Corticosteroids: The drugs to beat

Abstract

Corticosteroids are the most effective anti-inflammatory therapy for asthma and other chronic inflammatory and immune diseases. Recently new insights have been gained into the molecular mechanisms whereby corticosteroids suppress inflammation. Inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-κB and activator protein-1. These transcription factors bind to and activate coactivator molecules, which acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex. Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase, which inhibits MAP kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side effects. In some patients with steroid-resistant asthma there are abnormalities in GR signalling pathways. In chronic obstructive pulmonary disease (COPD) patients and asthmatic patients who smoke HDAC2 is markedly impaired as a result of oxidative and nitrative stress so that inflammation is resistant to the anti-inflammatory effects of corticosteroids. Corticosteroids are likely to remain the mainstay of asthma therapy and new therapeutic strategies may reverse the corticosteroid insensitivity in COPD and severe asthma.

Introduction

Corticosteroids (glucocorticosteroids) are widely used to treat a variety of inflammatory and immune diseases. The most common use of corticosteroids today is in the treatment of asthma and other allergic diseases and inhaled corticosteroids have now become established as first-line treatment in adults and children with persistent asthma. Despite intense efforts by the pharmaceutical industry it has proved extraordinarily difficult to find any new treatment that comes close to therapeutic benefit of corticosteroids in asthma (Barnes, 2004). This review will focus on the cellular and molecular mechanisms of corticosteroids in asthma and also discuss why they do not appear to work in some patients with asthma or in patients with chronic obstructive pulmonary disease (COPD). There have been major advances in understanding the molecular mechanisms whereby corticosteroids suppress inflammation, based on recent developments in understanding the fundamental mechanisms of gene transcription (Barnes and Adcock, 2003, Barnes et al., 2005). This has important clinical implications, as it will lead to a better understanding of the inflammatory mechanisms of many diseases and may signal the development of new anti-inflammatory treatments in the future. The new understanding of these molecular mechanisms also helps to explain how corticosteroids are able to switch off multiple inflammatory pathways, and it also provides insights into why corticosteroids apparently fail to work in patients with steroid-resistant asthma and in patients with COPD.

Solomon Solis-Cohen, a physician from Philadelphia, demonstrated that orally administered adrenal extract (adrenal substance pills) was beneficial in asthma (Solis-Cohen, 1900) and this led to the development of adrenaline (epinephrine) and sympathomimetics as bronchodilators. However the beneficial clinical effect described by Solis-Cohen are more likely to be due to the steroid content as adrenaline is not be absorbed in significant amounts from the gastrointestinal tract. This was not recognised at the time and it was not until cortisol was isolated from the adrenal cortex that the idea of corticosteroids as therapy for asthma became clear. The Nobel Prize for Medicine and Physiology was awarded in 1950 to Kendall and Reichstein who had independently isolated and synthesised cortisol and then adrenocorticotropic hormone (ACTH) and Philip Hench, a rheumatologist working at the Mayo Clinic, who had described its dramatic efficacy when given by intravenous injection in patients with rheumatoid arthritis. Only 6 months after Hench's demonstration of the clinical efficacy of ACTH in rheumatoid patients, Boardley and colleagues at John Hopkins University had shown that it had equally good effects in patients with asthma (Boardley et al., 1949). They described 5 patients with asthma, interestingly all of whom had eosinophilic sputum, who improved rapidly with intramuscular injections of ACTH over a 3 week period with disappearance of the sputum. They subsequently confirmed these observations in a larger group of patients. As a replacement for the injections it was subsequently shown that oral cortisone, widely used at the time to treat several inflammatory diseases, was an effective therapy in patients with difficult to control asthma (Schwartz, 1951). But there was scepticism in the UK leading to a Medical Research Council multicentre trial of cortisone in asthma patients, which was the first placebo-controlled trial performed in asthma (Medical Research Council, 1956). Surprisingly the results were disappointing with few clinical improvements that were not sustained during the 2 months of therapy. This may have reflected the low dose of cortisone used, the lack of objective measurements of lung function and the inclusion of many patients who had COPD. Despite this poor result oral steroids became used more and more in patients with severe asthma, but it was clear that side effects were a major problem resulting in stunting of growth in children, osteoporosis and metabolic disturbances. This immediately suggested the need to give corticosteroids by inhalation as a way of reducing systemic side effects, yet cortisone and dexamethasone by inhalation proved to be of little benefit. This turned out to be because of their lack of topical efficacy and led to a search for topically active steroids. McKenzie and Stoughton discovered that this topical efficacy was correlated with skin blanching, although the cellular basis for this test is still uncertain (McKenzie and Stoughton, 1962). Hydrocortisone turned out to be weak in the McKenzie test, but two synthetic steroids beclomethasone dipropionate (BDP) and betamethasone-17-valerate gave good skin blanching responses. Both of these steroids were effective as topical treatments for eczema, predicting that they may also be effective by inhalation. Both of these new steroids were developed for inhalation and an important paper by Morrow Brown and colleagues in 1972 established that inhaled BDP was very effective in reducing the need for oral corticosteroids and in many patients achieved better control (Brown et al., 1972). Interestingly, Brown reported that the patients who did best had high numbers of eosinophils in their sputum, an observation that has been confirmed in many subsequent studies. Subsequently, inhaled corticosteroids were introduced into clinical practice, initially as a means of reducing the dose of oral corticosteroids, but as their efficacy became apparent they came to be used as first-line therapy in most patients.