Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease which affects around 10% of UK population. COPD patients undergo events known as exacerbations or flare-ups in which symptoms get worse, lung function declines and inflammation is increased. These attacks in COPD patients are treated with corticosteroids, reducing the elevated inflammation. However, many COPD patients are found to be steroid insensitive. Our group has shown a subset of COPD patients responds better to corticosteroids and this can be used to direct therapy. These patients have high blood eosinophil counts and high Th2 type inflammation. Why these patients respond to corticosteroid treatment is currently unknown.
To understand the mechanism(s) by which COPD patients with high Th2 eosinophilic inflammation are more sensitive to corticosteroids.
This work is translational with a true bench to bedside approach. Patients with COPD will be studied and samples of blood, nasal and primary airway epithelial cells will be collected and utilised to answer the research question. By project end you will be competent in sample preparation, cell isolation, pharmacology, flow cytometry, infection techniques, molecular techniques, ELISA and statistical analysis.
Year 1. Establish essential methodologies e.g.sample preparation, cell isolation, cell counting. Obtain Good Clinical Practice competencies, work with COPD team
Year 2. Develop flow cytometry techniques and functional assays to investigate the effects of corticosteroid on eosinophils and airway epithelial cells from high Th2 eosinophilic and low Th2 COPD patients. Plan complete experimental plan
Year 3. Develop models of bacteria and viral exacerbations (infection) in eosinophils and airway epithelial cells, assessing changes in the cells responses and effect of corticoid steroids.
Year 4. Continue co-culture experiments of eosinophils and airway epithelial cells to determine interaction of cell types in an exacerbation setting and effect of corticosteroids on this.
Understanding the mechanism of steroid sensitivity in Th2 eosinophilic chronic obstructive pulmonary disease patients
1.Eosinophils in COPD: just another biomarker? Bafadhel M, Pavord ID, Russell REK.Lancet Respir Med. 2017 Sep;5(9):747-759. doi: 10.1016/S2213-2600(17)30217-5. Epub 2017 Jun 7.PMID: 28601554 2. Predicting treatment outcomes following an exacerbation of airways disease. Halner A, Beer S, Pullinger R, Bafadhel M, Russell REK.PLoS One. 2021 Aug 20;16(8):e0254425. doi: 10.1371/journal.pone.0254425. eCollection 2021.PMID: 34415919 3. Moving the pathway goalposts: COPD as an immune-mediated inflammatory disease. Cass SP, Cope AP, Nicolau DV Jr, Russell REK, Bafadhel M.Lancet Respir Med. 2022 Dec;10(12):1110-1113. doi: 10.1016/S2213-2600(22)00388-5. Epub 2022 Nov 3.PMID: 36335958
1. Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis. Baker JR, Mahdi M, Nicolau DV Jr, Ramakrishnan S, Barnes PJ, Simpson JL, Cass SP, Russell REK, Donnelly LE, Bafadhel M.Lancet Respir Med. 2022 Jun;10(6):545-556. doi: 10.1016/S2213-2600(22)00002-9. Epub 2022 Apr 7.PMID: 35397798 2. Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and Patients with Chronic Obstructive Pulmonary Disease. Paschalaki KE, Zampetaki A, Baker JR, Birrell MA, Starke RD, Belvisi MG, Donnelly LE, Mayr M, Randi AM, Barnes PJ.Am J Respir Crit Care Med. 2018 Mar 1;197(5):665-668. doi: 10.1164/rccm.201706-1304LE.PMID: 28753388 3. Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy.Baker JR, Donnelly LE.Int J Chron Obstruct Pulmon Dis. 2021 Jul 30;16:2227-2242. doi: 10.2147/COPD.S266394. eCollection 2021.PMID: 34354348