Regulation of the Release of Inflammatory Mediators From Lung Macrophages.

This study has been completed.
Sponsor:
Collaborators:
Novartis
Boehringer Ingelheim
Royal Brompton & Harefield NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT00147017
First received: September 5, 2005
Last updated: March 25, 2014
Last verified: September 2005
  Purpose

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
COPD
Chronic Bronchitis
Emphysema

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Regulation of the Release of Inflammatory Mediators From Lung Macrophages.

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • macrophage activation [ Time Frame: 24h ] [ Designated as safety issue: No ]
    measure release of inflammatory mediators from isolated macrophages


Biospecimen Retention:   Samples Without DNA

protein samples have been retained


Enrollment: 60
Study Start Date: June 2001
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   21 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

All subjects undergoing lung resection surgery

Criteria

Inclusion Criteria:

All subjects undergoing surgical resection of the lung -

Exclusion Criteria:

Anyone unable to understand the consent form

-

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00147017

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

No publications provided

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT00147017     History of Changes
Other Study ID Numbers: 01-093, DHTAB PN1257, DHTAB PC3608, DHTAB P00134
Study First Received: September 5, 2005
Last Updated: March 25, 2014
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by Imperial College London:
macrophage
inflammation
COPD

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

ClinicalTrials.gov processed this record on July 10, 2014