Why do some asthma patients respond poorly to glucocorticoid therapy?. (October 2020)

• Record Type: Journal Article
• Authors: Henderson, Ishbel; Caiazzo, Elisabetta; McSharry, Charles; Guzik, Tomasz J.; Maffia, Pasquale
• Is Part Of: Pharmacological research. Volume 160(2020)
• Publication Date: 2020-10
• Subjects: AP1 activator protein-1 -- CSF 3 colony-stimulating factor 3 -- FENO fractional exhaled nitric oxide -- FEV1 forced expiratory volume in 1 second -- GCs glucocorticosteroids -- GR GC receptor -- GRE GC response elements -- GWAS genomic wide association studies -- HDAC histone deacetylase -- HPA hypothalamic-pituitary-adrenal -- IAV influenza A virus -- ICS inhaled corticosteroids -- IL interleukin -- JNK c-Jun N-terminal kinase -- MAP mitogen-activated protein -- MAPK mitogen-activated protein kinase -- NF-κB Nuclear factor-κB -- NLRP3 NLR Family Pyrin Domain Containing 3 -- PBMCs peripheral blood mononuclear cells -- RSV respiratory syncytial virus -- TF transcription factors -- Th T helper -- VDBP vitamin D-binding protein; Asthma -- Glucocorticoids -- Glucocorticoid receptor -- Steroid-resistant asthma; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105189
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Glucocorticosteroids are the first-line therapy for controlling airway inflammation in asthma. They bind intracellular glucocorticoid receptors to trigger increased expression of anti-inflammatory genes and suppression of pro-inflammatory gene activation in asthmatic airways. In the majority of asthma patients, inhaled glucocorticoids are clinically efficacious, improving lung function and preventing exacerbations. However, 5–10 % of the asthmatic population respond poorly to high dose inhaled and then systemic glucocorticoids. These patients form a category of severe asthma associated with poor quality of life, increased morbidity and mortality, and constitutes a major societal and health care burden. Inadequate therapeutic responses to glucocorticoid treatment is also reported in other inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease; however, asthma represents the most studied steroid-refractory disease. Several cellular and molecular events underlying glucocorticoid resistance in asthma have been identified involving abnormalities of glucocorticoid receptor signaling pathways. These events have been strongly related to immunological dysregulation, genetic, and environmental factors such as cigarette smoking or respiratory infections. A better understanding of the multiple mechanisms associated with glucocorticoid insensitivity in asthma phenotypes could improve quality of life for people with asthma but would also provide transferrable knowledge for other inflammatory diseases. In this review, we provide an update on the molecular mechanisms behind steroid-refractory asthma. Additionally, we discuss some therapeutic options for treating those asthmatic patients who respond poorly to glucocorticoid therapy.