Retinoids stimulate the release of superoxide by neutrophils and change their morphology

Badwey, John A.; Robinson, John M.; Curnutte, John T.; Karnovsky, Morris J.; Karnovsky, Manfred L.

doi:10.1002/jcp.1041270206

Cited by 55 publications

(57 citation statements)

References 44 publications

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“…These are similar in appearance to the blebs described in cultured cells in response to a variety of influences that induce oxidant stress. 2 " 6 In these cultured preparations, the lesions were ascribed to oxidation of thiols with consequent alterations in the cytoskeleton of the cells. 7 Vascular smooth muscle in cerebral arterioles exposed to H 2 O 2 also showed evidences of damage consisting of vacuolization or the appearance of electron-dense inclusion bodies.…”

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confidence: 99%

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

1990

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We studied the mechanism of the vasodilator effect of H2O2 on cerebral arterioles and its effect on endothelium-dependent responses to acetylcholine. Topical application of H2O2 (0.1-1 microM) on the brain surface of anesthetized cats equipped with cranial windows induced dose-dependent arteriolar dilation, which was markedly inhibited by topical deferoxamine, showing that it was probably mediated by generation of hydroxyl radical. Higher concentrations of H2O2 (3 microM) also induced dilation, which was unaffected by deferoxamine, indicating the participation of other mechanisms. After topical application of H2O2, endothelium-dependent responses to acetylcholine were eliminated or converted to vasoconstriction, and in bioassay experiments, acetylcholine-mediated endothelium-derived relaxing factor (EDRF) was absent. Superoxide dismutase plus catalase restored the appearance of transferable EDRF after 1 microM H2O2 but not after 3 microM H2O2. Application of H2O2 in the assay window eliminated the responses to nitroprusside and nitric oxide but did not affect responses to adenosine, to EDRF from the donor window, or responses to S-nitroso-L-cysteine. The inhibiting effect of H2O2 on the response to nitroprusside was partially eliminated after topical application of N-acetyl-L-cysteine. The results show that H2O2 inhibits the vasodilator action of nitroprusside and nitric oxide probably because it oxidizes thiols in vascular smooth muscle and prevents the formation of a nitrosothiol. EDRF from acetylcholine and S-nitroso-L-cysteine still produce dilation in the presence of the blockade induced by H2O2. The findings suggest strongly that the EDRF from acetylcholine in cerebral vessels is a nitrosothiol like S-nitroso-L-cysteine.

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confidence: 99%

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

1990

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“…Retinoids do not only inhibit but also stimulate PKC in vitro under certain experimental conditions [13,14,23]. In addition, retinoids were reported to activate NADPH oxidase in neutrophils [24]. We found that retinoic acid and retinal did not induce 02 -formation in HL-60 cells (data not shown).…”

Section: Discussionmentioning

confidence: 70%

Studies with protein kinase C inhibitors presently available cannot elucidate the role of protein kinase C in the activation of NADPH oxidase

Seifert

Schächtele²

1988

Biochemical and Biophysical Research Communications

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The effects of various protein kinase C (PKC) inhibitors on NADPH oxidase (NO) activation by the phorbol ester PMA and by the chemotactic peptide FMLP were studied. H-7 reduced the effects of both stimuli in human neutrophils (HN) and HL-60 cells by 13-63%. Polymyxin B did not inhibit NO activation by PMA and FMLP in HN and reduced the effects of both stimuli in HL-60 cells by 27-55%. Retinal and retinoic acid enhanced the effects of PMA and FMLP in HL-60 cells and of FMLP in HN up to 4.5-fold. In contrast, retinoic acid inhibited the effect of PMA in HN, In the presence of cytochalasin B, retinal inhibited the effect of FMLP in HN, whereas retinoic acid inhibited NO activation by FMLP in both cell types. The dual PKC/calmodulin inhibitors trifluoperazine and W-7 abolished NO activation by PMA and FMLP in HN and HL-60 cells. Thus, the effects of PKC inhibitors on NO activation exhibit (I) cell type specificity, (2) stimulus dependency and (3) no correlation with in vitro inhibition of PKC. Our results suggest that studies with PKC inhibitors presently available cannot clarify the role of PKC in NO activation. ~1988Ac~d .... Press, Inc.Human neutrophils possess an NADPH oxidase which catalyzes 0 2" formation and can be activated by cell-permeable diacylglycerol and PMA via PKC [I,2] and by the chemotactic peptide, FMLP [3]. The mechanism by which FMLP activates 0 2 -formation is not known. There is a debate concerning the involvement of PKC in cellular activation by FMLP [3]. In recent studies, certain PKC

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“…Table 2 shows that AACOCF $ inhibited neither the fMLP-nor the PMA-induced free-radical generation, even at 60 µM, where the drug abolished the AA release triggered by either stimulus (Table 1). This result was rather surprising since exogenously applied AA is a well-known stimulator of the oxidase [42,43], and non-selective blockers of PLA # (like bromophenacyl bromide) can completely suppress superoxide generation [23,44]. These earlier findings lent credence to the assumption that endogenous AA production is mandatory for oxidase activation [45].…”

Section: Does Aacocf 3 Influence Nadph Oxidase or Other Ph-regulatorymentioning

confidence: 96%

Electrogenic H+ pathway contributes to stimulus-induced changes of internal pH and membrane potential in intact neutrophils: role of cytoplasmic phospholipase A2

Suszták

Mócsai

Ligeti

et al. 1997

Biochemical Journal

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The potential role of cytosolic phospholipase A2 (cPLA2) in the regulation of the electrogenic arachidonic acid (AA)-activatable H+ translocator of neutrophils was investigated. (1) The trifluoromethyl ketone analogue of arachidonate (AACOCF3), a newly developed selective blocker of cPLA2, inhibited both the N-formylmethionyl-leucylphenylalanine (fMLP)- and the phorbol-ester-induced rheogenic H+ efflux (K0.5 ≈ 5 μM) and abrogated the stimulus-triggered release of AA from these cells. The drug failed to reduce the fMLP-evoked Ca2+ signal or protein tyrosine phosphorylation and did not affect the activity of protein kinase C. By using the patch-clamp technique we verified that the agent did not interfere with the voltage- and the pH-dependent activation of the H+ conductance of the peritoneal macrophages and therefore is not a direct blocker of the H+ channel itself. AACOCF3, however, slightly decreased the AA-induced stimulation of the H+ currents. We conclude that AA, liberated by the agonist-induced stimulation of cPLA2, is a direct activator of H+ conductance. (2) AACOCF3 did not inhibit superoxide generation, indicating that activation of cPLA2 may not be a prerequisite for turning on NADPH oxidase. (3) Since neither acid generation by the oxidase, nor the basal or stimulated Na+/H+ exchange (the predominant acid-eliminating mechanism) were influenced by the drug, we could use AACOCF3 to address whether the H+ channel in fact opens and plays any physiological role during activation of neutrophils. Stimulus-induced cytosolic alkalinization was smaller, whereas depolarization became larger, in the presence of AACOCF3. Stimulated H+ conductance therefore does contribute to intracellular pH (pHi) homoeostasis and membrane potential changes of intact neutrophils.

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Retinoids stimulate the release of superoxide by neutrophils and change their morphology

Cited by 55 publications

References 44 publications

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

Studies with protein kinase C inhibitors presently available cannot elucidate the role of protein kinase C in the activation of NADPH oxidase

Electrogenic H+ pathway contributes to stimulus-induced changes of internal pH and membrane potential in intact neutrophils: role of cytoplasmic phospholipase A2

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