35 However, the difficulties with the measurement of endotoxin are reflected in the wide range of values in the literature and make this an unreliable indicator on which to base further management.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

et al. 2007

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Mortality in patients with alcoholic hepatitis (AH) remains high, and although corticosteroids are widely used for treatment, the results vary considerably. In AH, neutrophils are primed and infiltrate the liver to produce injury, but paradoxically, the main cause of death in such patients is infection. Our prospective study addressed this paradox of primed neutrophils on the one hand and increased risk of infection on the other. We hypothesized that the full activation of neutrophils by a humoral factor such as endotoxin renders them unable to respond to further bacterial challenge. We analyzed neutrophil oxidative burst and phagocytosis in whole blood by fluorescence-activated cell sorting analysis in 63 alcoholic patients with cirrhosis and patients with cirrhosis with superimposed AH (cirrhosis؉AH). In 16 patients, ex vivo studies determined whether the removal of endotoxin restored neutrophil function. A resting burst greater than or equal to 5%, indicating neutrophil activation and a reduced phagocytic capacity lower than 42%, was associated with significantly greater risk of infection, organ failure, and mortality. This defective neutrophil function was transmissible through patients' plasma to normal neutrophils, and patients' neutrophil function could be restored by normal plasma. The ex vivo removal of endotoxin from patients' plasma decreased the resting burst and increased the phagocytic function. Conclusions: Our study provides the rationale for a goal-directed approach to the management of patients with cirrhosis and AH, in which the assessment of neutrophil function may be an important biomarker to select patients for immunosuppressive therapy. The neutrophil dysfunction in cirrhosis and AH is reversible, with endotoxin-removal strategies providing new targets for intervention. (HEPATOLOGY 2007;46:831-840.)

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Section: Discussionmentioning

confidence: 99%

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

et al. 2007

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“…The NADPH oxidase assembles on flavocytochrome b 558 , which is expressed at low levels in the plasma membrane of resting cells. DeLeo and colleagues (3) reported that exposure of PMNs to LPS leads to an increase in the amount of flavocytochrome b 558 expressed in the plasma membrane from 25% to about 40% of total cellular content, suggesting that redistribution of this NADPH oxidase component is one mechanism by which the respiratory burst is primed. The results of the present study extend the observations of DeLeo et al (3) to a second priming agent, TNF␣, and provide further evidence that translocation of flavocytochrome b 558 to the plasma membrane is one mechanism by which PMN priming occurs.…”

Section: Discussionmentioning

confidence: 99%

“…In resting cells 10 -25% of flavocytochrome b 558 is located in the plasma membrane, with the remaining 75-90% distributed among secretory vesicles and gelatinase and specific granules (2,3).…”

Section: And Gp91mentioning

confidence: 99%

“…The increased expression of these components, however, cannot explain the increased respiratory burst response to a variety of stimuli. Recently, DeLeo et al (3) reported that LPS stimulated an increase in plasma membrane expression of flavocytochrome b 558 in PMNs, and subsequent stimulation of the cells with fMLP resulted in a 3-5-fold increase in translocation of p47…”

Section: And Gp91mentioning

confidence: 99%

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Priming of the Neutrophil Respiratory Burst Involves p38 Mitogen-activated Protein Kinase-dependent Exocytosis of Flavocytochrome b 558-containing Granules

Ward¹,

Nakamura²,

McLeish³

2000

Journal of Biological Chemistry

150

155

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The respiratory burst of human neutrophils is primed by a number of pro-inflammatory stimuli, including tumor necrosis factor-␣ (TNF␣) and lipopolysaccharide (LPS); however, the mechanism of priming remains unknown. LPS has been shown previously to increase membrane expression of flavocytochrome b 558 , a component of the NADPH oxidase. This study shows that TNF␣ also increases membrane expression of flavocytochrome b 558 . Mitogen-activated protein kinase (MAPK) modules have been implicated in the action of priming agents. Pharmacologic inhibitors of MAPKs, SB203580 and PD098059, revealed that priming of the respiratory burst and up-regulation of flavocytochrome b 558 are dependent on p38 MAPK but not on extracellular-signal regulated kinase (ERK). TNF␣ and LPS primed respiratory burst activity and increased membrane expression of CD35 and CD66b, specific markers of secretory vesicles and specific granules that contain flavocytochrome b 558 , with similar time courses and concentration dependences. These processes also required p38 MAPK but were independent of ERK. TNF␣ failed to prime respiratory burst activity or to increase membrane CD35 expression in enucleated neutrophil cytoplasts. These data suggest that one mechanism by which TNF␣ and LPS prime neutrophil respiratory burst activity is by increasing membrane expression of flavocytochrome b 558 through exocytosis of intracellular granules in a process regulated by p38 MAPK.

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“…Moore, Silliman, and others (52)(53)(54) have shown that PAF is a primary agent responsible for neutrophil priming in human trauma victims. In contrast, LPS and TNF␣ are the likely priming agents in acute pancreatitis (55,56), as well as in many patients with sepsis (57)(58)(59)(60)(61), and these agents have been directly implicated in causing acute lung injury (62)(63)(64)(65) and ischemia-induced acute renal failure (66).…”

mentioning

confidence: 99%

Distinct Ligand-dependent Roles for p38 MAPK in Priming and Activation of the Neutrophil NADPH Oxidase

Brown

Stewart

Bissonnette

et al. 2004

Journal of Biological Chemistry

103

108

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In response to certain cytokines and inflammatory mediators, the activity of the neutrophil NADPH oxidase enzyme is primed for enhanced superoxide production when the cells receive a subsequent oxidase-activating stimulus. The relative role of p38 MAPK in the priming and activation processes is incompletely understood. We have developed a 2-step assay that allows the relative contributions of p38 MAPK activity in priming to be distinguished from those involved in oxidase activation. Using this assay, together with in vitro kinase assays and immunochemical studies, we report that p38 MAPK plays a critical role in TNF␣ priming of the human and porcine NADPH oxidase for superoxide production in response to complement-opsonized zymosan (OpZ), but little, if any, role in neutrophil priming by platelet-activating factor (PAF) for OpZ-dependent responses. The OpZ-mediated activation process per se is independent of p38 MAPK activity, in contrast to oxidase activation by fMLP, where 70% of the response is eliminated by p38 MAPK inhibitors regardless of the priming agent. We further report that incubation of neutrophils with TNF␣ results in the p38 MAPK-dependent phosphorylation of a subpopulation of p47 phox and p67 phox molecules, whereas PAF priming results in phosphorylation only of p67 phox . Despite these phosphorylations, TNF␣ priming does not result in significant association of either of these oxidase subunits with neutrophil membranes, demonstrating that the molecular basis for priming does not appear to involve preassembly of the NADPH oxidase holoenzyme/cytochrome complex prior to oxidase activation.The neutrophil NADPH oxidase is a multiprotein enzyme that catalyzes the production of O 2 Ϫ from oxygen using NADPH as an electron donor (1, 2). The O 2 Ϫ is subsequently converted to powerful oxidizing agents such as hypohalides, singlet oxygen, peroxides, and chloramines, which together with proteases and ions, are primarily responsible for neutrophil-mediated killing of microorganisms (2-4). These oxidase products, however, are also highly destructive to nearby tissues (see Refs. 5-7). Consequently, tight temporal and spatial regulation of the oxidase is required so that it is activated only under appropriate circumstances.The NADPH oxidase holoenzyme consists of 6 subunits. In resting cells in which the oxidase is dormant, 4 of the subunits, p47 phox , p67 phox , p40 phox , and the small GTPase Rac2 are localized exclusively in the cytoplasm whereas the remaining two subunits, p22 phox and gp91 phox form a heterodimeric membrane-bound flavocytochrome known as cytochrome b 558 . Exposure of neutrophils to a variety of diverse stimuli results in translocation and docking of the cytosolic subunits with the membrane subunits (3, 8 -19), allowing electrons to flow from p67 phox -bound NADPH to molecular oxygen via an FAD moiety and two heme groups in the membrane-bound cytochrome (20). The subunit translocation and oxidase activation process is complex and requires multisite phosphorylation of the cytosolic subuni...

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Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly.

Cited by 288 publications

References 51 publications

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

Priming of the Neutrophil Respiratory Burst Involves p38 Mitogen-activated Protein Kinase-dependent Exocytosis of Flavocytochrome b 558-containing Granules

Distinct Ligand-dependent Roles for p38 MAPK in Priming and Activation of the Neutrophil NADPH Oxidase

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