Why smokers lung is resistant to steroid treatment

UK researchers think they are close to finding the first effective treatment to fight one of the biggest killer diseases in the UK. Professor Peter Barnes will present the work at the British Endocrine Societies 2005 meeting in Harrogate.

Scientists from Imperial College, London have found out why smokers lung – one of the most common fatal diseases in the UK – is resistant to steroid treatment. They have gone on to discover how to combat this resistance, and have begun clinical trials of a potential therapy.

Chronic Obstructive Pulmonary Disease (COPD) – chronic bronchitis and emphysema, or ‘smoker’s lung’ – currently affects 6% of the population. It is already the fourth most common cause of death in the UK and its prevalence keeps on rising.

Steroids would normally be effective at treating inflammatory diseases such as COPD. However, COPD patients do not respond to steroid therapy. This is a major clinical problem due to the prevalence of the disease and the fact that it gets progressively worse.

Inflammation is caused by cells producing certain chemical signals. They do this by ‘switching on’ specific genes. Switching these genes off – and stopping inflammation – requires an enzyme called Histone Deacetylase 2 (HDAC2).

Professor Peter Barnes and his colleagues discovered that steroids act as a ‘molecular bridge’ to recruit HDAC2 to the appropriate genes where it can act to switch them off.

The London researchers found that in COPD, levels of HDAC2 are very low compared to normal cells, so that the steroids have no effect in switching off the activated inflammatory genes.

They then found that in lung cells in vitro, and in rats, low doses of a cheap and widely available drug raised the levels of HDAC2 and broke the steroid resistance.

The first stages of clinical trials to test low doses of this drug, theophylline, in COPD patients are now underway. If successful, this may lead to a change in the treatment of COPD and other severe inflammatory diseases that do not respond well to steroid therapy.

Professor Peter Barnes commented, ‘COPD kills tens of thousands of people in the UK every year and currently we can only treat the symptoms, not the underlying problem of inflammation of the lungs. Our work has finally provided an explanation for steroid resistance in COPD, and has allowed us to identify ways to combat this.

We hope that the clinical trials of theophylline will be successful so that we can finally offer an effective therapy to COPD sufferers – a staggering 6% of the population.’

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