Inhaled Corticosteroids

Abstract

Inhaled corticosteroids (ICS) are the most effective controllers of asthma. They suppress inflammation mainly by switching off multiple activated inflammatory genes through reversing histone acetylation via the recruitment of histone deacetylase 2 (HDAC2). Through suppression of airway inflammation ICS reduce airway hyperresponsiveness and control asthma symptoms. ICS are now first-line therapy for all patients with persistent asthma, controlling asthma symptoms and preventing exacerbations. Inhaled long-acting β₂-agonists added to ICS further improve asthma control and are commonly given as combination inhalers, which improve compliance and control asthma at lower doses of corticosteroids. By contrast, ICS provide much less clinical benefit in COPD and the inflammation is resistant to the action of corticosteroids. This appears to be due to a reduction in HDAC2 activity and expression as a result of oxidative stress. ICS are added to bronchodilators in patients with severe COPD to reduce exacerbations. ICS, which are absorbed from the lungs into the systemic circulation, have negligible systemic side effects at the doses most patients require, although the high doses used in COPD has some systemic side effects and increases the risk of developing pneumonia.

Keywords: eosinophil; epithelial cell; glucocorticoid receptor; histone deacetylase; inflammation; inflammatory gene; long-acting β2-agonist; nuclear factor-κB; pneumonia.

Figure 1

Cellular effect of corticosteroids.

Figure 2

Inhaled corticosteroids may inhibit the transcription of several inflammatory genes in airway epithelial cells and thus reduce inflammation in the airway wall. NF-κB = nuclear factor κB; AP-1 = activator protein-1; GM-CSF = granulocyte-macrophage colony stimulating factor; IL-1 = interleukin-1; iNOS = inducible nitric oxide synthase; NO = nitric oxide; COX-2 = inducible cyclooxygenase; cPLA₂ = cytoplasmic phospholipase A₂; PG = prostaglandin; ET = endothelin; ICAM = intercellular adhesion molecule.

Figure 3

Corticosteroids may regulate gene expression in several ways. Glucocorticoids enter the cell to bind to glucocorticoid receptors in the cytoplasm that translocate to the nucleus. GR homodimers bind to glucocorticoid-response elements (GRE) in the promoter region of steroid-sensitive genes, which may encode anti-inflammatory proteins. Less commonly, GR homodimers interact with negative GREs to suppress genes, particularly those linked to side effects of corticosteroids. Nuclear GR also interact with coactivator molecules, such as CREB-binding protein (CBP), which is activated by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB), thus switching off the inflammatory genes that are activated by these transcription factors. Other abbreviations: SLPI: secretory leukoprotease inhibitor; MKP-1: mitogen-activated kinase phosphatase-1; IκB-α: inhibitor of NF-κB; GILZ: glucocorticoid-induced leucine zipper protein; POMC: proopiomelanocortin; CRH: corticotrophin releasing factor.

Figure 4

Corticosteroid suppression of activated inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as interleukin-1β (IL-1β) or tumour necrosis factor-α (TNF-α), resulting in activation of IKK2 (inhibitor of I-κB kinase-2), which activates the transcription factor nuclear factor κB (NF-κB). A dimer of p50 and p65 NF-κB proteins translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as CREB-binding protein (CBP) or p300/CBP-activating factor (pCAF), which have intrinsic histone acetyltransferase (HAT) activity. This results in acetylation of core histone H4, resulting in increased expression of genes encoding multiple inflammatory proteins. Glucocorticoid receptors (GR) after activation by glucocorticoids translocate to the nucleus and bind to coactivators to inhibit HAT activity directly and recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation leading in suppression of these activated inflammatory genes.

Figure 5

Mechanism of corticosteroid resistance in COPD, smoking asthma and severe asthma. Stimulation of mild asthmatic alveolar macrophages activates nuclear factor-κB (NF-κB) and other transcription factors to switch on histone acetyltransferase leading to histone acetylation and subsequently to transcription of genes encoding inflammatory proteins, such as tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8) and granulocyte-macrophage colony stimulating factor (GM-CSF). Corticosteroids reverse this by binding to glucocorticoid receptors (GR) and recruiting histone deacetylase-2 (HDAC2). This reverses the histone acetylation induced by NF-κB and switches off the activated inflammatory genes. In COPD patients and smoking asthmatics cigarette smoke generates oxidative stress (acting through the formation of peroxynitrite) and in severe asthma and COPD intense inflammation generates oxidative stress to impair the activity of HDAC2. This amplifies the inflammatory response to NF-κB activation, but also reduces the anti-inflammatory effect of corticosteroids, as HDAC2 is now unable to reverse histone acetylation.

Figure 6

Interaction between corticosteroids and long-acting β₂-agonists (LABA). Corticosteroids have anti-inflammatory effects but also increase the numbers of β₂-receptors, whereas β₂-agonists, as well as inducing direct bronchodilatation, act on glucocorticoid receptors to increase the anti-inflammatory effects of corticosteroids.

Figure 7

Pharmacokinetics of inhaled glucocorticoids. GI = gastrointestinal

Figure 8

Chemical structures of inhaled glucocorticoids.