Superoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma

doi:10.1016/0091-6749(89)90112-7

Journal of Allergy and Clinical Immunology

Volume 83, Issue 5, May 1989, Pages 960-966

https://doi.org/10.1016/0091-6749(89)90112-7 Get rights and content

Abstract

Airway inflammation with neutrophil infiltration may play a role in airway hyperreactivity. Neutrophils may exert their effects through the generation of Superoxide O₂ anion and other oxygen-derived free radicals. O₂⁻ generation by neutrophils has been demonstrated to be modulated by adenosine at physiologic concentrations. Therefore, we have investigated the function of peripheral blood neutrophils with respect to O₂⁻ anion generation and its regulation by adenosine in both subjects with asthma and normal subjects and also the relationship between O₂⁻ anion generation and airway hyperresponsiveness in subjects with asthma. Purified neutrophils were obtained from eight subjects with stable asthma and seven normal control subjects not taking chronic medications. O₂⁻ anion generation in subjects with asthma was significantly higher compared with that of normal subjects after stimulation with either N-formyl-methionyl-leucyl-phenylalanine (mean, 14.8 nmol/10⁶ cells for subjects with asthma versus mean, 9.6 nmol/10⁶ cells for normal subjects; p < 0.01) or phorbol myristate acetate (mean, 13.6 nmol/10⁶ cells versus mean, 8.1 nmol/10⁶ cells; p < 0.05). Adenosine inhibited N-formyl-methionyl-leucyl-phenylalanine-stimulated O₂⁻ anion generation in a dose-related fashion in subjects with asthma and normal subjects to a similar degree. Adenosine had no effect on O₂⁻ anion generation after phorbol myristate acetate stimulation. These results indicate that neutrophils from subjects with asthma produce more O₂⁻ anion when they are stimulated than do neutrophils from normal subjects and that this difference is not due to adenosine modulation. In subjects with asthma, O₂⁻ anion generation correlated with the degree of airway hyperresponsiveness to inhaled methacholine.

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Two series of new furanones substituted by methylsulfonylphenyl or methylsulfamidophenyl moieties were found to protect against oxidation damage by inhibiting or quenching free radicals and reactive oxygen species in in vitro experiments. The effect on lipid peroxidation was also examined. In addition, we investigated the activity of products in two models of inflammation: phorbol ester-induced ear edema in mice and carrageenan-induced paw edema in rat. The most powerful compounds and with reducing activity against DPPH (IC₅₀ = 1779 and 57 μM, respectively), superoxide anion quenching capacity (IC₅₀ = 511 and 49 μM, respectively), lipid peroxidation inhibitory effect and anti-inflammatory properties (about 50–65% inhibition of edema at 200 mg/kg ip in both tests used) were selected for further pharmacological and toxicological tests because of their attractive profile for the treatment of inflammatory diseases.
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^☆: Supported by a grant from the Department of Research and Education, Kaiser Hospitals.

^∗: Dr. P. Lad was supported in part by National Institutes of Health Grants AM30878 and AM34550.

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Original articleSuperoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma☆

Abstract

Am J Med

Biochim Biophys Acta

J Biol Chem

The sputum in bronchial asthma: pathognomonic patterns

J Pathol Bacteriol

A comparison of the quantitative anatomy of the bronchi in normal subjects in status asthmaticus, in chronic bronchitis, and in emphysema

Thorax

Rhinovirus and influenza type A infections as precipitants of asthma

Am Rev Respir Dis

Allergen-induced increase in nonallergic bronchial reactivity

Clin Allergy

Importance of airway inflammation for hyperresponsiveness induced by ozone

Am Rev Respir Dis

Effect of short-term, low-level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients

J Clin Invest

Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure

Am Rev Respir Dis

Arachidonic acid metabolism in polymorphonuclear leukocytes: effects of ionophore A23187

Original article
Superoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma☆