Intracellular pH modulates the generation of superoxide radicals by human neutrophils.

Simchowitz, L

doi:10.1172/jci112061

Cited by 161 publications

(86 citation statements)

References 43 publications

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“…The combination of extracellular alkalinization and A/-formyl-methionylleucyl-phenylalanine increased both pH, and the generation of superoxide in human neutrophils, but extracellular alkalinization alone did not affect either, suggesting that the intracellular alkalinization should be critical in enhanced superoxide production. 13 Also, endothelin, which increased pH, 23 produced superoxide in human alveolar macrophages. 24 Superoxide anion also has been indicated to be generated in endothelial cells, so it may act as a contracting factor.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.

Ando

Fujita

1994

Hypertension

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We designed the present study to clarify whether the intracellular pH change by ammonium chloride influences endothelium-dependent relaxation in thoracic aorta of 9-week-old Sprague-Dawley rats. Intracellular alkalinization with 3 mmol/L ammonium chloride, which did not affect resting vascular tone, attenuated acetylcholine-induced relaxation but not nitroglycerin vasodilation. Acetylcholine relaxation was more inhibited by a shorter duration of treatment. Thus, change in intracellular pH may be important in the effect because the alkalinizing effect of ammonium chloride disappears gradually. In support of this, the proton ionophore nigericin abolished the effect. Also, amiloride shortened the effect of ammonium chloride, suggesting that intracellular pH plays a role: sodium-proton antiport antagonizes the disappearance of ammonium chloride-induced intracellular alkalinization. The synthesis of vasoconstrictor prostaglandins, such as thromboxane A 2 , may be stimulated during acetylcholine A bnormal sodium-proton (Na + -H + ) antiport and /\ intracellular pH (pH,) have been reported in A. ^ hypertensive 1 and diabetic 14 subjects. It has been reported that increased pH, enhances and decreased pHi suppresses vascular tone, reactivity, or both. 58 Thus, a change in pH, might be important in the abnormal regulation of vascular tone in both diseases. The pH; of vascular smooth muscle cells may be important because change in the pH, of smooth muscle cells has been demonstrated to play a role in the regulation of vascular tone. 67 On the other hand, abnormal endothelial function may also result from increased pH, of endothelium because a few investigators have reported that endothelial pH, may affect vascular tone.5 -8 High CO 2 tension, which causes acidemia, attenuated norepinephrine contraction, which was partially normalized by denudation of the inner surface of the aorta. 5 Moreover, in a recent study, 8 we altered acetylcholine-induced relaxation by modifying Na + -H + antiport with low Na + medium and amiloride. However, it has not yet been concluded whether pHj change in endothelial cells contributes to the regulation of vascular tone.Vasoconstrictor prostaglandins have been suggested to contribute to vasoconstriction induced by intracellular alkalinization. Vasoconstriction with alkalosis was accompanied by increased levels of thromboxane B 2 and 6-ketoprostaglandin F la in perfused rabbit lungs. © 1994 American Heart Association, Inc.treatment, resulting in the attenuation of acetylcholine relaxation, because the relaxation was abolished by treatment with the phospholipase A 2 inhibitor quinacrine, cyclooxygenase inhibitor indomethacin, prostaglandin H 2 /thromboxane A 2 receptor antagonist S1452, and thromboxane A 2 synthase inhibitor dazmegrel. Phospholipase A 2 may contribute to the effect of intracellular alkalinization, which is compatible with the fact that the optimal pH of phospholipase A 2 is neutral to alkaline. In addition, superoxide dismutase attenuated the effect of ammonium chloride....

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Section: Discussionmentioning

confidence: 99%

“…13 Thus, vasoconstrictor prostaglandins and/or superoxide may be involved in alkalinization-induced vasoconstriction through endothelial cells. To clarify this hypothesis, we examined the effect of NH 4 C1 on acetylcholine-induced relaxation and its involvement with prostaglandins and superoxide in rat thoracic aorta.…”

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confidence: 99%

Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.

Ando

Fujita

1994

Hypertension

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“…However, both metal cations also inhibit calcium release activated calcium (CRAC) currents (28) and Na ϩ /Ca 2ϩ exchange (29). Hypothetically, either transporter, if present in basophils, might mediate the Ca 2ϩ influx that is required for histamine release in response to anti-IgE (30).…”

Section: Pathways That Activate Histamine Release and Proton Channels Inmentioning

confidence: 99%

A pH-stabilizing role of voltage-gated proton channels in IgE-mediated activation of human basophils

Musset¹,

Morgan²,

Cherny³

et al. 2008

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

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Eosinophils and other phagocytes use NADPH oxidase to kill bacteria. Proton channels in human eosinophils and neutrophils are thought to sustain NADPH oxidase activity, and their opening is greatly enhanced by a variety of NADPH oxidase activators, including phorbol myristate acetate (PMA). In nonphagocytic cells that lack NADPH oxidase, no clear effect of PMA on proton channels has been reported. The basophil is a granulocyte that is developmentally closely related to the eosinophil but nevertheless does not express NADPH oxidase. Thus, one might expect that stimulating basophils with PMA would not affect proton currents. However, stimulation of human basophils in perforated-patch configuration with PMA, N-formyl-methionyl-leucyl-phenylalanine, or anti-IgE greatly enhanced proton currents, the latter suggesting involvement of proton channels during activation of basophils by allergens through their highly expressed IgE receptor (Fc RI). The anti-IgE-stimulated response occurred in a fraction of cells that varied among donors and was less profound than that to PMA. PKC inhibition reversed the activation of proton channels, and the proton channel response to anti-IgE or PMA persisted in Ca 2؉ -free solutions. Zn 2؉ at concentrations that inhibit proton current inhibited histamine release elicited by PMA or anti-IgE. Studied with confocal microscopy by using SNARF-AM and the shifted excitation and emission ratioing of fluorescence approach, anti-IgE produced acidification that was exacerbated in the presence of 100 M Zn 2؉ . Evidently, proton channels are active in basophils during IgE-mediated responses and prevent excessive acidification, which may account for their role in histamine release.asthma ͉ histamine ͉ patch-clamp ͉ HNVCN1 ͉ allergy

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“…Furthermore, small interfering RNA (siRNA) 4 specific to TDAG8 was effective to suppress acidification-induced inhibitory cytokine production. To our best knowledge, this is the first indication that proton-sensing GTP-binding regulatory protein (G protein)-coupled receptors, such as TDAG8 receptors, are involved in the extracellular acid-induced attenuation of proinflammatory cytokine production in macrophages through a cAMP signaling pathway.…”

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confidence: 99%

Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages

Mogi¹,

Tobo²,

Tomura³

et al. 2009

The Journal of Immunology

149

127

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Extracellular acidification inhibited LPS-induced TNF-α protein production, which was associated with an inhibition of TNF-α mRNA expression, in mouse peritoneal macrophages. The LPS-induced cytokine production was also inhibited by Gs protein-coupled receptor agonists prostaglandin E1 and isoproterenol. Among OGR1 family proton-sensing GTP-binding regulatory protein-coupled receptors, TDAG8, OGR1, and G2A are expressed in the cells. The inhibitory action by acidic pH on TNF-α production was significantly attenuated in macrophages from TDAG8Tp/Tp mice but not in those from OGR1geo/geo mice. Moreover, small interfering RNA specific to TDAG8, but not to G2A, clearly attenuated the acidification-induced inhibition of TNF-α production. On the other hand, the down-regulation or deficiency of TDAG8 hardly affected prostaglandin E1- or isoproterenol-induced actions. LPS-induced IL-6 production was also inhibited by extracellular acidification in a manner that was sensitive to TDAG8 expression. The acidic pH-induced inhibitory action on the cytokine production was significantly reversed either by a small interfering RNA specific to Gs proteins or by a protein kinase A (PKA)-specific inhibitor H89. Indeed, a PKA-specific cAMP derivative inhibited LPS-induced cytokine production. Moreover, acidification induced cAMP accumulation in a TDAG8-specific way. We conclude that TDAG8, at least partly, mediates the extracellular acidification-induced inhibition of proinflammatory cytokine production through the Gs protein/cAMP/PKA signaling pathway in mouse macrophages.

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Intracellular pH modulates the generation of superoxide radicals by human neutrophils.

Cited by 161 publications

References 43 publications

Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.

Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.

A pH-stabilizing role of voltage-gated proton channels in IgE-mediated activation of human basophils

Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages

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