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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy controls | Other | Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness |
|
| Smokers | Other | Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness |
|
| COPD rapid decline | Other | Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness |
|
| COPD slow decline | Other | Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bronchoscopy | Other | Sampling of airways |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Public Health and Clinical Medicine, Division of medicine, Pulmonary medicine | Umeå | Sverige | SE-90185 | Sweden |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33317530 | Derived | Eriksson Strom J, Pourazar J, Linder R, Blomberg A, Lindberg A, Bucht A, Behndig AF. Airway regulatory T cells are decreased in COPD with a rapid decline in lung function. Respir Res. 2020 Dec 14;21(1):330. doi: 10.1186/s12931-020-01593-9. | |
| 30526599 | Derived | Eriksson Strom J, Pourazar J, Linder R, Blomberg A, Lindberg A, Bucht A, Behndig AF. Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking. Respir Res. 2018 Dec 7;19(1):244. doi: 10.1186/s12931-018-0940-7. |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| D001999 | Bronchoscopy |
| ID | Term |
|---|---|
| D003948 | Diagnostic Techniques, Respiratory System |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D004724 | Endoscopy |
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| Baseline |
| Arterial stiffness | Non-invasive measurement of arterial stiffness | Baseline |
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003949 | Diagnostic Techniques, Surgical |
| D019060 | Minimally Invasive Surgical Procedures |
| D013514 | Surgical Procedures, Operative |
| D013510 | Pulmonary Surgical Procedures |
| D019616 | Thoracic Surgical Procedures |