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Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

ABSTRACT: The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients.We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function.PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed.Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity.A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population.

SUBMITTER: Stephenson ST

PROVIDER: S-EPMC4530082 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

Stephenson Susan T ST Brown Lou Ann S LA Helms My N MN Qu Hongyan H Brown Sheena D SD Brown Milton R MR Fitzpatrick Anne M AM

The Journal of allergy and clinical immunology 20150306 2

<h4>Background</h4>The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients.<h4>Objective</h4>We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxi ...[more]

PMID: 25748343

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Project description:Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Project description:BackgroundAsthma, a common yet complex airway disorder affecting about 11% of Australians, is well-controlled in only 54% of people with asthma. Those with difficult-to-treat and severe asthma are more likely to experience recurrent and potentially life-threatening exacerbations. It is therefore important that GPs can initiate a systematic approach for the management of patients with difficult-to-treat asthma to identify those whose condition may improve by addressing contributory factors and those who require specialist input. We therefore aimed to develop and deliver an educational program for GPs on the systematic management of patients with difficult-to-treat and severe asthma and evaluate the effectiveness of this program.MethodsWe developed an educational program on the management of difficult-to-treat and severe asthma in primary care that was delivered to GPs and other health professionals between January and June 2018. We evaluated the effectiveness of the program using a retrospective pre-test with post-survey, administered to GPs directly after program participation.ResultsOver 1000 general practice health professionals participated in the educational program, including 890 GPs of whom 226 (25%) completed the survey. Following program participation, a greater proportion of GPs identified factors they would assess in managing a patient with poor asthma control, particularly for considering the risk of future adverse outcomes (+ 51%), changes in lifestyle (+ 38%), and self-management strategies (+ 35%). GPs indicated a greater awareness of the biologic therapies that specialists could consider prescribing to their patients with severe asthma (+ 75%), of the requirements for a patient to be prescribed a biologic therapy (+ 73%) and that patients with different phenotypic characteristics can respond differently to standard therapy (+ 67%). The proportion of GPs who would refer appropriate patients to a specialist also significantly increased.ConclusionsThis study suggests that an evidence-based educational program can improve GP knowledge, confidence and intended practice in managing patients with difficult-to-treat and severe asthma.

Dataset Information

Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

Publications

Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

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