Taming the neutrophil: calcium clearance and influx mechanisms as novel targets for pharmacological control

Tintinger, Gregory Ronald; Steel, Helen C.; Anderson, Ronald

doi:10.1111/j.1365-2249.2005.02800.x

Cited by 66 publications

(52 citation statements)

References 97 publications

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“…Multiple observations made in the study suggest that C 18 UFAs suppress respiratory burst and degranulation of human neutrophils through an increase in the clearance of cytosolic Ca 21 . It is well established that Ca 21 signaling is a key second messenger regulating neutrophil functions (34). Consistent with this, BAPTA-AM, a cell-permeable Ca 21 chelator, inhibited the generation of O 2…”

Section: Discussionmentioning

confidence: 52%

“…Because of this critical dependence of activation of the proinflammatory activities of neutrophils on Ca 21 , the mechanisms used by these cells to both mobilize and dispose of Ca 21 have been identified as potential targets for anti-inflammatory agents (34). We previously reported that cAMP-elevating agents can accelerate Ca 21 clearance from the cytosol as well as inhibit the generation of O 2…”

Section: Discussionmentioning

confidence: 99%

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Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils

Hwang

Chang

et al. 2009

Journal of Lipid Research

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The structure-activity relationship of 18-carbon fatty acids (C 18 FAs) on human neutrophil functions and their underlying mechanism were investigated. C 18 unsaturated (U)FAs potently inhibited superoxide anion production, elastase release, and Ca 21 mobilization at concentrations of UFAs did not reduce extracellular Ba 21 entry in FMLP-and thapsigargin-activated neutrophils. In summary, the inhibition of neutrophil functions by C 18 UFAs is attributed to the blockade of Ca 21 mobilization through modulation of PMCA. We also suggest that both the free carboxy group and the number of double bonds of the C 18 UFA structure are critical to providing the potent anti-inflammatory properties in human neutrophils.-Hwang,

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils

Hwang

Chang

et al. 2009

Journal of Lipid Research

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“…Our study is in accordance with recent reports showing that the A2aAR may antagonize proinflammatory stimuli and restore calcium homeostasis in neutrophils. 26,34 The action of Ado highlighted in this article appears to be restricted to certain cell types participating in the process of myocardial injury and remodeling. Whereas Ado reproducibly inhibited MMP-9 secretion by neutrophils, it had no effect on other inflammatory cells such as monocytes/macrophages.…”

Section: Downloaded Frommentioning

confidence: 99%

Adenosine Inhibits Matrix Metalloproteinase-9 Secretion By Neutrophils

Ernens

Rouy²,

Velot³

et al. 2006

Circulation Research

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Abstract-Matrix metalloproteinases (MMPs), and in particular MMP-9 secreted by neutrophils, are capable of degrading the matrix components of the heart and are thought to be the driving force behind myocardial matrix remodeling after infarction. Adenosine, a naturally produced nucleoside, has been shown to have cardioprotective effects and to inhibit secretion of various cytokines. The aim of our study was to determine the effect of adenosine on the secretion of MMP-9 by neutrophils. Neutrophils were isolated from healthy volunteers through Ficoll and Dextran sedimentation. Neutrophils were activated by N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence or absence of adenosine or adenosine analogs. Zymography and enzyme linked immunosorbent assay were used to measure MMP-9 secretion. Adenosine (1 mol/L) decreased the fMLP-induced MMP-9 secretion by 30Ϯ2% (nϭ8, PϽ0.001). The effect was dose-dependent and was not specific to fMLP because adenosine also inhibited MMP-9 secretion by LPS-or H 2 O 2 -stimulated neutrophils. The effect of adenosine was mimicked by the adenosine A2a receptor agonist CGS21680 and was inhibited by both the A2a antagonist SCH5826 and A2a RNA silencing. The A3 agonist IB-MECA moderately decreased fMLP-induced MMP-9 secretion. Agonists and antagonists of the other types of adenosine receptors had no significant effect. Adenosine increased intracellular cAMP concentration and accelerated the return to baseline of the intracytoplasmic calcium peak. The inhibition of MMP-9 secretion by adenosine, as well as the calcium effect, was prevented by the protein kinase A inhibitor H-89. In conclusion, we show here that adenosine inhibits MMP-9 secretion by neutrophils. Our results suggest that this effect implies the A2a receptor and is mediated through the cAMP/PKA/ Ca 2ϩ pathway. Therefore, adenosine may represent a new approach to prevent matrix degradation and remodeling after myocardial injury. (Circ Res. 2006;99:590-597.) Key Words: adenosine Ⅲ neutrophils Ⅲ myocardial remodeling Ⅲ protein kinase A Ⅲ matrix metalloproteinase-9 D espite reperfusion therapy with thrombolysis or percutaneous intervention, the development of left ventricular remodeling and heart failure after myocardial infarction has not significantly decreased and remains associated with a more than 10-fold elevated risk of death. 1 Enhanced activity of matrix metalloproteinases (MMPs) and in particular MMP-9 after infarction breaks down collagen contributing to myocyte slippage and ventricular remodeling. Recent observations 2 and the Framingham study have shown that levels of MMP-9 are elevated after myocardial infarction both in the acute and chronic phases. 3 We have identified MMP-9 as a risk marker for the development of left ventricular remodeling and heart failure after acute myocardial infarction. 4 Animal studies have shown that ventricular remodeling after infarction can be attenuated through the use of MMPs inhibitors. [5][6][7] However, recent results from the PREMIER (Prevention of Myocardial Infarction Ea...

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“…It is well established that Ca 2+ -signaling is a key second messenger in the regulation of neutrophil functions [27]. Thus, assuming that the above results demonstrate the ability of OA to induce both ROS generation and increases in [Ca 2+ ] i , we investigated whether these mechanisms are interconnected, and, if so, which event occurred first.…”

Section: Effect Of Bapta On Oa-induced Ros Productionmentioning

confidence: 99%

Activation of Human Neutrophils by Oleic Acid Involves the Production of Reactive Oxygen Species and a Rise in Cytosolic Calcium Concentration: a Comparison with N-6 Polyunsaturated Fatty Acids

Carrillo

Cavia

Roelofs

et al. 2011

Cell Physiol Biochem

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Background: There is a growing body of evidence showing that dietary constituents and lipids in particular, influence the function of the human immune system. However, although the beneficial effects of oleic acid (OA) are clear, its mechanism of action at the molecular level is poorly understood. Aims: To evaluate neutrophil activation under the influence of OA and compare this with several n-6 PUFAs. Methods: Two key aspects of neutrophil activation were investigated: oxygen radical (ROS) production and intracellular Ca²⁺ signaling. Results: OA and the n-6 PUFA arachidonic acid (AA) both induced ROS production in a dose-dependent manner, although AA was the more potent stimulus. When looking for the mechanisms behind these effects, we found that both FA induce increases in cytosolic calcium concentration [Ca²⁺]_i), but whereas OA-induced ROS production is totally mediated through Ca2+ signaling, this is not the case for AA since ROS generation by AA is only partly inhibited in BAPTA-treated cells. We also found evidence for the involvement of protein kinase C (PKC) in the OA-induced ROS generation; by contrast, other enzymes apart from PKC seem to be implicated in n-6 PUFA-induced ROS production. In addition, our results argue against the involvement of a pertussis toxin-sensitive receptor activated by OA. Conclusions: OA differs from the n-6 PUFA AA in the activation of human neutrophils and these differences may be related to their distinct inmunomodulatory properties.

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Taming the neutrophil: calcium clearance and influx mechanisms as novel targets for pharmacological control

Cited by 66 publications

References 97 publications

Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils

Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils

Adenosine Inhibits Matrix Metalloproteinase-9 Secretion By Neutrophils

Activation of Human Neutrophils by Oleic Acid Involves the Production of Reactive Oxygen Species and a Rise in Cytosolic Calcium Concentration: a Comparison with N-6 Polyunsaturated Fatty Acids

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