Glucocorticosteroids current and future directionsMolecular effects of inhaled glucocorticosteroids current and future directions therapy in asthma Direct effects of glucocorticosteroids on epidermal Langerhans cells Anabolic Steroids for Sale, Buy Steroids Online, Legal. Glucocorticoids are the most effective anti-inflammatory therapy for asthma yet glucocorticosetroids relatively ineffective in chronic obstructive pulmonary disease. Barnes PJ Glucocorticosteroids: Br J Pharmacol 1 Barnes PJ a Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. These effects mean an asthma attack is less likely to occur in the future. Masteron lowers cholesterol, individuals who use glucocorticosteroids to prevent future attacks of asthma typically remain hyper-responsive to some degree.
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Glucocorticoids are the most effective anti-inflammatory therapy for asthma yet are relatively ineffective in chronic obstructive pulmonary disease. Glucocorticoids suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors GR to co-activator molecules and recruitment of histone deacetylase-2 to the activated inflammatory gene transcription complex trans -repression.
At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects trans -activation. Glucocorticoids also have post-transcriptional effects and decrease stability of some pro-inflammatory mRNA species. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with chronic obstructive pulmonary disease.
Several molecular mechanisms of glucocorticoid resistance have now been identified which involve post-translational modifications of GR. Dissociated glucocorticoids and selective GR modulators which show improved trans -repression over trans -activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects.
In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance. This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http: Glucocorticosteroids also called glucocorticoids, corticosteroids or steroids are the most effective anti-inflammatory drugs available for the treatment of many chronic inflammatory and immune diseases, including asthma.
However, a minority of patients with these diseases show little or no response even to high doses of glucocorticoids. Several other inflammatory diseases, including chronic obstructive pulmonary disease COPD , interstitial pulmonary fibrosis and cystic fibrosis, appear to be largely glucocorticoid-resistant.
Both asthma and COPD involve chronic inflammation of the respiratory tract, with the activation and recruitment of many inflammatory cells and orchestrated by a complex network of inflammatory mediators Barnes, a , b ;. However, there are differences in the nature of this inflammation and its inflammatory consequences between these diseases and perhaps this is best demonstrated by the differing response to glucocorticoids, which is excellent in most patients with asthma but very poor in most patients with COPD.
There is now a much better understanding of how glucocorticoids suppress chronic inflammation in asthma and also why they fail to work in some patients with asthma and most patients with COPD, despite the fact that inflammatory genes are activated in these two diseases by similar molecular mechanisms.
This has given insights into how glucocorticoids might be improved in the future and how glucocorticoid resistance may be overcome with new classes of therapy Barnes and Adcock, The early use of inhaled corticosteroids ICS has revolutionized the management of asthma, with marked reductions in asthma morbidity and mortality.
ICS are now recommended as first-line therapy for all patients with persistent asthma, including children Bateman et al. Several topically acting glucocorticoids are now available for inhalation and all have similar efficacy, but have pharmacokinetic differences that account for differences in therapeutic ratio between these drugs.
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 Barnes et al. ICS were first introduced to reduce the requirement for oral glucocorticoids in patients with severe asthma and many studies have confirmed that the great majority of patients can be weaned off oral glucocorticoid.
There are local side effects of ICS, including increased oral candidiasis and dysphonia, but these are rarely a major problem. Systemic side effects, largely arising from absorption of ICS from the lung, are not a problem in patients treated with the usually required doses, but may become a problem in patients with severe asthma who require larger doses for asthma control.
Most patients with COPD have a poor response to glucocorticoids in comparison to asthma with little improvement in lung function or symptoms Suissa and Barnes, ; Barnes, a. However, even the effect on exacerbations has been questioned as it is largely explained by an artefact in trial design Suissa and Barnes, Several large studies have shown that glucocorticoids failed to reduce the progression in COPD [measured by annual fall in forced expiratory volume in 1 second FEV 1 ] Yang et al. These results are likely to reflect the resistance of pulmonary inflammation to glucocorticoid in COPD patients which is discussed below.
This overuse of glucocorticoids is likely to produce several long-term side effects, such as osteoporosis, diabetes, cataracts, hypertension and pneumonia Barnes, a. Oral glucocorticoids are used to treat acute exacerbations, although they are poorly effective. There have been major advances in understanding the molecular mechanisms whereby glucocorticoids suppress inflammation in asthma Rhen and Cidlowski, ; Barnes, b ; b ;.
Glucocorticoids activate many anti-inflammatory genes, and repress many pro-inflammatory genes that have been activated in inflammation Table 1 , as well as having several post-transcriptional effects. Understanding the molecular mechanisms of glucocorticoid action has also provided new insights into understanding molecular mechanisms involved in glucocorticoid resistance Barnes and Adcock, Glucocorticoids diffuse across the cell membrane and bind to GR in the cytoplasm Rhen and Cidlowski, ; Nicolaides et al.
Upon ligand binding, GR are activated and released from chaperone proteins heat shock protein and others and rapidly translocate to the nucleus where they exerts their molecular effects. In addition, there is evidence that multiple GR isoforms are generated by alternative splicing and alternative translation initiation.
These isoforms have unique tissue distribution patterns and transcriptional regulatory profiles. Furthermore, each is subject to various post-translational modifications that may affect receptor function, which determine the cell-specific response to glucocorticoids Lu and Cidlowski, Glucocorticoid receptors homodimerize and bind to glucocorticoid response elements GRE in the promoter region of glucocorticoid-responsive genes and this interaction switches on or occasionally switches off gene transcription.
Activation of glucocorticoid-responsive genes occurs via an interaction between the DNA-bound GR and transcriptional co-activator molecules such as CREB-binding protein, which have intrinsic histone acetyltransferase activity and cause acetylation of core histones particularly histone These effects may contribute to the anti-inflammatory actions of glucocorticoids Clark, ; Barnes, a.
GR interaction with negative GREs, or to GREs that cross the transcriptional start site, may suppress gene transcription and this may be important in mediating many of the side effects of glucocorticoids, such as inhibition of osteocalcin that is involved in bone synthesis Figure 2 Dostert and Heinzel, Glucocorticoid activation of anti-inflammatory gene expression. Glucocorticoids regulate gene expression in several ways. Glucocorticoids enter the cell to bind to glucocorticoid receptors GR 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.
The major action of glucocorticoids is to switch off multiple activated inflammatory genes that encode for cytokines, chemokines, adhesion molecules inflammatory enzymes and receptors Barnes and Adcock, These genes are activated through interactions with transcriptional co-activator molecules in a similar manner to that described above for GR-mediated gene transcription Barnes et al.
Reduction of histone acetylation more importantly occurs through the specific recruitment of histone deacetylase-2 HDAC2 to the activated inflammatory gene complex by activated GR, thereby resulting in effective suppression of activated inflammatory genes within the nucleus Figure 3. This may account for not only why glucocorticoids are so effective in the control of inflammation, but also why they are relatively safe, because genes other than those that encode inflammatory proteins are not affected.
The site of acetylation of GR is the lysine rich region with the sequence KKTK, which is analogous to the acetylation sites identified on other nuclear hormone receptors. Glucocorticoid 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 co-activators to inhibit HAT activity directly and recruiting histone deacetylase-2 HDAC2 , which reverses histone acetylation leading in suppression of these activated inflammatory genes.
Acetylation of glucocorticoid receptors GR. Additional mechanisms are also important in the anti-inflammatory actions of glucocorticoids. Glucocorticoids have potent inhibitory effects on mitogen-activated protein kinase MAPK signalling pathways through the induction of MKP-1 and this may inhibit the expression of multiple inflammatory genes Clark, ; Barnes, a Figure 5. An important effect of glucocorticoids in the treatment of allergic diseases is through suppression of Th2 cells and Th2 cytokines [interleukin IL 4, IL-5 and IL] and this may be mediated via inhibition of the transcription factor GATA3 which regulates the transcription of Th2 cytokine genes Maneechotesuwan et al.
A further immunosuppressive effect of glucocorticoids is through enhanced activity and expression of indoleamine-2,3-dioxygenase, a tryptophan-degrading enzyme that plays a key role in the regulation of T-lymphocyte function in allergic diseases through increased secretion of the anti-inflammatory cytokine IL Maneechotesuwan et al.
Interestingly, this effect of glucocorticoids on indoleamine-2,3-dioxygenase is further enhanced by statins Maneechotesuwan et al. Inhibition of p38 mitogen-activated protein MAP kinase by glucocorticoids. Corticosteroids induce the expression of MAP kinase phosphatase MKP -1, which inhibits p38 and thus prevents the stabilization of multiple inflammatory proteins. Glucocorticoids reverse this effect, resulting in rapid degradation of mRNA and reduced inflammatory protein secretion Bergmann et al.
This may be mediated through the increased gene expression of proteins that destabilize mRNAs of inflammatory proteins, such as the zinc finger protein tristetraprolin, which binds to the 3' AU-rich untranslated region of mRNAs Smoak and Cidlowski, At a cellular level glucocorticoids reduce the numbers of inflammatory cells in the airways, including eosinophils, T-lymphocytes, mast cells and dendritic cells Barnes et al.
These effects of glucocorticoids 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 the major cellular target for ICS, which are the mainstay of modern asthma management. ICS suppress many activated inflammatory genes in airway epithelial cells. Epithelial integrity is restored by regular ICS Barnes et al. The suppression of mucosal inflammation is relatively rapid with a significant reduction in eosinophils detectable within 3 h and associated with reduced airway hyperresponsiveness Gibson et al.
This almost certainly accounts for the clinical benefits seen with inhalation of budesonide and formoterol combination inhaler as a rescue therapy in asthma, as this is likely to stop the evolution of an exacerbation Barnes, However, reversal of airway hyperresponsiveness may take several months to reach a plateau, probably reflecting recovery of structural changes in the airway Juniper et al. This glucocorticoid resistance has been demonstrated by the failure of high doses of ICS to reduce inflammatory markers in sputum or bronchial biopsies of COPD patients Keatings et al.
The reason why ICS fail to suppress inflammation cannot be explained by impaired access of the inhaled drug to sites of inflammation as an oral glucocorticoid is equally ineffective Keatings et al. This has been demonstrated in human lung in vitro Mak et al. Patients with severe asthma have a poor response to glucocorticoids, which necessitates the need for high doses and a very small number of patients are completely resistant.
These patients are difficult to manage as they get side effects from high doses of glucocorticoids, despite their lack of clinical benefit. Asthmatics who smoke are also relatively glucocorticoid-resistant and require increased doses of glucocorticoids for asthma control Thomson and Spears, ; Ahmad et al.
Several molecular mechanisms have now been identified to account for glucocorticoid resistance in severe asthma and COPD Adcock and Barnes, ; Barnes and Adcock, Several distinct molecular mechanisms contributing to decreased anti-inflammatory effects of glucocorticoids have now been identified, so that there is heterogeneity of mechanisms even within a single disease Table 2 Adcock and Barnes, ; Barnes and Adcock, Similar molecular mechanisms have also been identified in different inflammatory diseases indicating that there may be common therapeutic approaches to glucocorticoid-resistant diseases in the future.
The early descriptions of glucocorticoid-resistant asthma suggested that it was more commonly found within families Carmichael et al.
Microarray studies of peripheral blood mononuclear cells PBMC from glucocorticoid-sensitive and glucocorticoid-insensitive asthma patients identified 11 genes that discriminated between these patients Hakonarson et al. The very rare inherited syndrome familial glucocorticoid resistance is characterized by high circulating levels of cortisol without signs or symptoms of Cushing's syndrome Lamberts, Inheritance appears to be dominant with variable expression, but only about a dozen cases have so far been reported.
Sporadic cases have also been described. Several abnormalities in GR function have been described in peripheral blood leukocytes or fibroblasts from patients with familial glucocorticoid resistance, including decreased binding for cortisol, reduced numbers, thermolability and an abnormality binding to DNA, all of which are due to mutations of GR.
These patients are clearly different from patients with glucocorticoid-resistant inflammatory diseases and in patients with glucocorticoid-resistant asthma mutational analysis demonstrated no obvious abnormality in GR structure Lane et al. These polymorphisms have yet to be associated with glucocorticoid resistance in airway diseases, however. There is increased expression of IL-2 and IL-4 in the airways of patients with glucocorticoid-resistant asthma Leung et al.
IL alone mimics this effect in monocytes Spahn et al. In support of this p38 MAPK shows a greater degree of activation in alveolar macrophages from asthmatics with a poor response to glucocorticoids than patients who show a normal response Bhavsar et al. GR may be phosphorylated by several kinases that may alter its binding, stability, translocation to the nucleus, binding to DNA and interaction with other proteins, such as transcription factors and molecular chaperones Weigel and Moore, The serine residue phosphorylated by p38 MAPK is not yet certain and may be Ser or Ser , or this may be an indirect effect Irusen et al.
In patients with glucocorticoid-resistant asthma a large proportion show reduced nuclear translocation of GR and reduced GRE binding in PBMC following glucocorticoid exposure and this may be explained by GR phosphorylation Matthews et al. Microbial superantigens induce glucocorticoid resistance in T cells in vitro via activation of extracellular receptor kinase pathways, resulting in GR phosphorylation Li et al. Macrophages from MKP-1 gene knock-down mice show reduced anti-inflammatory responses to glucocorticoids in vitro Abraham et al.