부산대학교 도서관

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38[alpha] would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for > 1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38a, and AZD7624 specifically inhibited p38a and p38[beta] isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-[alpha] by 56.6% and 85.4%, respectively (p Conclusion: Although p38[alpha] is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD. Keywords: COPD, inflammation, p38 mitogen-activated protein kinase
Plain language summary Despite optimal treatment, patients with COPD often experience exacerbations. Anti-inflammatory drugs such as inhaled corticosteroids can reduce the incidence of exacerbations. p38 mitogen-activated protein kinase (MAPK) plays [...]