Regulation of the Release of Inflammatory Mediators From Blood Leukocytes
Regulation of the Release of Inflammatory Mediators From Blood Leukocytes
Chronic obstructive pulmonary disease (COPD for short) involves inflammation inside the air
 passages of the lungs. This inflammation might be partly responsible for the shortness of
 breath, cough and susceptibility to chest infections that form part of COPD. Inflammation is
 caused, in part, by white blood cells that are attracted from the blood into the air
 passages. Once inside the air passages, the white blood cells may change (or 'differentiate')
 and release substances that produce inflammation and attract more white cells. The hypothesis
 is that the lifespan of these cells may also be prolonged such that they produce more
 inflammatory mediators and in turn perpetuate inflammation. The cycle of inflammation may
 damage the lungs, so we want to see what mediators are released by white blood cells and
 determine if we can inhibit this effect with existing and new drugs. We would also like to
 see the effect of these drugs on the life-span and function of white blood cells. We will
 compare the behaviour and characteristics of white cells with those from healthy smokers and
 healthy non-smokers to find out if there is anything different about cells from COPD
 patients.
The aim of this study is to investigate the mechanisms that regulate the survival of blood
 leukocytes as well as the synthesis and release of inflammatory mediators from cells from
 normal individuals and subjects with COPD. The hypothesis is that in COPD the life-span of
 leukocytes, such as the neutrophil, is enhanced and this may contribute to inflammation, a
 prominent characteristic of this disease, by secreting and releasing inflammatory mediators.
 We also suggest that differences may exist in the sensitivity of the various leukocytes to
 different therapies.

 Leukocytes will be purified from the peripheral venous blood of patients with COPD as well as
 healthy individuals. We will then investigate the effects of novel and existing therapeutic
 agents on leukocyte survival and inflammatory mediator synthesis and release. We will also
 examine the regulation and release of enzymes known to damage lung tissue. Further studies
 will be carried out to elucidate the signal transduction pathways that lead to the
 activation, altered longevity and function of leukocytes. In other experiments ribonucleic
 acids or RNA may be extracted form leukocytes to investigate which genes are involved. The
 primary objective is to identify the mechanisms that enhance leukocyte longevity and
 inflammatory mediator and/or enzyme synthesis and release with a view to identifying novel
 targets for drug therapy.
Inclusion Criteria:

 Healthy non-smoking subjects: All normal volunteers will meet the following criteria:

 -  Age 21-70 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 40-75 years.

 -  A smoking history of at least 20 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 b2-agonist of <15% of predicted FEV1: all three criteria are required.

 -  Current smokers or smokers who had ceased smoking for at least 6 months.

 -  No history of exacerbation, oral steroid or antibiotic use within the preceding 6
 weeks.

 -  Normal serum a-1 antitrypsin level.

 -  No history of other respiratory or allergic disease.

 -  No evidence of atopy on skin prick testing to common aeroallergens (grass pollen, cat
 hair, house dust mite or Aspergillus fumigatus

 -  These tests will have already been performed as part of routine assessment in
 Professor Barnes' COPD clinic and we will not need to repeat them for this study.

 Healthy Smokers: All healthy smoking volunteers in trials will meet the following criteria:

 -  Age 21-70 years.

 -  Smoking history of at least 10 pack years (1 pack year = 20 cigarettes per day for 1
 year).

 -  No history of respiratory or allergic disease.

 -  Normal baseline spirometry as predicted for age, sex and height.

 -  No history of upper respiratory tract infection in the preceding six weeks.

 -  Not taking regular medication.

 Exclusion Criteria:

 Subjects will not included in this study if they meet any of the following exclusion
 criteria:

 -  Clinically significant findings in the medical history or on physical examination
 other than those of COPD in the COPD group.

 -  Pregnant women or mothers who are breastfeeding.

 -  Subjects who are unable to give informed consent.