The Role of Free Radicals in Airway Obstruction in Asthmatic Patients

doi:10.1378/chest.100.5.1319

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Volume 100, Issue 5, November 1991, Pages 1319-1322

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Neutrophils from asthmatic patients seem to be in an activated state. This study demonstrated that superoxide radical (O₂^–) production was enhanced in asthmatic patients compared with healthy control subjects. Production of (O₂^–) also increased with progression of disease and with disease duration. In addition, (O₂^–) release was inversely correlated with FEV₁ and midflows and was greater in neutrophils from patients with exacerbated disease than in those from patients with stable disease. These findings suggest that oxygen metabolites may play a direct or indirect role in the modulation of airway inflammation.

Section snippets

Subjects

The subjects who participated in this study were 11 patients with bronchial asthma, ranging in age from 21 to 69 years (mean, 43.5 years) (Table 1), and five healthy control subjects, ranging in age from 27 to 70 years (mean, 45.0 years). The two groups were matched by age and sex. All asthmatic subjects were clinically stable nonsmokers who had never experienced exacerbation of symptoms and had no signs suggestive of respiratory infection for at least one month before the study. A diagnosis of

Results

The PMA- or fMLP-stimulated production of O₂^-by neutrophils was significantly greater in the asthmatic patients than in the normal control subjects (Table 2). Comparison between the two asthmatic subgroups, continuous inhalers of bronchodilators (who had attacks frequently) and intermittent inhalers, showed that O₂^- production was apt to be greater in the former subgroup (O₂^- release; 2.57 ± 0.70 vs 1.70 ± 0.30 nmol/ml). There was a positive correlation between disease duration and O₂^-

Discussion

This study revealed the O₂^- production by peripheral blood neutrophils was distinctly enhanced in asthmatic patients compared with healthy control subjects. A majority of our patients were receiving theophylline and beta-stimulatants. These substances, which are known to increase the intracellular concentration of cyclic adenosine monophosphate,¹⁸ must have inhibited O₂^- generation by peripheral blood neutrophils, that is, the O₂^- production was most probably underestimated in our patients.

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Delayed kinetics of phagocytosis related respiratory burst in blood is a distinctive feature of moderate exacerbation of bronchial asthma
2019, Free Radical Biology and Medicine
Citation Excerpt :
O2− was higher in BA patients versus healthy individuals and correlated with forced expiratory volume in 1 s (FEV1). It increased with the disease progression and was greater in exacerbation versus stable disease [15]. Controversially, low activity of neutrophils in respiratory burst induced with bacterial peptide was demonstrated during BA exacerbation [16].
Atopic bronchial asthma based on allergy history and chronic inflammation is hazardous to patients due to the risk of exacerbation. The sign of severe exacerbation is considered an abundant number and high activity of granulocytes in respiratory system and blood. Relationships between the ability of cells in blood to produce reactive radicals and their metabolites and the severity of asthma remain largely unclear. Kinetics of respiratory burst evoked by microbe particles in blood samples of patients was studied to reveal the most significant predictors distinguishing states of moderate exacerbation and out of exacerbation. Asthmatic patients with exacerbation (n = 18) or out of exacerbation (n = 62) and healthy individuals (n = 43) were characterized on respiratory function, cell count in blood and kinetics of generation of reactive radicals and their metabolites during phagocytosis. Mean values of respiratory parameters forced expiratory volume in 1 s and peak expiratory flow rate in patients with exacerbation were significantly differed compared with same of patients out of exacerbation and healthy individuals. Mean values of cell count in blood did not significantly differed in patients with exacerbation and out of exacerbation. Receiver operating characteristic analysis showed that both cell count and respiratory indexes did not discriminate patients with exacerbation from out of exacerbation. A delayed response to opsonized zymosan was revealed in patients with exacerbation compared to other examinees: lengthened lag-time and T_max, reduced production of reactive species. T_max was the most statistically significant predictor to discriminate bronchial asthma exacerbation from bronchial asthma out of exacerbation (area under curve >90%, p < 10⁻⁵) and controls (area under curve >80%, p < 10⁻⁵).
Thus kinetic parameters of the phagocyte response to opsonized zymosan in the whole blood are the best predictors of bronchial asthma exacerbation in comparison with respiratory parameters and blood cell count. This test can be used for immunological monitoring of bronchial asthma status to prevent exacerbation.
Accelerated reactivity of blood granulocytes in patients with atopic bronchial asthma out of exacerbation
2018, Immunobiology
Citation Excerpt :
Hyperactivated phenotype with decreased (Mattheyse et al., 2001) or increased ROS production (Vargas et al., 1998) was detected during the acute BA stage using luminol-dependent CL. Also increased production of superoxide anion was recorded on reduction of cyt c in BA (Kanazawa et al., 1991). During exacerbations, even without stimulation granulocytes of BA patients had an increased ROS-generating response versus controls and patients without exacerbation.
Reactive oxygen species (ROS) are important in bronchial asthma (BA) pathogenesis owing to accumulation of activated granulocytes in the lungs. But the ROS-producing activity of the cells is insufficiently understood in the blood of BA patients. This study analyzes the kinetics of phagocyte respiratory burst in the blood to improve the methods of BA patients monitoring. Patients with atopic BA out of exacerbation (n = 60) and healthy controls (n = 43) were recruited. The time-course of respiratory response to opsonized zymosan (OZ) was recorded in the whole blood using luminol-dependent chemiluminescence (CL), and its activation kinetics (lag-time, rate, amplitude, ROS production) was calculated. The discriminative power of ROS generation kinetics was defined by Receiver Operating Characteristic (ROC) curve analysis. Standard physiological respiratory parameters of patients did not differ from the controls. More rapid response to OZ was recorded in BA patient samples versus the controls. The primed state of phagocytes in the blood of BA patients was corroborated by significant weakening formyl peptide priming effect. The adhesion of granulocytes to cultured human endothelial cells was two-fold higher in BA patients versus controls. ROC curve analysis exhibited good discriminative effectiveness of the CL kinetics to compare BA individuals with the controls. The highest power (86% sensitivity and 90% specificity) was achieved at a linear combination of the parameters. We assume that the assessment of phagocyte reactivity based on the analysis of the response kinetic profile is a good test for monitoring of the state in BA patients.
Improved lung function following dietary antioxidant supplementation in exercise-induced asthmatics
2016, Respiratory Physiology and Neurobiology
Citation Excerpt :
Frei et al. (1988) showed that AsA and α-tocopherol act to decrease the release of cellular radicals. If there were a decrease in cellular radicals then there would likely be a decrease in direct stimulation for bronchoconstriction in our EIA subjects (Barnes, 1990; Kanazawa et al., 1991; Calhoun et al., 1992). This likely also reduced a chemotactic effect of other leukocytes in the area (Perez et al., 1980) and lowering histamine and ROS producing leukocytes in the lung (Lopez et al., 1988).
Oxidative stress is a characteristic of exercise-induced asthma (EIA), however antioxidant supplementation may attenuate EIA. The purpose of this study was to determine if ascorbic (AsA) and α-tocopherol supplementation would improve airway function in subjects with EIA.
A single-blind randomized crossover design with eight clinically diagnosed EIA subjects (22.0 ± 0.7 year) and five healthy control subjects (28.2 ± 1.4 year) was used. Subjects consumed vitamins (V) (AsA 500 mg; α-tocopherol 300 IU) or placebo (PLA) daily for three weeks, followed by a three week washout period and then three weeks of the alternative treatment. Ten-minute treadmill tests (90% VO2_peak) were performed with pulmonary function testing (forced vital capacity (FVC), forced expiratory volume in one second (FEV₁) and between 25 and 75% (_FEF25–75%), and peak expiratory flow rates (PEFR)) measured pre-exercise and 1, 5, 15, and 30 min post-exercise.
Supplementation led to significant improvements at minute 5 and minute 15 in FVC; FEV₁; PERF; FEF_25–75% and minute 30 in FEV₁ and FEF_25–75% post-exercise.
AsA and α-tocopherol may aid the recovery of pulmonary function in subjects with EIA.
Airway and systemic oxidant-antioxidant dysregulation in asthma: A possible scenario of oxidants spill over from lung into blood
2014, Pulmonary Pharmacology and Therapeutics
Asthma is characterized by repeated episodes of airway obstruction and an ongoing cycle of airway inflammation. Reactive oxygen species (ROS) produced by inflammatory cells in the lung play a key role in the pathogenesis as well as amplification of inflammation in asthmatic airways. Several enzymatic and non-enzymatic antioxidants are available in the lung and systemic circulation to counteract ROS-mediated damage on various biomolecules such as lipid membranes, proteins, and DNA; however during asthmatic inflammation these defenses are overwhelmed due to excessive production of ROS thereby leading to inflammatory events in the airways/systemic circulation. ROS-mediated damage may result in increased vascular permeability, mucus hypersecretion, smooth muscle contraction, epithelial shedding and impairment in the responsiveness of β-adrenergic receptors. Strategies aimed to boost the endogenous antioxidants either through dietary or pharmacological intervention to redress oxidant-antioxidant imbalance in asthma is the current area of research in many laboratories throughout the world. This review aims at providing a comprehensive overview of the available literature on oxidative stress and antioxidants imbalance in asthma with a focus both on lung and blood components and bring forth correlations between lung/blood oxidative stress/antioxidant parameters and lung function.
Sulfite-mediated oxidation of myeloperoxidase to a free radical: Immuno-spin trapping detection in human neutrophils
2013, Free Radical Biology and Medicine
Citation Excerpt :
Our immuno-spin trapping studies are based on the following observations: (i) neutrophils have been implicated in the pathology of many chronic inflammatory conditions and lung diseases [18]. Influx of inflammatory neutrophils into the airways in asthma results in increased generation of reactive oxygen species in asthmatic patients [19,20], and it is likely that these species play a significant role in the pathophysiology of asthma [21–23]. ( ii) Myeloperoxidase (MPO), an abundant heme protein stored in neutrophils, has the unique ability to use halides as physiological substrates and to generate hypohalous acids, with subsequent formation of other reactive oxygen species [24].
Previous studies focused on catalyzed oxidation of (bi)sulfite, leading to the formation of the reactive sulfur trioxide (^•SO₃⁻), peroxymonosulfate (⁻O₃SOO^•), and sulfate (SO₄^•−) anion radicals, which can damage target proteins and oxidize them to protein radicals. It is known that these very reactive sulfur- and oxygen-centered radicals can be formed by oxidation of (bi)sulfite by peroxidases. Myeloperoxidase (MPO), an abundant heme protein secreted from activated neutrophils that play a central role in host defense mechanisms, allergic reactions, and asthma, is a likely candidate for initiating the respiratory damage caused by sulfur dioxide. The objective of this study was to examine the oxidative damage caused by (bi)sulfite-derived free radicals in human neutrophils through formation of protein radicals. We used immuno-spin trapping and confocal microscopy to study the protein oxidations driven by sulfite-derived radicals. We found that the presence of sulfite can cause MPO-catalyzed oxidation of MPO to a protein radical in phorbol 12-myristate 13-acetate-activated human neutrophils. We trapped the MPO-derived radicals in situ using the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide and detected them immunologically as nitrone adducts in cells. Our present study demonstrates that myeloperoxidase initiates (bi)sulfite oxidation leading to MPO radical damage, possibly leading to (bi)sulfite-exacerbated allergic reactions.
Formation of reactive sulfite-derived free radicals by the activation of human neutrophils: An ESR study
2012, Free Radical Biology and Medicine
The objective of this study was to determine the effect of (bi)sulfite (hydrated sulfur dioxide) on human neutrophils and the ability of these immune cells to produce reactive free radicals due to (bi)sulfite oxidation. Myeloperoxidase (MPO) is an abundant heme protein in neutrophils that catalyzes the formation of cytotoxic oxidants implicated in asthma and inflammatory disorders. In this study sulfite (^•SO₃⁻) and sulfate (SO₄^•−) anion radicals are characterized with the ESR spin-trapping technique using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in the reaction of (bi)sulfite oxidation by human MPO and human neutrophils via sulfite radical chain reaction chemistry. After treatment with (bi)sulfite, phorbol 12-myristate 13-acetate-stimulated neutrophils produced DMPO–sulfite anion radical, –superoxide, and –hydroxyl radical adducts. The last adduct probably resulted, in part, from the conversion of DMPO–sulfate to DMPO–hydroxyl radical adduct via a nucleophilic substitution reaction of the radical adduct. This anion radical (SO₄^•−) is highly reactive and, presumably, can oxidize target proteins to protein radicals, thereby initiating protein oxidation. Therefore, we propose that the potential toxicity of (bi)sulfite during pulmonary inflammation or lung-associated diseases such as asthma may be related to free radical formation.

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Reprint requests: Dr. Kanazawa, 1-5-7 Asahi-machi, Abenoku, 1st Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan 545

Manuscript received December 7; revision accepted March 4.

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Clinical InvestigationsThe Role of Free Radicals in Airway Obstruction in Asthmatic Patients

Section snippets

Subjects

Results

Discussion

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Life Sci

J Biol Chem

Airway responsiveness to histamine and methacholine: relationship to minimum treatment control symptoms of asthma.

Thorax

Role of inflammation in the hyperreactivity of the airways in asthma.

Thorax

Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs.

Am Rev Respir Dis

Airways reversibility after predonisolone therapy in chronic asthma is associated with alteration in leukocyte function.

Am Rev Respir Dis

Clinical Investigations
The Role of Free Radicals in Airway Obstruction in Asthmatic Patients