Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

Lewis, Brandon W.; Ford, Maria L.; Rogers, Lynette K.; Britt, Rodney D.

doi:10.3390/antiox10091335

Cited by 38 publications

(39 citation statements)

References 305 publications

(367 reference statements)

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“…Corticosteroid insensitivity has been attributed to alterations in glucocorticoid receptor (GR) expression and diminished GR activity, enabling airway inflammation to persist in severe asthma ( Barnes, 2013 ; Lewis et al, 2021a ). To assess GR activity and its relationship to corticosteroid sensitivity, we measured expression of anti-inflammatory and antioxidant genes known to be regulated GR.…”

Section: Discussionmentioning

confidence: 99%

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

et al. 2022

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Type 2-high severe asthma is described as a distinct endotype with Th2 inflammation, high eosinophil lung infiltration, impaired lung function, and reduced corticosteroid sensitivity. While the inflammatory milieu is similar to mild asthma, patients with type 2-high severe asthma likely have underlying mechanisms that sustain asthma pathophysiology despite corticosteroid treatments. Acute and chronic allergen models induce robust type 2 inflammatory responses, however differences in corticosteroid sensitivity remains poorly understood. In the present study, we sensitized and challenged mice with ovalbumin (OVA; acute model) or mixed allergens (MA; chronic model). Corticosteroid sensitivity was assessed by administering vehicle, 1, or 3 mg/kg fluticasone propionate (FP) and examining key asthmatic features such as airway inflammation, remodeling, hyperresponsiveness, and antioxidant capacity. Both acute and chronic allergen exposure exhibited enhanced AHR, immune cell infiltration, airway inflammation, and remodeling, but corticosteroids were unable to fully alleviate inflammation, AHR, and airway smooth muscle mass in MA-challenged mice. While there were no differences in antioxidant capacity, persistent IL-4+ Th2 cell population suggests the MA model induces type 2 inflammation that is insensitive to corticosteroids. Our data indicate that chronic allergen exposure is associated with more persistent type 2 immune responses and corticosteroid insensitivity. Understanding differences between acute and chronic allergen models could unlock underlying mechanisms related to type 2-high severe asthma.

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Section: Discussionmentioning

confidence: 99%

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

et al. 2022

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“…Prior works involving animal models and clinical studies have emphasized the role of eosinophils and neutrophils as effector cells in the pathogenesis of severe asthma [ 25 , 32 , 33 ]. Our findings align with many others where a close correlation between the location and activation of these cells with pathological changes such as airway hyperreactivity, mucus secretion, and peribronchiolar fibrosis were observed [ 25 , 32 , 33 ]. Steroid anti-inflammatory drugs are often effective inhibitors of airway eosinophilia, but higher doses are needed to block this event under severe asthma [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both inflammation and oxidative stress are critical players in the pathophysiology of steroid-insensitive asthma [ 33 , 43 ]. In line with this concept, we found that intranasal allergen stimulation led to a marked rise in oxidative damage, measured by MDA formation in the lung tissue.…”

Section: Discussionmentioning

confidence: 99%

“…In line with this concept, we found that intranasal allergen stimulation led to a marked rise in oxidative damage, measured by MDA formation in the lung tissue. Increased formation of reactive oxygen and nitrogen species is commonly linked with the loss of antioxidant capacity in patients with severe asthma and COPD [ 33 ]. Indeed, we showed that allergen provocation caused a reduction in catalase activity.…”

Section: Discussionmentioning

confidence: 99%

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Gold Nanoparticles Inhibit Steroid-Insensitive Asthma in Mice Preserving Histone Deacetylase 2 and NRF2 Pathways

et al. 2022

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Background: Gold nanoparticles (AuNPs) can inhibit pivotal pathological changes in experimental asthma, but their effect on steroid-insensitive asthma is unclear. The current study assessed the effectiveness of nebulized AuNPs in a murine model of glucocorticoid (GC)-resistant asthma. Methods: A/J mice were sensitized and subjected to intranasal instillations of ovalbumin (OVA) once a week for nine weeks. Two weeks after starting allergen stimulations, mice were subjected to Budesonide or AuNP nebulization 1 h before stimuli. Analyses were carried out 24 h after the last provocation. Results: We found that mice challenged with OVA had airway hyperreactivity, eosinophil, and neutrophil infiltrates in the lung, concomitantly with peribronchiolar fibrosis, mucus production, and pro-inflammatory cytokine generation compared to sham-challenged mice. These changes were inhibited in mice treated with AuNPs, but not Budesonide. In the GC-resistant asthmatic mice, oxidative stress was established, marked by a reduction in nuclear factor erythroid 2-related factor 2 (NRF2) levels and catalase activity, accompanied by elevated values of thiobarbituric acid reactive substances (TBARS), phosphoinositide 3-kinases δ (PI3Kδ) expression, as well as a reduction in the nuclear expression of histone deacetylase 2 (HDAC2) in the lung tissue, all of which sensitive to AuNPs but not Budesonide treatment. Conclusion: These findings suggest that AuNPs can improve GC-insensitive asthma by preserving HDAC2 and NRF2.

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“…Chronic obstructive pulmonary disease (COPD), a progressive airway disorder, is a major cause of disability and death worldwide, and the number of patients is increasing [ 1 ]. Smoking and air pollution leading to increased inflammation and free radicals in the respiratory tract cause an increased burden of oxidative stress, which leads to the development and progression of COPD [ 2 , 3 ]. Oxidative stress is reported to induce structural changes in the essential components of the lung, including irreversible damage to both the parenchyma and airway wall [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Paraoxonase 1 and Chronic Obstructive Pulmonary Disease: A Meta-Analysis

2021

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Oxidative stress is a driving factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). While paraoxonase 1 (PON1) is an antioxidant enzyme and a potential biomarker of this disease, data regarding the status of PON-1 in COPD are inconclusive. In this regard, to shed light on this issue, we performed a meta-analysis of data on PON1 activity in COPD. Electronic databases (MEDLINE, Embase and CENTRAL) were searched for available studies on PON1 activity in patients with stable COPD published before October 2021. A meta-analysis was performed using random-effects models. Twelve studies (12 studies on paraoxonase and three on arylesterase) were identified. Patients with COPD had lower levels of paraoxonase activity (standard mean difference [SMD] −0.77, 95% confidence interval [CI] −1.35 to −0.18) and arylesterase activity (SMD −1.15, 95% CI −1.95 to −0.36) in comparison to healthy controls. In subgroup analyses, paraoxonase activity was lower in patients of studies as consisted of mainly non-severe COPD (SMD −1.42, 95% CI −2.04 to −0.79) and, by contrast, slightly higher in patients of studies including severe COPD (SMD 0.33, 95% CI 0.02 to 0.64) in comparison to healthy controls. Arylesterase activity showed a similar trend. Overall, PON1 activity was lower in patients with COPD, suggesting that PON1-related antioxidant defense is impaired in COPD. Future studies are warranted.

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Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

Cited by 38 publications

References 305 publications

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

Gold Nanoparticles Inhibit Steroid-Insensitive Asthma in Mice Preserving Histone Deacetylase 2 and NRF2 Pathways

Paraoxonase 1 and Chronic Obstructive Pulmonary Disease: A Meta-Analysis

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