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Thorax doi:10.1136/thoraxjnl-2013-203498
  • Editorial

P38 inhibition in COPD; cautious optimism

  1. Dave Singh
  1. Correspondence to Prof Dave Singh, University Of Manchester, Medicines Evaluation Unit, Manchester M23 9QZ, UK; dsingh{at}meu.org.uk

The nature of inflammation varies greatly between COPD patients, leading to heterogeneity in clinical manifestations. For example, emphysema is severe in some patients but minimal in others.1 The varied nature of COPD inflammation means that a novel anti-inflammatory drug is unlikely to be effective in all patients. This is certainly true for established anti-inflammatory therapies such as inhaled corticosteroids, which are most effective in the subgroup of patients with a history of exacerbations,2 and also those with evidence of increased sputum eosinophils.3 The PDE4 inhibitor, roflumilast, also shows greater efficacy in a COPD subgroup; those with chronic bronchitis and a history of exacerbations.4

The p38 mitogen activated protein kinase (MAPK) signalling pathway promotes inflammation by enhancing inflammatory gene transcription, stabilising mRNAs and increasing protein translation.5 p38 MAPK signalling is activated by different extracellular stimuli that are relevant to COPD, such as cytokines, toll-like receptor agonists and oxidative stress including components of cigarette smoke.5–7 Furthermore, lung immunohistochemistry studies have demonstrated increased p38 MAPK activation in COPD patients compared with healthy controls.8 ,9 p38 MAPK inhibitors reduce cytokine production from different COPD lung cells in vitro, including alveolar macrophages,6 lymphocytes and bronchial epithelial cells.8 These observations from laboratory studies indicate that p38 MAPK activation contributes to COPD inflammation, and have encouraged the development of p38 MAPK inhibitors to treat COPD.10 ,11

Orally administered p38 MAPK inhibitors have been developed for the treatment of inflammatory diseases including rheumatoid arthritis.12 ,13 Unfortunately, these drugs have caused unacceptable side effects including liver toxicity and skin reactions. Additionally, the efficacy appears to be transient; initial improvements in systemic inflammatory biomarkers including C-reactive protein (CRP) disappear within weeks.12 ,13 This may be due to ‘redundancy’, where blocking one pathway within a …

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