Theophylline has been used as a bronchodilator in the treatment of COPD for over 70 years, but has lost popularity as better tolerated and more effective bronchodilators have been introduced. However, new insights into the molecular action of theophylline have raised the possibility that this old drug may come back into favour as an anti-inflammatory treatment and may even reverse steroid resistance in COPD.¹ A paper by Hirano et al in this issue of Thorax provides further support for the anti-inflammatory effects of theophylline in patients with COPD.²

CURRENT USE OF THEOPHYLLINE IN COPD

In the major guidelines for the treatment of COPD, theophylline is relegated to a third line bronchodilator after inhaled anticholinergics and β₂ agonists. Nevertheless, it is recognised that theophylline is a useful treatment in patients with severe COPD as its withdrawal leads to significant clinical worsening of the disease.³ Many older clinicians have been convinced by its clinical value in severe disease.

THEOPHYLLINE AS A BRONCHODILATOR

Traditionally, theophylline was used as a bronchodilator in the treatment of airway disease but, to achieve significant bronchodilatation comparable with that of a β₂ agonist, relatively high plasma concentrations are needed (10–20 mg/l). Theophylline relaxes human airway smooth muscle in vitro through inhibition of phosphodiesterases (PDE), enzymes that break down cyclic nucleotides in the cell resulting in increased cyclic AMP concentrations. Unfortunately, at doses of theophylline that inhibit PDE, side effects that are also due to PDE inhibition are common so many patients are not able to tolerate theophylline at these “therapeutic” concentrations.

NON-BRONCHODILATOR EFFECTS

Many patients appear to derive clinical benefit from theophylline at doses that give a plasma concentration well below that needed for bronchodilatation. This suggests that theophylline must have some additional beneficial effect, and this is exemplified by the worsening of disease control when theophylline is withdrawn.³ There is now good evidence for inhibitory effects of theophylline on airway inflammation in COPD, and these effects are seen at plasma concentrations below 10 mg/l.^4,5 This is particularly striking as corticosteroids have no demonstrable anti-inflammatory effects on the same parameters, even at high doses. These data are now confirmed by Hirano et al² who have confirmed that a low dose of theophylline significantly reduces sputum neutrophils.

MECHANISMS OF ANTI-INFLAMMATORY EFFECTS

Many different mechanisms have been proposed for the anti-inflammatory effects of theophylline, but none of these can account for the effects of low doses of theophylline that are effective clinically as high concentrations are needed to demonstrate these actions in vitro.⁶ However, these mechanisms can account for all of the side effects of theophylline. PDE inhibition accounts for nausea, vomiting, headaches and diuresis, whereas adenosine receptor antagonism explains the cardiac arrhythmias and seizures that occur with very high plasma concentrations. These mechanisms cannot account for the clinical effects of low doses of theophylline, and this indicates that there must be some other mechanism responsible for its anti-inflammatory effects.

HISTONE DEACETYLASE ACTIVATION

Expression of inflammatory genes is regulated by the balance between histone acetylation and deacetylation.⁷ In COPD a number of inflammatory genes are activated through pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB), which leads to histone acetylation and increased transcription. This process is reversed by the recruitment of histone deacetylases (HDAC) to the activated inflammatory gene promoter site within the nucleus. We have previously shown that corticosteroids suppress inflammation by recruiting HDAC2 to activated inflammatory genes, thus switching off their expression. This molecular mechanism is defective in COPD patients as HDAC2 activity and expression is markedly reduced, thus accounting for the steroid resistance of COPD.⁸ We have shown that theophylline is an activator of HDACs and enhances the anti-inflammatory effect of corticosteroids, as well as reversing steroid resistance in cells from COPD patients.^9,10 This action of theophylline is seen at low plasma concentrations (optimally 5 mg/l) and is independent of PDE inhibition and adenosine antagonism. The effect of theophylline is completely blocked by an HDAC inhibitor called trichostatin A and by knocking out HDAC2 using interference RNA.¹¹ The reason why theophylline selectively activates HDAC activity is not yet known, but appears to be indirect through the activation of kinase and phosphatase pathways in the cell.

ROLE OF OXIDATIVE AND NITRATIVE STRESS

We have proposed that the defect in HDAC2 function and expression that is seen in COPD cells and lungs is the result of increased oxidative and nitrative stress.¹² Reactive oxygen species and nitric oxide generated from inducible nitric oxide synthase avidly interact to form peroxynitrite, an unstable radical that may nitrate tyrosine residues in proteins to alter their function and stimulate its enzymatic destruction. HDAC2 in COPD lungs shows excessive nitration and this is associated with reduced HDAC activity.¹³ Hirano and colleagues now show that theophylline significantly reduces the concentrations of 3-nitrotyrosine, the stable product of peroxynitrite, which is raised in sputum cells of COPD patients.^2,14 By contrast, an inhaled corticosteroid had little effect. This suggests that theophylline might restore HDAC activity in two ways: through activation of the enzyme as described above and through reduction in tyrosine nitration of the enzyme, thus increasing HDAC activity in COPD patients. This would have an anti-inflammatory action in its own right but, of more importance, may reverse the resistance to the anti-inflammatory effects of corticosteroids. A clinical trial to explore whether low dose theophylline restores corticosteroid responsiveness in COPD is currently underway.

CLINICAL IMPLICATIONS

It is predicted from the in vitro studies in COPD cells and (unpublished) animal studies that low dose theophylline (giving a plasma concentration of ∼5 mg/l) will reverse steroid resistance in COPD patients and thus control inflammation. Theophylline may have a unique effect in the treatment of COPD by restoring reduced HDAC activity to normal levels, thus suppressing inflammation but also potentially making the patients responsive to corticosteroids. If this is correct this should improve symptoms, reduce exacerbations, and reduce the progression of the disease. Furthermore, at these low doses of theophylline, side effects are not a problem. Moreover, this treatment would be relatively cheap and may be an appropriate approach to the global epidemic of COPD, although not popular with major pharmaceutical companies. Perhaps theophylline will be reinstated in the future when long term clinical trials have been completed.

If the signal transduction pathways responsible for HDAC activation by theophylline can be defined, this might lead to the development of new anti-inflammatory therapies that are completely free of the side effects seen with high doses of theophylline, providing a novel therapeutic approach to COPD.