The Mechanisms of Inflammation and Immunity in COPD and Their Relationship to Exacerbations and Disease Progression

COPD (which used to be called chronic bronchitis and emphysema) is a common disease which causes considerable difficulty to sufferers. The pharmaceutical industry has been relatively unsuccessful in bringing new treatments to the marketplace for COPD, with many products failing when they are first given to patients because they do not have the effects that were predicted from studies in animals. A way of circumventing this problem is to test new potential medicines in cells and tissues obtained from COPD sufferers and develop laboratory models of COPD using these cells to predict more accurately the approaches that are likely to succeed in patients. Many patients with COPD have progressive changes in their airways and airspaces which are currently unresponsive to any of the current COPD medicines. By understanding how these processes develop, we will identify new pathways that the medicines of tomorrow can target. We will also gain information on molecules that we can measure in patients that will accurately predict whether a patients airways or airspaces are getting destroyed.

COPD is characterised by extensive lung remodelling for which there is currently no effective treatment. The co-existence of airways fibrosis and emphysema in COPD points to both pro-fibrotic and tissue destructive mechanisms being operative at the same time, which could be explained by differences in fibroblast function between the airways and parenchyma. The main insults underlying the cycle of tissue damage and frustrated repair that fails to result in restitution of tissue integrity are oxidative stress and infection. We propose that the effect of these is channelled through the epithelium to the underlying mesenchymal cells, resulting in tissue fibrosis in the airways and alveolar destruction.
In a step change for translational research and drug development, this workpackage brings together leading academic respiratory research groups and pharmaceutical companies to address the widely perceived key unmet needs in COPD: 1) understanding the mechanisms of injury and repair, 2) validated human lung tissue models for the ex vivo study of COPD pathogenesis, 3) pre-clinical proof of efficacy of drugs in development and 4) biomarkers which assist drug development.
Our hypothesis is that lung epithelial damage, caused by a combination of exogenous and endogenous radical oxygen species and virus infections, drives remodelling in COPD, with varying degrees of fibrosis and destruction in the airway and parenchymal compartments depending on the relative involvement of TGF? and metalloproteases. We will apply our validated lung ex vivo models using samples from deeply characterised COPD patients and controls, enabling integration of clinical and experimental data that should help focus drug development to appropriate COPD phenotypes. We will use bronchial and alveolar epithelial cultures alone or co-cultures with fibroblasts or smooth muscle cells, progressing to whole tissue explant (biopsy, wedge resection, dissected small airways); applying disease-relevant stimuli, including oxidants and viruses, we will study disease mechanisms, looking for differences between the airways and lung parenchyma. We will extend our pilot observations of carbonyl-modified proteins which act as auto-antigens and induce auto-antibodies in correlation with COPD severity and study their destructive role. Progressing from simple, single cell type (high-throughput) models to complex tissue explants, we will provide proof of efficacy for an array of tool compounds from pharma. The focused and well integrated approach that we are applying should deliver within 2-3 years a step change in the understanding of remodelling mechanisms in COPD and an advance in drug development through provision of proof of concept for novel drugs.