Innate Immunity in COPD

Study Overview
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Brief Summary
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Chronic Obstructive Pulmonary Disease (COPD) causes obstruction to airflow when breathing out. It is a leading cause of chronic lung disease, hospitalization and death. Smoking is the major cause of COPD but why some smokers develop COPD while others do not is poorly understood. A central feature of COPD is accumulation of inflammatory blood cells, macrophages and neutrophils, in the airway, leading to lung injury and airway damage. The small airways of many patients with COPD contain bacteria, which are absent in healthy smokers or non-smokers. These bacteria stimulate recruitment of neutrophils, macrophages and other inflammatory cells, further accelerating airway injury. The investigators and others have shown resident macrophages in the lung and inflammatory cells (neutrophils and macrophages) recruited from the blood, which normally clear bacteria, have reduced anti-bacterial capacity in COPD and that their altered function impairs the resolution of inflammation. The investigators now wish to test why these cells fail to clear bacteria focusing in particular on how they use molecules as food to generate energy, a process termed metabolism, since this is an important determinant of immune cell function. Comparison will be made between lung resident cells (obtained by performing bronchoscopy and washing a segment of lung to flush out immune cells) and those from the blood to determine if the alterations are specific to the lung. The investigators will identify alterations in responses to bacteria in relation to changes in metabolism . A major focus will be on how structures in the cell that normally are key for energy production (i.e. mitochondria) become dysfunctional and how this impacts responses to bacteria. The investigators will relate findings to the clinical features of COPD and to healthy non-smokers and smokers to separate smoking-related changes from COPD. The aim is to develop new approaches with which to treat and manage COPD.

Detailed Description
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COPD has become one of the major causes of ill health throughout the world. COPD has major economic impact being the second commonest causes of hospital admission and days lost to work in the UK where an estimated 10% of the population over 40 are affected. The disease causing mechanisms are not well defined but a central feature is development of a chronic inflammatory process. Inflammation in COPD is progressive and persists after inciting factors, such as cigarette smoke, are removed. The stimuli to persistent inflammation and the failure of normal cues to resolve this inflammation are poorly characterised. Lung inflammation in COPD is largely resistant to the antiinflammatory actions of corticosteroids, currently used as treatment, which fail to modify disease progression or mortality. Existing therapeutic approaches for COPD are therefore flawed and do not alter the central chronic inflammatory process. Better understanding of COPD pathogenesis is essential if new therapeutic strategies are to be developed that will alter the course of the disease. A sub-set of COPD patients have more frequent exacerbations, which are associated with more rapid decline in pulmonary function tests and increased mortality. Bacterial infection is a frequent cause of these exacerbations. In addition some of the high-risk patients with COPD are more susceptible to bacterial pneumonia. In COPD, the lower respiratory tract is colonised with a higher density of bacteria (including Haemophilus influenzae or Streptococcus pneumoniae), whereas in non-smoking subjects and smokers with normal lung function the density of bacteria is much lower. This suggests there may be a defect in immune responses to bacteria in patients with COPD, in particular involving the part of the immune response which is termed 'innate', which provides the most rapid and generic response to bacteria. Lung host defence against bacteria requires the co-ordinated action of both immune cells and factors released into the airway termed humoral factors. Alveolar macrophage (AM) competence is essential to maintain sterility in the lower airway and bacterial phagocytosis and killing is complemented by a delayed programme of cell death termed apoptosis, which provides a significant increment to bacterial killing and shuts off the inflammatory response. When this component of host defence is over-whelmed recruited cells that ingest bacteria termed phagocytes (i.e. neutrophils and macrophages) become key effectors of the host response. Research suggests that monocyte-derived macrophages (MDM) isolated from patients with COPD have impaired capacity for phagocytosis of bacteria as compared to healthy donors or smokers without COPD. That this defect is apparent in cells isolated from the blood suggests it may reflect a systemic defect in bacterial clearance. In addition there is a marked defect in AM isolated from the lung, suggesting additional defects imposed by the lung environment, that impacts uptake of bacteria coated with antibody. The investigators have also shown that macrophages are impaired in their ability to kill the bacteria they ingest. The molecular basis of the decreased clearance of bacteria is unclear but research by the investigators has found that macrophages fail to produce an increment in a factor that kills bacteria that is produced by mitochondria, termed mitochondrial reactive oxygen species (mROS) and this may contribute to both impaired ingestion and killing of bacteria. Mitochondria are structures in cell that generate energy but how they burn fuels in the form of molecules adapts to aid immune function. The investigators believe that in COPD mitochondria in macrophages fail to adapt during bacterial challenge and this underpins the immune defect observed for bacteria. Similarly, the investigators have shown that peripheral blood neutrophils have impaired killing of bacteria in COPD and that this is associated with impaired gluconeogenesis, a process that stores glucose in the form of glycogen. This glycogen is normally used by neutrophils as a source of glucose to help prime responses to bacteria and this defect in COPD neutrophils impairs their capacity to kill bacteria This has not been previously addressed and the investigators will focus on four main aspects: i) the molecules myeloid cells burn as fuel sources during metabolism in COPD in at rest and in response to bacteria and other inflammatory stimuli, ii) alterations in mitochondrial function in myeloid cells in COPD, iii) whether alterations are confined to myeloid cells in the lung or expressed at sites removed from the lung and the mechanisms of these effects and iv) methods to recalibrate altered responses determined by the investigators in myeloid cells in COPD. The cells and materials that will be generated will allow additional research and will be used to help test other hypotheses and identify additional mechanism underlying immune dysfunction and promotion of inflammation in COPD that emerge as work by the investigators and the field progresses during the lifetime of this research.

Official Title
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Analysis of Innate Immune Competence in People With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Procedure: Bronchoscopy for sample collection
* Procedure: Blood donation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COPD patients: COPD patients aged 18-77 years who are GOLD Stage 1 or 2 or 3; for patients undergoing bronchoscopy already for a clinical reason. COPD patients aged 18-77 years old who are GOLD Stage 1,2 or 3 for patients who are donating blood only. COPD patients aged 18-69 years who are GOLD Stage 1 or 2 for patients undergoing bronchoscopy for research purposes. COPD- Defined by radiological investigation of chest either chest X-ray or High-resolution CT scan in previous 12 months Ability to provide informed consent Healthy volunteers: Any healthy volunteer aged 18-77 years Ability to provide informed consent Exclusion Criteria: COPD patients: Individuals known to have active malignancy, immunosuppression, diabetes mellitus, chronic kidney disease or hepatic failure. Individuals with a history of anaemia Individuals who have donated >250 ml of blood for any reason within the last 6 months Individuals who are pregnant or breast feeding. Current participation in any other clinical trial, except those directly relating to this cohort and study. Individuals who have had a febrile illness or other symptoms of acute infectious illness (respiratory, enteric or soft tissue) within the last 2 weeks Individuals who have received a vaccine in the past 2 weeks Inability to communicate in English or convey willingness to participate. For bronchoscopy - Any significant lung condition that would contra-indicate bronchoscopy including: active acute lung infection (with the exception of asymptomatic pulmonary colonisation) or malignancy, significant coexisting interstitial lung disease or additional pulmonary diagnosis in addition to COPD. Healthy volunteers: Individuals known to have active malignancy, immunosuppression, diabetes mellitus, chronic kidney disease or hepatic failure Individuals with anaemia on the screening full blood count (FBC) Individuals who donated >250 ml of blood for any reason within the last 6 months Individuals who are pregnant or breast feeding Current participation in any other clinical trial Individuals who have had a febrile illness or other symptoms of acute infectious illness (respiratory, enteric or soft tissue) within the last 2 weeks. Individuals who have received a vaccine in the past 2 weeks Chronic or acute respiratory disease. Any chronic medical condition or receipt of regular prescription medication other than the oral contraceptive pill. Inability to communicate in English or convey willingness to participate For bronchoscopy - Any active lung condition including any lung infection or asthma Any significant abnormality on CXR that would contraindicate bronchoscopy FEV1 <65% predicted (BTS Guidelines, 2001)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 77 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| COPD patients<br>Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection. | Procedure: Bronchoscopy for sample collection<br>* Participants will undergo a single bronchoscopy and bronchoalveolar lavage to obtain immune cells.<br>Procedure: Blood donation<br>* Participants will donate a single blood sample for isolation of immune cells from peripheral blood.<br>|
| Healthy controls - smokers<br>Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection. | Procedure: Bronchoscopy for sample collection<br>* Participants will undergo a single bronchoscopy and bronchoalveolar lavage to obtain immune cells.<br>Procedure: Blood donation<br>* Participants will donate a single blood sample for isolation of immune cells from peripheral blood.<br>|
| Healthy controls - non-smokers<br>Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection. | Procedure: Bronchoscopy for sample collection<br>* Participants will undergo a single bronchoscopy and bronchoalveolar lavage to obtain immune cells.<br>Procedure: Blood donation<br>* Participants will donate a single blood sample for isolation of immune cells from peripheral blood.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of immunometabolic responses in immune cells required for microbicidal activity. | This programme will identify core features of the immunometabolic response and of mitochondrial function that are required for optimal macrophage responses to bacteria and establish how these core responses are perturbed in COPD. Outcomes will be related back to clinical phenotypes of the patients enrolled in the study. The investigators will also develop models and therapeutic approaches with which to translate this programme and suggest approaches for future clinical trials that may include use of repurposed agents. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alveolar macrophages, Peripheral blood mononuclear cells, Neutrophils, Bactericidal mechanisms, Immune cell metabolism, Epigenetics