Introduction Acute Inflammation and Brief Symptoms Mechanisms: Experimentally Induced Allergic Reactions Clinical Consequences and Treatment Chronic Inflammation Site of the Inflammation in Asthma Cell Survival in Airway Tissues Characteristics of Chronic Inflammation Chronic Inflammation in the Different Forms of Asthma Clinic Consequences Treatment of Exacerbations Onset and Duration of Treatment Remodeling of the Airways Characteristics of Airways Remodeling in Asthma Clinical Consequences Radiographic Findings Treatment and Prevention of Airways Remodeling Conclusions

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.161.5.9903102

Asthma. From bronchoconstriction to airways inflammation and remodeling.

1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this anti-inflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents. 2. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the widespread anti-inflammatory actions of glucocorticoids. 3. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes (cytokines, enzymes, receptors and adhesion molecules). This cannot be due to a direct interaction between glucocorticoid receptors and GRE, as these binding sites are absent from the promoter regions of most inflammatory genes. It is more likely to be due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors, such as nuclear factor-kappa B and activator protein-1, which regulate the inflammatory gene expression. 4. It is increasingly recognized that glucocorticoids change the chromatin structure. Glucocorticoid receptors also interact with CREB-binding protein (CBP), which acts as a co-activator of transcription, binding several other transcription factors that compete for binding sites on this molecule. Increased transcription is associated with uncoiling of DNA wound around histone and this is secondary to acetylation of the histone residues by the enzymic action of CBP. Glucocorticoids may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression. 5. Rarely patients with chronic inflammatory diseases fail to respond to glucocorticoids, although endocrine function of steroids is preserved. This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). 'Dissociated' steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-kappa B, are also targets for novel anti-inflammatory therapies.

Anti-inflammatory actions of glucocorticoids : molecular mechanisms

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60326-3.pdf

Glucocorticoid resistance in inflammatory diseases

Efficacy and safety of inhaled corticosteroids. New developments.

Asthma and inflammation.

Fifty-eight patients with chronic asthma in whom airflow obstruction was relieved by bronchodilator aerosols but not by oral corticosteroids were compared with 58 other chronic asthmatics who responded equally well to both treatments. The two groups were matched for age and sex. The only significant clinical differences between the two groups were that in the "corticosteroid-resistant" patients there was a more frequent family history of asthma and a longer duration of symptoms. Resistant patients also had a relatively lower peak expiratory flow rate in the morning than later in the day and a greater degree of bronchial reactivity to methacholine. Such features, however, may not be specific criteria of corticosteroid resistance since they were also observed in untreated asthmatics who subsequently responded well to corticosteroids. The failure of prednisolone to inhibit a monocyte-mediated bronchial reaction may explain why some chronic asthmatics do not respond to corticosteroids. Patients with corticosteroid-resistant asthma should be recognised at an early stage so that regular treatment with oral corticosteroids may be withdrawn. Failure to do this results in needless exposure to the risk of developing serious side effects.

https://www.bmj.com/content/bmj/282/6274/1419.full.pdf

Corticosteroid resistance in chronic asthma

In a double-blind study 10 patients with chronic asthma received beclomethasone dipropionate 400 mug daily in a Freon propellant from a pressurized dispenser, and 10 patients received the Freon propellant alone. At the start of the trial each patient was receiving long-term maintenance treatment with oral prednisolone in a dose of 7.5 to 15 mg daily. The daily dose of prednisolone was reduced by 1 mg every four weeks and the patient's progress followed by regular clinical assessment and studies of pituitary-adrenal function. The trial was continued until the dose of prednisolone was reduced to zero or until asthmatic symptoms increased to an unacceptable level.In the 10 patients who received beclomethasone the mean maintenance dose of oral prednisolone was reduced by 5.6 mg/day but in only two cases could this drug be withdrawn completely. In the placebo group the mean reduction in dose was only 1.3 mg, thus there was a significant difference between the two groups (P <0.01). Studies of pituitary-adrenal function showed that a normal adrenal response to tetracosactrin stimulation returned only in the two patients from whom prednisolone was withdrawn.Hence the addition of beclomethasone dipropionate by inhalation to systemic corticosteroid therapy allows useful reductions to be made in the oral maintenance doses of corticosteroid. Reductions must be made with caution since there is wide individual variation in response to beclomethasone and in only a minority of patients can oral treatment by completely withdrawn.

Substitution of Beclomethasone Aerosol for Oral Prednisolone in the Treatment of Chronic Asthma

not be forthcoming from anywhere else Politically it sometimes seems to be under a cloud because of doubtful ethics in the advertising and selling of their products Sometimes there is criticism of the profits they make Yet the industry is responsible for most of the major therapeutic advances in medicine Certainly it makes advances available to a wide medical public by marketing Doctors are obviously needed in the industry in both laboratory and clinical work, and to maintain liaison with doctors in all fields of medicine Doctors in the industry are also needed to assess medical publications and the worth of the ideas they contain to see if they might be exploited, for the benefit of the public and the firm Moreover, these doctors carry a heavy responsibility in writing up drug information sheets for doctors who will prescribe their products and so in providing unbiased information in a commercial world Doctors of high calibre are needed, and normally will be expected to hold higher degrees or diplomas Advertisements for vacant posts appear regularly in the medical journals Anyone who is interested might also write to the medical director of any of the major pharmaceutical companies for career advice Law and medicine

Asthma in New Zealand

Monocyte complement receptors (MCR) and enhancement of MCR by a monocyte chemotactic factor (casein) (CRE) were measured in corticosteroid-resistant and corticosteroid-responsive chronic asthmatics. In newly-diagnosed patients who subsequently responded to corticosteroids, the percentage of MCR and CRE was lower after taking oral prednisolone for 7 days and returned to pretreatment values when prednisolone was withdrawn. MCR and CRE in corticosteroid-responsive asthmatics receiving prednisolone were significantly lower than in corticosteroid-resistant asthmatics taking prednisolone. However, there was no significant difference in MCR and CRE between non-responders taking prednisolone and non-responders receiving other forms of therapy. These results suggest that one of the effects of systemic corticosteroids in asthmatics who respond to this form of treatment is a decrease in both MCR and the degree of CRE. Since these changes were not found in corticosteroid-resistant chronic asthmatics such patients may have a defect in the expression and mobilization of complement receptors on the monocyte cell membrane.

Corticosteroid-resistant chronic asthma and monocyte complement receptors.

In a controlled trial 7 patients with airways obstruction were treated with beclomethasone by inhalation (2 mg/day) and then with prednisolone by mouth (20 mg/day), each for a period of 7 days. In 4 patients the airways obstruction was partially relieved by beclomethasone, but further improvement was recorded in 3 of these patients after subsequent treatment with prednisolone. There was evidence of impairment of hypothalamo-pituitary-adrenal (HPA) function following the administration of beclomethasone by inhalation in 5 of the 7 patients and of complete suppression in all 7 after subsequent treatment with prednisolone by mouth. It was concluded that beclomethasone by inhalation in a dose of 2 mg/day had no real advantage over prednisolone by mouth (20 mg/day) in the treatment of airways obstruction, in terms either of increase in FEV 1 or of preservation of normal HPA function. Limited experience with a smaller dose of beclomethasone (0·4 mg/day) by inhalation in an earlier uncontrolled trial suggested that this dose did not impair HPA function but was insufficient in most cases to relieve airways obstruction.

Ian W B Grant

Papers

Corticosteroid resistance in chronic asthma

Substitution of Beclomethasone Aerosol for Oral Prednisolone in the Treatment of Chronic Asthma

Asthma in New Zealand

Corticosteroid-resistant chronic asthma and monocyte complement receptors.

Beclomethasone dipropionate by inhalation in the treatment of airways obstruction.