The mechanism of corticosteroids in treating asthma.Inhaled corticosteroids ICS are the most effective controllers of asthma. They female bodybuilding contests 2017 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. This appears to be due to a reduction in HDAC2 activity and expression as a result of corticosteroid inhaler mechanism of action stress.
The mechanism of corticosteroids in treating asthma. - PubMed - NCBI
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.
This appears to be due to a reduction in HDAC2 activity and expression as a result of oxidative stress.
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. Inhaled corticosteroids ICS, also known as glucocorticosteroids, glucocorticoids, steroids are by far the most effective controllers used in the treatment of asthma and the only drugs that can effectively suppress the characteristic inflammation in asthmatic airways, even in very low doses.
There have been major advances in understanding the molecular mechanisms whereby ICS suppress inflammation in asthma, based on recent developments in understanding the fundamental mechanisms of gene transcription [ 1 , 2 ]. Corticosteroids activate and suppress many genes relevant to understanding their action in asthma Table 1. Progress has also been made in understanding the molecular mechanisms of corticosteroid resistance in severe asthma and COPD [ 3 ].
At a cellular level inhaled corticosteroids reduce the numbers of inflammatory cells in asthmatic airways, including eosinophils, T-lymphocytes, mast cells and dendritic cells Figure 1. These effects of corticosteroids are produced through inhibiting the recruitment of inflammatory cells into the airway by suppressing the production of chemotactic mediators and adhesion molecules and by inhibiting the survival in the airways of inflammatory cells, such as eosinophils, T-lymphocytes and mast cells.
Epithelial cells may be a major cellular target for ICS, which are the mainstay of modern asthma management. ICS suppress many activated inflammatory genes in airway epithelial cells Figure 2.
Epithelial integrity is restored by regular ICS. The suppression of mucosal inflammation is relatively rapid with a significant reduction in eosinophils detectable within six hours and associated with reduced airway hyperresponsiveness [ 4 , 5 , 6 ]. Reversal of airway hyperresponsiveness may take several months to reach a plateau, probably reflecting recovery of structural changes in the airway [ 7 ]. Inhaled corticosteroids may inhibit the transcription of several inflammatory genes in airway epithelial cells and thus reduce inflammation in the airway wall.
Corticosteroids diffuse across the cell membrane and bind to glucocorticoid receptors GR in the cytoplasm 2. Activated GRs rapidly translocate to the nucleus where they produce their molecular effects. A pair of GRs GR homodimer bind to glucocorticoid response elements GRE in the promoter region of steroid-responsive genes and this interaction switches on and sometimes switches off gene transcription Figure 3.
These effects may contribute to the anti-inflammatory actions of corticosteroids [ 10 , 11 ]. GR interaction with negative GREs may suppress gene transcription and it is though that this may be important in mediating many the side effects of corticosteroids.
For example, corticosteroids inhibit the expression of osteocalcin that is involved in bone synthesis [ 12 ]. 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.
The major action of corticosteroids is to switch off multiple activated inflammatory genes that encode for cytokines, chemokines, adhesion molecules inflammatory enzymes and receptors [ 1 ]. This results in acetylation of core histones, which opens up the chromatin structure so that gene transcription is facilitated [ 13 ].
Reduction of histone acetylation also occurs through the recruitment of histone deacetylase-2 HDAC2 to the activated inflammatory gene complex by activated GR, thereby resulting in effective suppression of all activated inflammatory genes within the nucleus Figure 4.
This accounts for why corticosteroids are so effective in the control of asthmatic inflammation, but also why they are safe, since other activated genes are not affected. Corticosteroid suppression of activated inflammatory genes. 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.
There may be additional mechanisms that are also important in the anti-inflammatory actions of corticosteroids. Corticosteroids have potent inhibitory effects on mitogen-activated kinase signalling pathways through the induction of MKP-1 and this may inhibit the expression of multiple inflammatory genes [ 10 , 11 ]. Some inflammatory genes, for example granulocyte-macrophage colony stimulating factor, have an unstable messenger RNA that is rapidly degraded by certain RNAses but stabilised when cells are stimulated by inflammatory mediators.
Corticosteroids reverse this effect, resulting in rapid degradation of mRNA and reduced inflammatory protein secretion [ 16 ]. This may be through the inhibition of proteins that stabilize mRNAs of inflammatory proteins, such as tristretraprolin [ 17 ]. Patients with severe asthma have a poor response to corticosteroids, which necessitates the need for high doses and a few patients are completely resistant.
All patients with COPD show corticosteroid resistance. Asthmatics who smoke are also relatively corticosteroid-resistant and require increased doses of corticosteroids for asthma control [ 18 ]. Several molecular mechanisms have now been identified to account for corticosteroid resistance in severe asthma and COPD [ 3 , 19 ].
In patients with COPD, smoking asthmatics and severe asthma there is a reduction in HDAC2 activity and expression, which prevents corticosteroids switching off activated inflammatory genes Figure 5 [ 20 , 21 , 22 ]. In steroid-resistant asthma other mechanisms may also contribute to corticosteroid insensitivity, including reduced translocation of GR as a result of phosphorylation by p38 MAP kinase [ 23 ] and abnormal histone acetylation patterns [ 24 ].
Mechanism of corticosteroid resistance in COPD, smoking asthma and severe asthma. 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 has been demonstrated in human lung in vitro [ 26 ] and nasal mucosa in vivo after topical application of a glucocorticoid [ 27 ].
The pharmacokinetics of ICS is important in relation to systemic effects [ 32 , 33 , 34 ]. The fraction of steroid which is inhaled into the lungs acts locally on the airway mucosa, but may be absorbed from the airway and alveolar surface. This fraction therefore reaches the systemic circulation Figure 7. The fraction of ICS which is deposited in the oropharynx is swallowed and absorbed from the gut. The absorbed fraction may be metabolized in the liver before reaching the systemic circulation first-pass metabolism.
Budesonide and fluticasone propionate have a greater first pass metabolism than beclomethasone dipropionate BDP and are therefore less likely to produce systemic effects at high inhaled doses. The use of a large volume spacer chamber reduces oropharyngeal deposition and therefore reduces systemic absorption of corticosteroids, although this effect is minimal in corticosteroids with a high first pass metabolism [ 35 ].
Mouth rinsing and discarding the rinse has a similar effect and this procedure should be used with high dose dry powder steroid inhalers, since spacer chambers cannot be used with these devices.
The ideal ICS with optimal therapeutic index should have high lung bioavailability, negligible oral bioavailability, low systemic absorption, high systemic clearance and high protein binding [ 36 ].
Ciclesonide is an inactive prodrug that is activated by esterases in the lung to the active metabolite des-ciclesonide [ 37 ]. This may reduce oropharyngeal side effects as esterases appear to be less active in this site than in the lower airways. Ciclesonide is also claimed to be effective as a once daily therapy.
There is no doubt that the early use of ICS has revolutionized the management of asthma, with marked reductions in asthma morbidity and improvement in health status. ICS are now recommended as first-line therapy for all patients with persistent asthma [ 38 ]. Several topically acting corticosteroids are now available for inhalation Figure 8. ICS are very effective in controlling asthma symptoms in asthmatic patients of all ages and severity. ICS improve the quality of life of patients with asthma and allow many patients to lead normal lives, improve lung function, reduce the frequency of exacerbations and may prevent irreversible airway changes.
They were first introduced to reduce the requirement for oral corticosteroids in patients with severe asthma and many studies have confirmed that the majority of patients can be weaned off oral corticosteroids [ 3 ]. As experience has been gained with ICS they have been introduced in patients with milder asthma, with the recognition that inflammation is present even in patients with mild asthma.
Although the effects of ICSs on AHR may take several months to reach a plateau, the reduction in asthma symptoms occurs much more rapidly and reduced inflammation is seen within hours [ 4 , 5 , 6 ].
High dose ICS may be used for the control of more severe asthma. This markedly reduces the need for maintenance oral corticosteroids [ 43 ]. ICS are the treatment of choice in nocturnal asthma, which is a manifestation of inflamed airways, reducing nocturnal awakening and reducing the diurnal variation in airway function. ICS effectively control asthmatic inflammation but must be taken regularly.
When ICS are discontinued there is usually a gradual increase in symptoms and airway responsiveness back to pretreatment values. Reduction in the dose of ICS is associated with an increase in symptoms and this is preceded by an increase in exhaled NO and sputum eosinophils [ 44 , 45 ].
ICS are equally effective in children. Nebulized budesonide reduces the need for oral corticosteroids and also improved lung function in children under the age of three [ 46 ]. ICS given via a large volume spacer improve asthma symptoms and reduce the number of exacerbations in preschool children and in infants. Surprisingly, the dose-response curve for the clinical efficacy of ICS is relatively flat and, while all studies have demonstrated a clinical benefit of ICS, it has been difficult to demonstrate differences between doses, with most benefit obtained at the lowest doses used [ 47 , 48 ].
This is in contrast to the steeper dose-response for systemic effects, implying that while there is little clinical benefit from increasing doses of ICS the risk of adverse effects is increased.
However, the dose-response effect of ICS may depend on the parameters measured and, while it is difficult to discern a dose-response when traditional lung function parameters are measured, there may be a dose-response effect in prevention of asthma exacerbations. These findings suggest that pulmonary function tests or symptoms may have a rather low sensitivity in the assessment of the effects of ICS.
This is obviously important for the interpretation of clinical comparisons between different ICS or inhalers. It is also important to consider the type of patient included in clinical studies. Patients with relatively mild asthma may have relatively little room for improvement with ICS, so that maximal improvement is obtained with relatively low doses.
Patients with more severe asthma or with unstable asthma may have more room for improvement and may therefore show a greater response to increasing doses, but it is often difficult to include such patients in controlled clinical trials. More studies are needed to assess whether other outcome measures such as AHR or more direct measurements of inflammation, such as sputum eosinophils or exhaled NO, may be more sensitive than traditional outcome measures such as symptoms or lung function tests [ 50 , 51 , 52 , 53 ].
Higher doses of ICS are needed to control AHR than to improve symptoms and lung function, and this may have a better long-term outcome in terms of reduction in structural changes of the airways [ 54 ]. Measurement of sputum eosinophils to adjust the dose of ICS may reduce the overall dose requirement for ICS and exacerbations [ 55 , 56 ]. Monitoring of exhaled NO may also reduce the requirement for corticosteroids but is not yet practical in clinical practice [ 57 ].
Some patients with asthma develop an element of irreversible airflow obstruction, but the pathophysiological basis of these changes is not yet understood. It is likely that they are the result of chronic airway inflammation and that they may be prevented by treatment with ICS. There is some evidence that the annual decline in lung function may be slowed by the introduction of ICS [ 58 ] and this is supported by a five year study of low dose budesonide in patients with mild asthma [ 59 , 60 ].
Increasing evidence also suggests that delay in starting ICS may result in less overall improvement in lung function in both adults and children [ 61 , 62 , 63 ].
These studies suggest that introduction of ICS at the time of diagnosis is likely to have the greatest impact [ 62 , 63 ]. So far there is no evidence that early use of ICS is curative and even when ICS are introduced at the time of diagnosis, symptoms and lung function revert to pretreatment levels when corticosteroids are withdrawn [ 61 ].
In a retrospective review of the risk of mortality and prescribed anti-asthma medication, there was a significant protection provided by regular ICS therapy [ 64 ]. The increase in use of rescue therapy should result in an increase in the maintenance dose of ICS. Several ICS are currently on the market for use in asthma, although their availability varies between countries.