Regulation of the Release of Inflammatory Mediators From Lung Macrophages.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00147017
Recruitment Status : Completed
First Posted : September 7, 2005
Last Update Posted : March 24, 2015
Boehringer Ingelheim
Royal Brompton & Harefield NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London

Brief 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. 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.

Condition or disease
COPD Chronic Bronchitis Emphysema

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 Type : Observational
Actual Enrollment : 60 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Regulation of the Release of Inflammatory Mediators From Lung Macrophages.
Study Start Date : June 2001
Actual Primary Completion Date : December 2010
Actual Study Completion Date : December 2010

Primary Outcome Measures :
  1. macrophage activation [ Time Frame: 24h ]
    measure release of inflammatory mediators from isolated macrophages

Biospecimen Retention:   Samples Without DNA
protein samples have been retained

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   21 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All subjects undergoing lung resection surgery

Inclusion Criteria:

All subjects undergoing surgical resection of the lung -

Exclusion Criteria:

Anyone unable to understand the consent form

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00147017

United Kingdom
Royal Brompton Hospital/NHLI Imperial College London
London, United Kingdom, SW3 6LY
Sponsors and Collaborators
Imperial College London
Boehringer Ingelheim
Royal Brompton & Harefield NHS Foundation Trust
Principal Investigator: Louise E Donnelly, PhD Imperial College London

Responsible Party: Imperial College London Identifier: NCT00147017     History of Changes
Other Study ID Numbers: 01-093
DHTAB P00134
First Posted: September 7, 2005    Key Record Dates
Last Update Posted: March 24, 2015
Last Verified: September 2005

Keywords provided by Imperial College London:

Additional relevant MeSH terms:
Bronchitis, Chronic
Pathologic Processes
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Pulmonary Disease, Chronic Obstructive