Mechanisms, impact and therapeutic targeting of bacterial colonisation in COPD

Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema and is a very common cause of chronic disability and mortality in the UK. There is an underlying inflammation in the lungs of COPD patients which has so far proved very difficult to treat, so that there is a real need to find more effective treatments in the future. This will depend on better understanding the inflammation that occurs in the lungs of COPD patients, which is usually initiated by cigarette smoking. However, once the disease is established stopping smoking does not clear up the problem so we need to find new and more effective treatments. This grant application brings together some of the key centres for COPD research in the UK to explore a new idea. We know that bacteria (bugs) are present the lungs of COPD patients, unlike the lungs of smokers without COPD and non smokers which are sterile. The presence of these bacteria may drive inflammation, which then results in worsening of the disease and also increases the flare-ups, called exacerbations, which may lead to hospital admission. We believe that this is due to failure to remove bacteria from the lungs and therefore these bacteria grow and cause infections. We have evidence that cells that usually defend the lungs (called macrophages and neutrophils) do not eat up and clear the bacteria as they normally do. In addition, these cells fail to clear all the damaged cells from the lung making the inflammation even worse. We have found that these abnormalities can be explained by abnormal functioning of the macrophages and neutrophils and we have identified some of the mechanisms that have gone wrong. This means that we may be able to find treatments that can restore normal function to these cells so that they can sterilise the lung. This should mean that we can clean up the lung normally, which will lead to a reduction in flare-ups and halting the worsening of the disease. We plan to work closely with several pharmaceutical companies so that we can test any new treatments as soon as possible, so that we may be able to find treatments faster. We hope that this innovative research will therefore lead to new treatment approaches for COPD in the future.

Lower airway bacterial colonisation (LABC) affects approximately 50% of patients with COPD at all stages of disease and may be important in driving inflammation and impairing the resolution of inflammation. Our central hypothesis is that defective innate and/or adaptive immunity (impaired macrophage and neutrophil phagocytosis and killing of bacteria or humoral and cellular responses) results in failure to clear bacterial and apoptotic cells from the lower airways in smokers who develop COPD. We suggest that the resulting LABC (usually with Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis) drives a persistent inflammatory response, which is resistant to cues for resolution of inflammation. This collaborative application brings together major UK centres with expertise in COPD mechanisms, microbiology and immunology. We aim to explore the links between LABC, chronic inflammation and clinical outcomes, including exacerbation frequency and disease progression in COPD patients. We will determine the prevalence and impact of LABC in COPD patients at all stages of the disease and examine how this may reflect impaired innate immunity and resultant chronic inflammation and altered immune responses. We will elucidate the molecular mechanisms for reduced bacterial phagocytosis and killing reported in alveolar macrophages, monocyte-derived macrophages (MDM) and circulating neutrophils and for the impaired clearance of innate immune cells (efferocytosis) in order to identify novel therapeutic targets. Preliminary studies have identified abnormalities in microtubular stability and sphingosine-1-phosphate signalling in defective bacterial clearance by macrophages that are reversible in-vitro. Delays in macrophage apoptosis also reduce bacterial clearance and can be targeted therapeutically. We will investigate the effect of reducing LABC in COPD patients with antibiotic therapy (oral and inhaled) on inflammation and immune responses as proof-of-concept. Finally, we will perform PoC studies in COPD patients with drugs identified as correcting defective bacterial clearance in COPD cells, including microtubule stabilisers, sphingosine signalling inhibitors and apoptosis modulators. We will study carefully phenotyped COPD patients from existing well characterised cohorts and collaborate closely with other work packages of the consortium. We will interact closely with several industrial partners who have agreed to provide tool compounds, technological skills, data analyses and expertise in trial design. This proposal represents a series of focused and deliverable projects that, through collaborative scientific discovery, will act as a unique platform for therapeutic translation. We believe that exploring LABC and abnormal innate immunity will enhance understanding of disease mechanisms and identify new therapeutic approaches and provide novel biomarkers for the assessment of new treatments.