The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation

Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells

Andrew Higham,1,2 Pradeep Karur,1,2 Natalie Jackson,2 Danen M Cunoosamy,3 Paul Jansson,3 Dave Singh1,2 1Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK; 2Medicines Evaluation Unit, The University Hospital of South Manchester, Manchester, UK; 3RIA IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden Background: The effects of anti-inflammatory drugs in COPD patients may vary between different cell types. The aim of the current study was to assess the anti-inflammatory effects of the corticosteroid budesonide and a p38 MAPK inhibitor (AZD7624) on different cell types obtained from COPD patients and healthy controls.Methods: Eight healthy smokers, 16 COPD infrequent exacerbators, and 16 frequent COPD exacerbators (≥2 exacerbations in the last year) were recruited for bronchoscopy and blood sampling. The anti-inflammatory effects of budesonide and AZD7624 were assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages and peripheral blood mononuclear cells and polyinosinic:polycytidylic acid-stimulated bronchial epithelial cells.Results: The anti-inflammatory effects of budesonide varied greatly within a patient according to the cell type studied. Bronchial epithelial cells showed the lowest sensitivity to budesonide, while peripheral blood mononuclear cells showed the greatest sensitivity. AZD7624 had a greater effect than budesonide on cytokine production from bronchial epithelial cells. Exacerbation frequency did not influence corticosteroid sensitivity.Conclusion: We observed variable corticosteroid and p38 MAPK inhibitor anti-inflammatory responses within the same individual depending on the cell type studied. These findings support the use of multiple anti-inflammatory strategies in COPD patients due to differences between cell types. Keywords: PBMC, corticosteroid, inflammation, exacerbation, macrophage, epithelial cel

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

Naimish R Patel,1,2 Danen M Cunoosamy,1 Malin Fagerås,1 Ziad Taib,1 Sara Asimus,1 Tove Hegelund-Myrbäck,1 Sofia Lundin,1 Katerina Pardali,1 Nisha Kurian,1 Eva Ersdal,1 Cecilia Kristensson,1 Katarina Korsback,1 Robert Palmér,1 Mary N Brown,3 Steven Greenaway,4 Leonard Siew,4 Graham W Clarke,4,5 Stephen I Rennard,6,7 Barry J Make,8 Robert A Wise,9 Paul Jansson11Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA, 3Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA; 4Quintiles Drug Research Unit at Guy’s Hospital, London, 5Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK; 6Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA; 7Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK; 8Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, 9Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USABackground: 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 p38α 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 p38α, and AZD7624 specifically inhibited p38α and p38β 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-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.Conclusion: Although p38α 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 kinas