COPDNCT00147017
Regulation of the Release of Inflammatory Mediators From Lung Macrophages.
An observational study of COPD and Chronic Bronchitis, run by Imperial College London at 1 site in United Kingdom.
Trial summary
The aim of this study is to investigate the mechanisms whereby specific white cells called macrophages found in the lung release inflammatory mediators or chemicals together with enzymes that destroy the surrounding lung tissue. Read more about this study
- Who is it for?
- Ages 21 to 75 years
- Conditions the study is for
- COPD, Chronic Bronchitis, Emphysema
- How many people
- 17 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jun 2001to Dec 2010
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: All subjects undergoing lung resection surgery
Who may be able to join
- All subjects undergoing surgical resection of the lung
Who cannot join
- Anyone unable to understand the consent form
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Brompton Hospital/NHLI Imperial College London
London, SW3 6LY
About this study
The aim of this study is to investigate the mechanisms whereby specific white cells called macrophages found in the lung release inflammatory mediators or chemicals together with enzymes that destroy the surrounding lung tissue. The hypothesis is that in diseases such as chronic obstructive pulmonary disease (COPD), lung macrophages release either more or different types of inflammatory mediators and/or destructive enzymes compared to subjects without COPD. We will isolate macrophages from small pieces of lung parenchyma. These samples are derived from lobes resected for carcinoma of the lung. We would aim to examine the responses of tissue derived macrophages in three groups of subjects, namely (i) non-smoking controls (lung carcinoma as secondary metastasis), (ii) smokers without clinical or histological signs of COPD and (iii) smokers with COPD. The resected lung tissue will be cut into small pieces and washed in order to release the macrophages from the tissue. The macrophages will then be isolated from other cell types in the washings. We will then use these isolated cells in vitro to examine the cell surface receptors in order to compare these macrophage cells with macrophages reported from bronchoalveolar lavage and monocyte derived macrophage models. We will then examine inflammatory mediator synthesis and release following stimulation of these cells. We will also examine the regulation and release of enzymes known to damage lung tissue. Using these two models we will then examine the signal transduction pathways that lead to this activation of the macrophages and investigate the effects of novel therapeutic agents to inhibit inflammatory mediator and/or enzyme synthesis and release. The objective is to identify the mechanisms whereby macrophages respond to pro-inflammatory conditions seen in COPD with a view to identify novel targets for drug therapy.
Read the detailed description
Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death in the UK and is the only common cause of death that is increasing. COPD is currently 6th in the global impact of diseases and is predicted to by the 3rd leading cause of death by 2020. In the UK for 2000-2001 the estimated cost of COPD related illness is estimated at ~£980 million of which pharmacotherapy accounts for 48% of expenditure. At present pharmacotherapy for COPD is purely symptomatic with no drugs currently available that can halt the relentless progression of this disease. Therefore, there is a need for improved therapy for the treatment of COPD. Cigarette smoking is the major risk factor in the development of COPD, yet for reasons unknown only ~15% of smokers develop this disease, suggesting there is an underlying genetic component.
COPD encompasses chronic bronchitis, small airways disease and emphysema and is associated with increased inflammatory cells in the lung including neutrophils, macrophages and CD8+ T-lymphocytes. This inflammatory infiltrate is thought to be responsible for all the pathophysiological features of COPD but the precise mechanisms underlying this inflammatory response are unknown.In particular the macrophage is thought to mediate all the pathophysiological features of this disease. To this end, macrophages will be isolated from lung parenchyma using discontinuous percoll gradients. The cells will then be cultured overnight prior to assessment of inflammatory mediator release. Cells will be stimulated by a variety of agents including but not exclusively LPS, IL-1beta or TNF-alpha. The release of inflammatory mediators into the cell culture media will be measured using ELISA techniques. Enzyme activity will also be measured in both the cells and the culture media. Cell surface expression of specific markers will be assessed using immunocytochemistry and FACS analysis. Function of macrophages will be assessed by measuring phagocytotic activity by FACS analysis and fluorimetry. Specific signal transduction pathways will be assessed by the use of specific pathway inhibitors and gene expression measured by real-time PCR. The effects of novel therapeutic agents will be tested on these outputs with the aim to identify novel therapies for COPD.
- Conditions
- COPD, Chronic Bronchitis, Emphysema
- Keywords
- macrophage, inflammation, COPD
- Medical subject headings
- Pulmonary Disease, Chronic Obstructive, Bronchitis, Chronic, Emphysema, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Smokers | All subjects had a smoking history of >15 pack years | |
| Ex-smokers | Ex-smokers had ceased smoking for >6 months. | |
| Emphysema lung transplant | The emphysema subjects were all undergoing lung transplants. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Macrophage Activation, TNF-a
measure release of inflammatory mediators from isolated macrophages
Measured: 20 hours
Macrophage Activation, GM-CSF
GM-CSF, granulocyte macrophage-colony stimulating factor
Measured: 20 hours
Interleukin, IL-8
Measured: 20 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Sep 2005 (estimated)
- Study startJun 2001
- Primary completionDec 2010
- Study completionDec 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for COPDStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis, Boehringer Ingelheim, Royal Brompton & Harefield NHS Foundation Trust
- Responsible party
- Sponsor
- Investigators
- Louise E Donnelly, PhD, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00147017
- Sponsor's protocol ID
- 01-093
- Other IDs
- DHTAB PN1257, DHTAB PC3608, DHTAB P00134
- Status last verified
- Nov 2019
- First submitted
- 5 Sep 2005
- Last updated
- 10 Dec 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS, Giembycz MA, Barnes PJ, Donnelly LE. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol. 2006 Oct;149(4):393-404. doi: 10.1038/sj.bjp.0706885. Epub 2006 Sep 4.
PubMed 16953188
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Regulation of the Release of Inflammatory Mediators From Lung Macrophages.
- ClinicalTrials.gov ID
- NCT00147017
- Acronym / sponsor ID
- 01-093
- Conditions
- COPD, Chronic Bronchitis, Emphysema
- Keywords
- macrophage, inflammation, COPD
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- Novartis, Boehringer Ingelheim, Royal Brompton & Harefield NHS Foundation Trust
- Study start
- Jun 2001 (actual)
- Primary completion
- Dec 2010 (actual)
- Study completion
- Dec 2010 (actual)
- First posted
- 7 Sep 2005 (estimated)
- Results
- Posted 27 Nov 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of this study is to investigate the mechanisms whereby specific white cells called macrophages found in the lung release inflammatory mediators or chemicals together with enzymes that destroy the surrounding lung tissue. The hypothesis is that in diseases such as chronic obstructive pulmonary disease (COPD), lung macrophages release either more or different types of inflammatory mediators and/or destructive enzymes compared to subjects without COPD. We will isolate macrophages from small pieces of lung parenchyma. These samples are derived from lobes resected for carcinoma of the lung. We would aim to examine the responses of tissue derived macrophages in three groups of subjects, namely (i) non-smoking controls (lung carcinoma as secondary metastasis), (ii) smokers without clinical or histological signs of COPD and (iii) smokers with COPD. The resected lung tissue will be cut into small pieces and washed in order to release the macrophages from the tissue. The macrophages will then be isolated from other cell types in the washings. We will then use these isolated cells in vitro to examine the cell surface receptors in order to compare these macrophage cells with macrophages reported from bronchoalveolar lavage and monocyte derived macrophage models. We will then examine inflammatory mediator synthesis and release following stimulation of these cells. We will also examine the regulation and release of enzymes known to damage lung tissue. Using these two models we will then examine the signal transduction pathways that lead to this activation of the macrophages and investigate the effects of novel therapeutic agents to inhibit inflammatory mediator and/or enzyme synthesis and release. The objective is to identify the mechanisms whereby macrophages respond to pro-inflammatory conditions seen in COPD with a view to identify novel targets for drug therapy.
Detailed description
Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death in the UK and is the only common cause of death that is increasing. COPD is currently 6th in the global impact of diseases and is predicted to by the 3rd leading cause of death by 2020. In the UK for 2000-2001 the estimated cost of COPD related illness is estimated at ~£980 million of which pharmacotherapy accounts for 48% of expenditure. At present pharmacotherapy for COPD is purely symptomatic with no drugs currently available that can halt the relentless progression of this disease. Therefore, there is a need for improved therapy for the treatment of COPD. Cigarette smoking is the major risk factor in the development of COPD, yet for reasons unknown only ~15% of smokers develop this disease, suggesting there is an underlying genetic component.
COPD encompasses chronic bronchitis, small airways disease and emphysema and is associated with increased inflammatory cells in the lung including neutrophils, macrophages and CD8+ T-lymphocytes. This inflammatory infiltrate is thought to be responsible for all the pathophysiological features of COPD but the precise mechanisms underlying this inflammatory response are unknown.In particular the macrophage is thought to mediate all the pathophysiological features of this disease. To this end, macrophages will be isolated from lung parenchyma using discontinuous percoll gradients. The cells will then be cultured overnight prior to assessment of inflammatory mediator release. Cells will be stimulated by a variety of agents including but not exclusively LPS, IL-1beta or TNF-alpha. The release of inflammatory mediators into the cell culture media will be measured using ELISA techniques. Enzyme activity will also be measured in both the cells and the culture media. Cell surface expression of specific markers will be assessed using immunocytochemistry and FACS analysis. Function of macrophages will be assessed by measuring phagocytotic activity by FACS analysis and fluorimetry. Specific signal transduction pathways will be assessed by the use of specific pathway inhibitors and gene expression measured by real-time PCR. The effects of novel therapeutic agents will be tested on these outputs with the aim to identify novel therapies for COPD.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Smokers | – | –All subjects had a smoking history of >15 pack years |
| Ex-smokers | – | –Ex-smokers had ceased smoking for >6 months. |
| Emphysema lung transplant | – | –The emphysema subjects were all undergoing lung transplants. |
Who may qualify
- Ages
- 21 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- All subjects undergoing lung resection surgery
Key inclusion criteria (1 listed)
- All subjects undergoing surgical resection of the lung
Key exclusion criteria (1 listed)
- Anyone unable to understand the consent form
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Macrophage Activation, TNF-a
Time frame: 20 hours
measure release of inflammatory mediators from isolated macrophages
Macrophage Activation, GM-CSF
Time frame: 20 hours
GM-CSF, granulocyte macrophage-colony stimulating factor
Interleukin, IL-8
Time frame: 20 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 16953188Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS, Giembycz MA, Barnes PJ, Donnelly LE. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol. 2006 Oct;149(4):393-404. doi: 10.1038/sj.bjp.0706885. Epub 2006 Sep 4.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Louise E Donnelly, PhD principal investigator
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of COPD and Chronic Bronchitis, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Macrophage Activation, TNF-a (time frame: 20 hours). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00147017, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2019.