Chronic Bronchitis, Chronic Obstructive Pulmonary Disease, Emphysema
Conditions
Keywords
macrophage, phagocytosis, exacerbation
Brief summary
Patients with chronic obstructive pulmonary disease (COPD) that have frequent chest infections are the patients most likely to become worse over time. Why these people are more susceptible to chest infections is not known. One reason might be that the white cells in their lungs called macrophages do not work properly. Normally, these cells remove all the debris inhaled into the lung. This can also include bacteria. In patients with COPD, these macrophages are not able to remove these particles. The research question addresses why this happens
Detailed description
Chronic obstructive pulmonary disease (COPD) comprises chronic bronchitis, small airways disease and emphysema. The major risk factor for the development of COPD is cigarette smoking therefore, the prevalence of this disease is increasing. COPD accounts for increasing numbers of hospital admissions due to increased numbers of chest infections and exacerbations. This may be related to the reduced capacity of macrophages from COPD patients to phagocytose bacteria and apoptotic cells. The reasons for this defect in the innate immune response in these subjects is unclear but there are suggestions that scavenger receptors may be altered by oxidative stress and reduce the phagocytotic pathway. This would be relevant in COPD, as increased oxidative stress is associated with cigarette smoking. We have preliminary data that shows a similar reduce phagocytotic response in monocyte-derived macrophages (MDM) from COPD patients compared with smokers and non-smokers. As these cells have not been exposed to oxidative stress other mechanisms may play a role in reducing phagocytosis. Using this MDM model, by taking blood from patients with COPD, we aim to investigate the mechanism of defective phagocytosis in COPD. We will measure the expression and regulation of cell surface scavenger receptors in cells of disease patients and control subjects and examine the signalling pathways leading to actin polymerization and phagosome formation. Finally, we aim to identify novel therapeutic strategies to reverse this effect and augment phagocytosis of macrophages in patients with COPD. Such a strategy would reduce chest infections and exacerbations and hence improve quality of life.
Interventions
None listed
Sponsors
Imperial College London
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy non-smoking subjects: All normal volunteers will meet the following criteria: Age 21-75 years. No history of respiratory or allergic disease. Normal baseline spirometry as predicted for age, sex and height. Non-smokers. No history of upper respiratory tract infection in the preceding six weeks. Not taking regular medication COPD subjects: COPD is diagnosed according to American Thoracic Society, European Respiratory Society and British Thoracic Society guidelines by the doctors in Professor Barnes' COPD clinic. All COPD volunteers will meet the following criteria: Age between 35-75 years. A smoking history of at least 10 pack years. ( 1 pack year = 20 cigarettes per day for 1 year) FEV1:FVC ratio of \<0.7, post-bronchodilator FEV1 of \<85% predicted, reversibility with inhaled beta2-agonist of \<15% of predicted FEV1: all three criteria are required.
Exclusion criteria
Subjects will not included in this study if they meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phagocytosis of H. Influenzae Concentration | 1 hour | Measurement of phagocytosis in vitro, Phagocytosis of H. influenzae concentration |
| Phagocytosis of S. Pneumoniae Concentration | 1 hour | Measurement of phagocytosis in vitro, Phagocytosis of S. pneumoniae concentration |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Non Smokers Non smokers included no history of respiratory or allergic disease, normal baseline spirometry | 20 |
| Smokers Smoking history of at least 10 pack years | 17 |
| COPD Patients with stable COPD | 19 |
| Total | 56 |
Baseline characteristics
| Characteristic | Non Smokers | Smokers | COPD | Total |
|---|---|---|---|---|
| Age, Continuous | 48 years STANDARD_DEVIATION 3 | 53 years STANDARD_DEVIATION 2 | 70 years STANDARD_DEVIATION 2 | 57 years STANDARD_DEVIATION 3 |
| FEV1 (%predicted) | 102.7 percent predicted STANDARD_DEVIATION 2.6 | 93.8 percent predicted STANDARD_DEVIATION 3.8 | 50.6 percent predicted STANDARD_DEVIATION 4 | 80.5 percent predicted STANDARD_DEVIATION 20 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 20 participants | 17 participants | 19 participants | 56 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 11 Participants | 32 Participants |
| Smoking history | 0 pack/years STANDARD_DEVIATION 0 | 33 pack/years STANDARD_DEVIATION 4.6 | 45 pack/years STANDARD_DEVIATION 4.9 | 15.3 pack/years STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 17 | 0 / 19 |
| other Total, other adverse events | 0 / 20 | 0 / 17 | 0 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 17 | 0 / 19 |
Outcome results
Primary
Phagocytosis of H. Influenzae Concentration
Measurement of phagocytosis in vitro, Phagocytosis of H. influenzae concentration
Time frame: 1 hour
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non Smokers | Phagocytosis of H. Influenzae Concentration | concentration 0.3g/ml | 0.042 relative fluorescence unit | Standard Error 0.008 |
| Non Smokers | Phagocytosis of H. Influenzae Concentration | concentration 1g/ml | 0.06 relative fluorescence unit | Standard Error 0.01 |
| Smokers | Phagocytosis of H. Influenzae Concentration | concentration 0.3g/ml | 0.042 relative fluorescence unit | Standard Error 0.007 |
| Smokers | Phagocytosis of H. Influenzae Concentration | concentration 1g/ml | 0.059 relative fluorescence unit | Standard Error 0.008 |
| COPD | Phagocytosis of H. Influenzae Concentration | concentration 0.3g/ml | 0.014 relative fluorescence unit | Standard Error 0.002 |
| COPD | Phagocytosis of H. Influenzae Concentration | concentration 1g/ml | 0.025 relative fluorescence unit | Standard Error 0.004 |
p-value: 0.05Kruskal-Wallis
Primary
Phagocytosis of S. Pneumoniae Concentration
Measurement of phagocytosis in vitro, Phagocytosis of S. pneumoniae concentration
Time frame: 1 hour
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non Smokers | Phagocytosis of S. Pneumoniae Concentration | concentration 0.3g/ml | 0.066 relative fluescence | Standard Error 0.02 |
| Non Smokers | Phagocytosis of S. Pneumoniae Concentration | concentration 1g/ml | 0.077 relative fluescence | Standard Error 0.021 |
| Smokers | Phagocytosis of S. Pneumoniae Concentration | concentration 0.3g/ml | 0.056 relative fluescence | Standard Error 0.012 |
| Smokers | Phagocytosis of S. Pneumoniae Concentration | concentration 1g/ml | 0.072 relative fluescence | Standard Error 0.016 |
| COPD | Phagocytosis of S. Pneumoniae Concentration | concentration 0.3g/ml | 0.012 relative fluescence | Standard Error 0.011 |
| COPD | Phagocytosis of S. Pneumoniae Concentration | concentration 1g/ml | 0.022 relative fluescence | Standard Error 0.014 |
p-value: 0.05Kruskal-Wallis