Respiratory and Cardiovascular Effects in COPD (KOLIN)

• ClinicalTrials.gov Identifier: NCT02729220
• Recruitment Status: Completed
• First Posted: April 6, 2016
• Last Update Posted: April 6, 2016
• Sponsor: Dr Annelie F Behndig, MD PhD
• Information provided by (Responsible Party): Dr Annelie F Behndig, MD PhD, University Hospital, Umeå

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Pulmonary Disease, Chronic Obstructive	Other: Bronchoscopy	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Respiratory and Cardiovascular Effects in COPD - Report From a Bronchoscopy Investigation Based on the Obstructive Lung Disease In the Northern Sweden (OLIN) Studies
• Study Start Date: January 2012
• Actual Primary Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Healthy controls; Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness	Other: Bronchoscopy; Sampling of airways
Smokers; Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness	Other: Bronchoscopy; Sampling of airways
COPD rapid decline; Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness	Other: Bronchoscopy; Sampling of airways
COPD slow decline; Bronchoscopy with collection of bronchial biopsies and lavages Arterial stiffness	Other: Bronchoscopy; Sampling of airways

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Metals in airway lavages [ Time Frame: Baseline ]
   Airway lavages collected by bronchoscopy will be analysed for metals using mass spectrometry
2. Lymphocyte subsets in bronchoalveolar lavage [ Time Frame: Baseline ]
   Airway lavages collected by bronchoscopy will be analysed for lymphocyte subsets using flow cytometry.
3. Arterial stiffness [ Time Frame: Baseline ]
   Non-invasive measurement of arterial stiffness

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Sweden

Department of Public Health and Clinical Medicine, Division of medicine, Pulmonary medicine

Umeå, Sverige, Sweden, SE-90185

Sponsors and Collaborators

Dr Annelie F Behndig, MD PhD

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Eriksson Ström 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.

Eriksson Ström 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.

• Responsible Party: Dr Annelie F Behndig, MD PhD, Investigator, University Hospital, Umeå
• ClinicalTrials.gov Identifier: NCT02729220
• Other Study ID Numbers: 2011-147_31M
• First Posted: April 6, 2016
• Last Update Posted: April 6, 2016
• Last Verified: March 2016

Keywords provided by Dr Annelie F Behndig, MD PhD, University Hospital, Umeå:

Aging; Oxidative stress; Proteases; Bronchoscopy

Additional relevant MeSH terms:

Pulmonary Disease, Chronic Obstructive; Lung Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive