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.

In clinical medicine, perhaps more than in any other area of scientific endeavour, we are prone to become prisoners of our traditional preconceptions. Gradually in most cases, but rapidly in a few, many of these preconceptions have been swept away. It took centuries for bed rest in the treatment of many serious diseases, such as pulmonary tuberculosis and coronary thrombosis, to be discredited, and decades for the barbarous practice of removing healthy tonsils from healthy children to be abandoned. In contrast, the discovery that high-concentration oxygen therapy in patients with ventilatory failure could cause coma and death had an immediate impact. In some of these instances, and in many others, therapeutic policy has turned full circle and forms of treatment once considered logical and beneficial have come to be regarded as irrational or even positively harmful. The iconoclast in medicine, although not always a popular figure in the profession, has often helped to open the way to major therapeutic advances. Yet it is important to realize that there can be false iconoclasts as well as false icons and that in their separate ways both can be dangerous. George Bernard Shaw, although not a doctor, was a powerful opponent of vaccination against smallpox, asserting in his well-publicized ignorance that the decline in the incidence of that disease was the result not of vaccination but of improved sanitation. He has now been proved completely wrong, but one of my most painful personal recollections is that of witnessing the death of an intelligent and well-read young soldier from haemorrhagic smallpox in India during the War after he had refused vaccination in the belief that the opinion of a man with the intellect of Shaw was more to be trusted than that of a Regimental Medical Officer. Although that is, of course, a bizarre example of the damage which can stem from a misinformed iconoclastic approach, it epitomizes the grave responsibility which doctors must accept when they publicize views which are diametrically opposed to those of the majority of their colleagues. No such crisis of conscience arises when a doctor, even perhaps quite wrongly, deems dangerous a drug which has been used uncritically for many years, but for which there is an adequate substitute. It is a different matter, however, to condemn a form of treatment which in certain circumstances may be life-saving, but, even if it is not, can do no harm if administered for short periods. The views expressed in Dr Luksza’s two articles, questioning the value of corticosteroids in the treatment of severe acute asthma, come into the second category. In purely scientific terms there is a lot to be said in his support. It has never been proved by a controlled clinical trial that corticosteroids in this condition actually save lives, and

Are corticosteroids necessary in the treatment of severe acute asthma

Cis-platinum and vindesine in combination in the treatment of non-small cell lung cancer

A wet aerosol of 0.5 per cent salbutamol was administered for 3 minutes via a Bennett intermittent positive pressure ventilator driven by compressed air to 8 patients considered to be in status asthmaticus. Arterial blood gas analysis performed before and after salbutamol administration showed marked individual rises and falls in the partial pressure of oxygen with no predictable pattern of response. No dysrhythmia was observed on the E.C.G. but small changes of a non-specific nature occurred in the level of S-T segments and in the height of T-waves. It was concluded that in the dosage employed a salbutamol aerosol administered by I.P.P.V. produced no significant disturbance of myocardial function.

Salbutamol by intermittent positive pressure ventilation in status asthmaticus.

A comparative study of the clinical response to salbutamol nebulized by an Inspiron Mini-Neb using flow rates of 4 and 8 litres/min is described. Forty patients with chronic asthma were given doses of approximately 1 mg and 5 mg of salbutamol using flow rates of either 4 or 8 litres/min. The two flow rates and the two dosages produced similar increases in FEV1 and FVC and similar changes in pulse rate. These results demonstrate that flow rates of 4 litres/min, such as can be produced by a domestic oxygen cylinder, and doses of 1 mg salbutamol are effective in the treatment of patients with chronic reversible airflow obstruction. While we do not advocate the general use of oxygen cylinders to drive nebulizers, our study shows that this form of administration produces a bronchodilator response similar to that using a flow rate of 8 litres/min.

A comparative study of two doses of salbutamol nebulized at 4 and 8 litres per minute in patients with chronic asthma

not found the presence of these tender areas to be ofhelp in predicting the outcome oftranscutaneous electrical nerve stimulation. Some of the patients who responded to the treatment did not have these sensitive areas, while others in whom they were present were not helped. We thank Dr Homer for the chance to explain ourresults further. Transcutaneous electrical nerve stimulation requires a cutaneous sensation for it to work. This means that the construction ofa double blind trial is difficult. For this reason we decided to perform an open trial without a control group for comparison. The data we obtained from the study were discussed with a statistician, who advised that the use of mathematics to show a small p value would not increase the study's validity. Furthermore, as the data at three and six months were incomplete because 14 of the subjects had discontinued treatment (eight because no help, four insufficient benefit to warrant cost, two could not afford machine) the application of the statistical tests suggested by Dr Homer would have necessitated several unwarranted assumptions. We therefore decided that the results should be described in terms of the number of the subjects responding and not responding to the treatment, as has been done by others.3 Dr Homer states that the benefit of transcutaneous electrical nerve stimulation at three and six months may be a placebo response. In our paper we draw attention to this point but suggested that factors responsible for the placebo effect in the irritable bowel rarely last more than two months.4 Our main concem was to draw attention to the use of transcutaneous electrical nerve stimulation as a possible treatment for unexplained abdominal pain, a condition in which new treatments are always desired. We agree that further studies to prove its effectiveness are required. As with all forms of treatment of chronic pain the message with transcutaneous electrical nerve stimulation in functional abdominal pain is to try it and see. Our policy is to lend a machine to the patient for one to two months to see if it is of benefit. Patients who find it to be helpful are usually more than happy to buy a machine for themselves, possibly the best indicator of its benefit. GARRY KENDALL KAREN SYLVESTER J E LENNARD-JONES St Mark's Hospital, London EC1V 2PS

https://www.bmj.com/content/bmj/293/6542/286.full.pdf

Ian W B Grant

Papers

Are corticosteroids necessary in the treatment of severe acute asthma

Cis-platinum and vindesine in combination in the treatment of non-small cell lung cancer

Salbutamol by intermittent positive pressure ventilation in status asthmaticus.

A comparative study of two doses of salbutamol nebulized at 4 and 8 litres per minute in patients with chronic asthma

Hazards of bronchoscopy.