title: Heterogeneity in mechanisms influencing glucocorticoid sensitivity: the need for a systems biology approach to treatment of glucocorticoid-resistant inflammation.
abstract: Glucocorticoids (GCs) have impressive anti-inflammatory and immunosuppressive effects and show a diversity of actions across a variety of cell phenotypes. Implicit in efforts to optimize GCs as anti-inflammatory agents for any or all indications is the notion that the relevant mechanism(s) of action of GCs are fully elucidated. However, recent advances in understanding GC signalling mechanisms have revealed remarkable complexity and contextual dependence, calling into question whether the mechanisms of action are sufficiently well-described to embark on optimization. In the current review, we address evidence for differences in the mechanism of action in different cell types and contexts, and discuss contrasts in mechanisms of glucocorticoid insensitivity, with a focus on asthma and Chronic Obstructive Pulmonary Disease (COPD). Given this complexity, we consider the potential breadth of impact and selectivity of strategies directed to reversing the glucocorticoid insensitivity.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Keenan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Danica
authors.initials: D
authors.lastname: Radojicic
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Meina
authors.initials: M
authors.lastname: Li
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Radwan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: astew@unimelb.edu.au.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D001682:Biological Availability; D005938:Glucocorticoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D049490:Systems Biology; D015533:Transcriptional Activation; D017211:Treatment Failure
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid
keywords: Airways; Asthma; COPD; Cytokines; Idiopathic pulmonary fibrosis; Innate host defence