Responses Induced by Smoking in Individuals Being Susceptible and Non-Susceptible for Development of COPD

Acute and Chronic Inflammatory Responses Induced by Smoking in Individuals Being Susceptible and Non-Susceptible for Development of COPD: From Specific Disease Phenotyping Towards Novel Made Therapy (Study 1)

COPD is ranked number 3 by the WHO list of important diseases worldwide and is the only disease with increasing mortality. The pathogenesis of cigarette smoke-induced COPD is obscure, therefore more insight is needed to design effective anti-inflammatory agents. We hypothesize that healthy individuals who are susceptible to smoking demonstrate a higher and aberrant inflammatory response to cigarette smoke. This susceptibility is caused by heterogeneous factors and is associated with various polymorphic genes that interact with each other and with the environment.

Objective:

• To define mediators involved in the early induction of COPD in susceptible smokers (and so to define new drug targets)
• To develop new biological and clinical markers for the early diagnosis and monitoring of COPD
• To compare between susceptible and non-susceptible individuals the corticosteroid responsiveness of bronchial epithelial cells in vitro, and to study the mechanisms of smoking-induced corticosteroid unresponsiveness.
• To study the role of candidate genes that may play a role in the development of fixed airway obstruction, and to identify clues for patient's responsiveness to specific drugs.

Primary study parameters/outcome of the study:

• Local inflammation before and after cigarette smoking assessed by exhaled breath condensate, microprobe sampling and bronchial biopsies.
• Systemic inflammation before and after cigarette smoking assessed by the expression of established and newly developed markers on innate immune cells associated with pre-activation.
• Extensive clinical characterisation including life style factors, lung function, CT scanning of the lung.
• Corticosteroid responsiveness of epithelial cells in vitro.
• Distribution of candidate genes (SNPs) for COPD between the 5 different groups ( see description below) and associations with the inflammatory responses on acute smoking.

Inclusion Criteria:

• Age 18-75 years
• Age, pack years, FEV1/FVC and FEV1% predicted must fit in one of the 5 groups described above.
• Able to stop smoking for 10 days and start smoking 3-4 cigarettes within 1 hour
• Physically and mentally able to undergo the total study protocol
• Written informed consent

Exclusion Criteria:

• Participation in another study
• Alpha-1-antitrypsin deficiency
• Selected grade 1-3 co-morbidity listed in the ACE-27
• Active pulmonary infection like tuberculosis, pneumonia, flue, tracheobronchitis
• Active extra-pulmonary infection like hepatitis A-C, cystitis, gastro-enteritis etc
• Pulmonary diseases like sarcoidosis, IPF, silicosis, hypersensitivity pneumonitis
• Life threatening diseases like carcinoma, AIDS (including HIV+), acute leukaemia etc
• Medication that may affect the results of the study: NSAID's, immunosuppressive agents like prednisolon, metotrexate, azathioprine,Acenocoumarol