Mechanisms of glucocorticoid action and insensitivity in airways disease

doi:10.1016/j.pupt.2014.08.008

Pulmonary Pharmacology & Therapeutics

Volume 29, Issue 2, December 2014, Pages 129-143

https://doi.org/10.1016/j.pupt.2014.08.008 Get rights and content

Abstract

Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.

Introduction

Glucocorticoids are important in the regulation of numerous physiological functions in the body and because of their powerful anti-inflammatory and immunosuppressive actions, glucocorticoids are among the most widely prescribed drugs in the world today [1], [2]. As a result glucocorticoids are used to treat a broad spectrum of inflammatory and autoimmune diseases, such as asthma, allergy, sepsis, rheumatoid arthritis, ulcerative colitis, and multiple sclerosis [3], [4]. Glucocorticoids are also among the most widely used drugs for treating asthma and chronic obstructive pulmonary disease (COPD). However, in a substantial proportion of patients with these disorders, glucocorticoids are not effective because of tissue-specific glucocorticoid insensitivity induced by disease-related factors. Individual differences in glucocorticoid sensitivity have been recognized in health and disease and can be caused by genetic and acquired factors. In this Review, we discuss recent insights into the mechanisms that influence glucocorticoid sensitivity in health and disease. Possible strategies to modulate glucocorticoid sensitivity and improve the outcomes of glucocorticoid therapy are also discussed.

Section snippets

Glucocorticoids secretion and the hypothalamic–pituitary–adrenal axis

Endogenous glucocorticoids are hormones essential for life that regulate a variety of physiological processes involved in development, intermediary metabolism, homeostasis, immune and cardiovascular function, reproduction and cognition. In addition, synthetic glucocorticoids are widely prescribed drugs for many inflammatory diseases including asthma and COPD.

Cortisol, the endogenous glucocorticoid hormone in humans, is synthesized and released under the regulation of the

Glucocorticoid actions in airway diseases

Inhaled glucocorticoids (also called as inhaled corticosteroids or ICS) are used widely in airways disease for their anti-inflammatory effects and are considered the gold standard of asthma treatment, although a subset of severe asthmatics as well as patients with COPD are relatively insensitive to these drugs [46]. In addition, there is evidence that long-term usage of particularly high doses of ICS in asthma may cause adverse effects such as adrenal suppression, osteoporosis and growth

Glucocorticoid effects in sensitive individuals

Glucocorticoids affect most cells and tissues in the body producing profound anti-inflammatory and immunosuppressive effects. They inhibit goblet cell hyperplasia and mucus hypersecretion [74], a major clinical feature of chronic airway diseases. They also inhibit plasma exudation [75] and modulate the expression of adhesion molecules and chemokines resulting in the redistribution of inflammatory cells, depletion of basophils and eosinophils and increased apoptosis of lymphoid cells, therefore

Glucocorticoid insensitivity in airway diseases

The anti-inflammatory activity of cortisone was first documented by Philip Hench in 1948, and since then glucocorticoids have been shown to be highly effective in controlling a myriad of inflammatory diseases [3], [65], [108], [109], [110], [111], [112], [113], [114]. However, prolonged exposure results in an array of side effects, which limit the therapeutic potential of systemic glucocorticoids. The side effects include e.g. adrenal suppression, the onset of diabetes, myopathy (muscular

Novel strategies to modulate glucocorticoid insensitivity in airway diseases

Inhaled glucocorticoids or inhaled corticosteroids (ICS) are very effective in treating many inflammatory and immune diseases such as asthma. However, patients with severe asthma, and other inflammatory diseases, including chronic obstructive pulmonary disease and interstitial pulmonary fibrosis, do not respond well to ICS treatment and at high risk of adverse effects [87], [126]. There are evidences in literature to support the limitation in the transrepression hypothesis, as there is a

Summary and future perspectives

The inflammatory processes in airways disease are complex and heterogeneous [221], [222]. Differences in glucocorticoid sensitivity can be recognized in health and disease, and both genetic and acquired factors can modulate local or systemic glucocorticoid sensitivity. Glucocorticoid insensitivity may contribute to disease severity. Variable intensity of inflammation may explain the very common clinical observation that insensitivity is relative. Glucocorticoid insensitivity in chronic airways

Acknowledgements

All authors declare no conflicts of interest. CB and MMP are supported by Imperial College, UK. AG is supported by studentship from College of Medicine, Biological Sciences and Psychology, University of Leicester, UK. YCX is supported by National Health and Medical Research Council, Australia. PS is supported by career development award from Alberta Innovates Health Solutions and Canadian Institute of Health Research/Canadian Lung Association/GlaxoSmithKline Rx&D Fellowship, Canada.

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Mechanisms of glucocorticoid action and insensitivity in airways disease

Abstract

Introduction

Section snippets

Glucocorticoids secretion and the hypothalamic–pituitary–adrenal axis

Glucocorticoid actions in airway diseases

Glucocorticoid effects in sensitive individuals

Glucocorticoid insensitivity in airway diseases

Novel strategies to modulate glucocorticoid insensitivity in airway diseases

Summary and future perspectives

Acknowledgements

Trends Endocrinol Metab

Trends Pharmacol Sci

Trends Pharmacol Sci

Steroids

Pharmacol Ther

Mol Cell

Biochimica Et Biophys Acta Gene Struct Expr

J Steroid Biochem Mol Biol

J Allergy Clin Immunol

J Biol Chem

J Biol Chem

Gastroenterology

Biochem Biophys Res Commun

J Allergy Clin Immunol

Biochem Biophys Res Commun

J Allergy Clin Immunol

J Allergy Clin Immunol

Steroids

Pharmacol Ther

Mol Cell Biology Res Commun

Trends Endocrinol Metabolism

Lancet

J Pharmacol Sci

Trends Endocrinol Metab

Drug Discov Today

Mol Cell Endocrinol

Neurobiol Aging

Trends Endocrinol Metab

Biochem Pharmacol

Antiinflammatory action of glucocorticoids – new mechanisms for old drugs

N. Engl J Med

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions

Endocr Rev

Stress and the brain: from adaptation to disease

Nat Rev Neurosci

Glucocorticoid sensitivity in health and disease

Nat Rev Endocrinol

Th2 cytokine-induced upregulation of 11β-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function

Am J Physiol Lung Cell Mol Physiol

Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

Cell Death Dis

Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells

Immunobiology

Mechanisms generating diversity in glucocorticoid receptor signaling

Ann NY Acad Sci

CD38 expression is insensitive to steroid action in cells treated with Tumor Necrosis factor-α and interferon-γ by a mechanism involving the up-regulation of the glucocorticoid receptor β isoform

Mol Pharmacol

Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids

Mol Endocrinol

Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

Mol Cancer Ther

How do corticosteroids work in asthma?

Ann Intern Med

Expression and subcellular distribution of the β-isoform of the human glucocorticoid receptor

Endocrinology

Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform: a mechanism for the generation of glucocorticoid resistance

Proc Natl Acad Sci USA

Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural cells

Am J Respir Cell Mol Biol

Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor β

J Exp Med

Decreased steroid responsiveness at night in nocturnal asthma

Am J Respir Crit Care Med

Increased glucocorticoid receptor β in airway cells of glucocorticoid-insensitive asthma

Am J Respir Crit Care Med

Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma

Am J Respir Crit Care Med

Alpha and beta glucocorticoid receptors: relevance in airway diseases

Curr Allergy Asthma Rep