Inflammation and Muscle Weakness in COPD: Considering a Renewed Role for Theophylline?

Abstract

© 2018 Bentham Science Publishers. Background: The methyl-xanthine drug theophylline has been used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) for several decades. Phosphodiesterase inhibition leading to smooth muscle relaxation is its main mode of action as a broncho-dilating agent, requiring blood theophylline concentrations close to the toxic range and a consequent problem with side effects. It also has anti-inflammatory effects that occur at relatively low concentrations. Objective: To explore supporting evidence for how other properties of theophylline could be of considerable clinical utility, particularly in reducing weakness and overt sarcopenia, based on its antiinflammatory, steroid-sparing and immune-modulating properties. Methods: PUBMED and MEDLINE were scanned using the search terms: theophylline, antiinflammatory, cytokine, inflammation, ageing, sarcopenia, frailty, chronic obstructive airways disease, pulmonary rehabilitation. High quality articles were selected, read in-depth and discussed by the authors, then used as the basis for a proposition on the potential anti-inflammatory and antisarcopenic use of theophylline. Findings: The anti-inflammatory properties of theophylline are mainly mediated by histone deacetylase induction in immune competent cells with a resulting shift toward the expression of a less inflamed phenotype, including a reduction of the release of pro-inflammatory cytokines and the associated increase in anti-inflammatory cytokines. These effects occur at blood theophylline concentrations well below the range for direct broncho-dilatation. Conclusion: There are potential therapeutic benefits of theophylline that are systemic and not confined to airways inflammation in COPD. There is scope for a beneficial effect in other chronic inflammatory states and post-acute inflammation with slow resolution. There is compelling evidence that theophylline could be used for anti-inflammatory adjunctive treatment to improve independent function, muscle strength and other outcomes in individuals recovering from acute inflammatory episodes, including but not limited to exacerbations of COPD, and as a pharmaceutical intervention in support of pulmonary rehabilitation.