Respiratory and Cardiovascular Effects in COPD (KOLIN)

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

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Other: Bronchoscopy

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 Type: Interventional
• Enrollment (Actual): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Sverige
    • Umeå, Sverige, Sweden, SE-90185
      • Department of Public Health and Clinical Medicine, Division of medicine, Pulmonary medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr Annelie F Behndig, MD PhD

Publications and helpful links

General Publications

• 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 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: February 24, 2016
• First Submitted That Met QC Criteria: April 5, 2016
• First Posted (Estimate): April 6, 2016

Study Record Updates

• Last Update Posted (Estimate): April 6, 2016
• Last Update Submitted That Met QC Criteria: April 5, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Oxidative stress; Bronchoscopy; Aging; Proteases
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 2011-147_31M