Respiratory and Cardiovascular Effects in COPD

Study Overview
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Brief Summary
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The purpose of this study is to find out if subjects with chronic obstructive pulmonary disease have signs of accelerated ageing in their airways.

Detailed Description
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The age-related impairment of innate immunity and antioxidant defenses likely impacts on development and disease progression of chronic obstructive pulmonary disease, COPD. It has been suggested that aging-related declines in function are accelerated in COPD due to recurrent cycles of inflammation, tissue injury and repair, associated with long-term exposure to cigarette smoke or other airway irritants. Here, the investigators aim to follow up on previous observations of impaired antioxidant responses in the lung of COPD patients, to establish the extent to which this reflects an accelerated aging phenotype, to characterize the molecular mechanisms resulting in this functional deficiency. The proposed studies will employ well-characterized patients with COPD of varying severity and smoking habits, as well as carefully age and smoking history-matched controls. Accelerated aging within the COPD lung will be assessed in endobronchial mucosal biopsies and airway macrophages by assessment of established senescence markers using immunohistochemical, biochemical and PCR-based methods. These markers of tissue age will then be related to the functional activation of transcription factors, known to be induced by oxidative stress and related to cytoprotection such as Nrf2 and AP1. The investigators will also examine whether COPD is associated with an enhanced secretion of inflammatory mediators from senescent cells, consistent with the accelerated aging paradigm and establish how this influences cell function. Deficiencies in metal handling, antioxidant defenses and diminished airway innate immune defenses at the air-lung interface will be assessed. The aim is to identify biomarkers for the risk of rapid lung function deterioration in COPD patients.

Official Title
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Respiratory and Cardiovascular Effects in COPD - Report From a Bronchoscopy Investigation Based on the Obstructive Lung Disease In the Northern Sweden (OLIN) Studies

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Other: Bronchoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of COPD, GOLD stage 2-3. Smoking history of at least 10 packyears. Exclusion Criteria: Severe ischemic heart disease. Other severe disease. Respiratory infection within four weeks.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy controls<br>Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness | Other: Bronchoscopy<br>* Sampling of airways<br>|
| Other: Smokers<br>Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness | Other: Bronchoscopy<br>* Sampling of airways<br>|
| Other: COPD rapid decline<br>Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness | Other: Bronchoscopy<br>* Sampling of airways<br>|
| Other: COPD slow decline<br>Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness | Other: Bronchoscopy<br>* Sampling of airways<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cellular senescence marker - Ki67 | Endobronchial mucosal biopsies collected by bronchoscopy. Immunohistochemistry for the cellular senescence markers Ki67 will be performed. | Baseline | 
| Matrix metalloproteinase 12 (MMP12) and the inhibitor TIMP1 | Airway lavages collected by bronchoscopy and serum will be analysed for MMP and TIMP using ELISAs. | Baseline | 
| Levels of oxidized proteins, 4 HNE | The accumulation of oxidized proteins, 4-Hydroxynonenal, will be assessed in bronchial biopsies. | Baseline | 
| Antioxidant-related transcription factor Nrf2 | Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor known to be induced by oxidative stress and related to cytoprotection. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metals in airway lavages | Airway lavages collected by bronchoscopy will be analysed for metals using mass spectrometry | Baseline | 
| Lymphocyte subsets in bronchoalveolar lavage | Airway lavages collected by bronchoscopy will be analysed for lymphocyte subsets using flow cytometry. | Baseline | 
| Arterial stiffness | Non-invasive measurement of arterial stiffness | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aging, Oxidative stress, Proteases, Bronchoscopy