Innate Immunity in COPD

NCT05743582 | Recruiting

• 1 other identifier: AC23003
• Study Type: observational
• Target: 189
• Locations: 1 country
• Sites: 2

Brief Summary

Chronic Obstructive Pulmonary Disease (COPD) causes obstruction to airflow when breathing out. It is a leading cause of chronic lung disease, hospitalization and death. Smoking is the major cause of COPD but why some smokers develop COPD while others do not is poorly understood. A central feature of COPD is accumulation of inflammatory blood cells, macrophages and neutrophils, in the airway, leading to lung injury and airway damage. The small airways of many patients with COPD contain bacteria, which are absent in healthy smokers or non-smokers. These bacteria stimulate recruitment of neutrophils, macrophages and other inflammatory cells, further accelerating airway injury. The investigators and others have shown resident macrophages in the lung and inflammatory cells (neutrophils and macrophages) recruited from the blood, which normally clear bacteria, have reduced anti-bacterial capacity in COPD and that their altered function impairs the resolution of inflammation. The investigators now wish to test why these cells fail to clear bacteria focusing in particular on how they use molecules as food to generate energy, a process termed metabolism, since this is an important determinant of immune cell function. Comparison will be made between lung resident cells (obtained by performing bronchoscopy and washing a segment of lung to flush out immune cells) and those from the blood to determine if the alterations are specific to the lung. The investigators will identify alterations in responses to bacteria in relation to changes in metabolism . A major focus will be on how structures in the cell that normally are key for energy production (i.e. mitochondria) become dysfunctional and how this impacts responses to bacteria. The investigators will relate findings to the clinical features of COPD and to healthy non-smokers and smokers to separate smoking-related changes from COPD. The aim is to develop new approaches with which to treat and manage COPD.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

Alveolar macrophages; Peripheral blood mononuclear cells; Neutrophils; Bactericidal mechanisms; Immune cell metabolism; Epigenetics

Outcome Measures

Primary Outcomes (1)

• Identification of immunometabolic responses in immune cells required for microbicidal activity.

  This programme will identify core features of the immunometabolic response and of mitochondrial function that are required for optimal macrophage responses to bacteria and establish how these core responses are perturbed in COPD. Outcomes will be related back to clinical phenotypes of the patients enrolled in the study. The investigators will also develop models and therapeutic approaches with which to translate this programme and suggest approaches for future clinical trials that may include use of repurposed agents.

  5 years

Study Arms (3)

COPD patients

Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection.

Procedure: Bronchoscopy for sample collection; Procedure: Blood donation

Healthy controls - smokers

Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection.

Procedure: Bronchoscopy for sample collection; Procedure: Blood donation

Healthy controls - non-smokers

Bronchoscopy to retrieve bronchoalveolar lavage fluid for isolation of immune cells, and phlebotomy for blood sample collection.

Procedure: Bronchoscopy for sample collection; Procedure: Blood donation

Interventions

Bronchoscopy for sample collection PROCEDURE

Participants will undergo a single bronchoscopy and bronchoalveolar lavage to obtain immune cells.

COPD patients; Healthy controls - non-smokers; Healthy controls - smokers

Blood donation PROCEDURE

Participants will donate a single blood sample for isolation of immune cells from peripheral blood.

COPD patients; Healthy controls - non-smokers; Healthy controls - smokers

Eligibility Criteria

• Age: 18 Years - 77 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

189 participants split evenly into: COPD patients, healthy smokers, healthy non-smokers (63 each)

You may qualify if:

• COPD patients:
• COPD patients aged 18-77 years who are GOLD Stage 1 or 2 or 3; for patients undergoing bronchoscopy already for a clinical reason.
• COPD patients aged 18-77 years old who are GOLD Stage 1,2 or 3 for patients who are donating blood only.
• COPD patients aged 18-69 years who are GOLD Stage 1 or 2 for patients undergoing bronchoscopy for research purposes.
• COPD- Defined by radiological investigation of chest either chest X-ray or High-resolution CT scan in previous 12 months
• Ability to provide informed consent
• Healthy volunteers:
• Any healthy volunteer aged 18-77 years
• Ability to provide informed consent

You may not qualify if:

• COPD patients:
• Individuals known to have active malignancy, immunosuppression, diabetes mellitus, chronic kidney disease or hepatic failure.
• Individuals with a history of anaemia
• Individuals who have donated \>250 ml of blood for any reason within the last 6 months
• Individuals who are pregnant or breast feeding.
• Current participation in any other clinical trial, except those directly relating to this cohort and study.
• Individuals who have had a febrile illness or other symptoms of acute infectious illness (respiratory, enteric or soft tissue) within the last 2 weeks
• Individuals who have received a vaccine in the past 2 weeks
• Inability to communicate in English or convey willingness to participate.
• For bronchoscopy - Any significant lung condition that would contra-indicate bronchoscopy including:
• active acute lung infection (with the exception of asymptomatic pulmonary colonisation) or malignancy, significant coexisting interstitial lung disease or additional pulmonary diagnosis in addition to COPD.
• Healthy volunteers:
• Individuals known to have active malignancy, immunosuppression, diabetes mellitus, chronic kidney disease or hepatic failure
• Individuals with anaemia on the screening full blood count (FBC)
• Individuals who donated \>250 ml of blood for any reason within the last 6 months

Sponsors & Collaborators

• University of Edinburgh: lead

Study Sites (2)

University of Edinburgh

Edinburgh, EH16 4TJ, United Kingdom

NOT YET RECRUITING

Royal Infirmary of Edinburgh

Edinburgh, EH16 5SA, United Kingdom

RECRUITING

Related Publications (7)

• Dockrell DH, Marriott HM, Prince LR, Ridger VC, Ince PG, Hellewell PG, Whyte MK. Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection. J Immunol. 2003 Nov 15;171(10):5380-8. doi: 10.4049/jimmunol.171.10.5380.

  PMID: 14607941 BACKGROUND

• Taylor AE, Finney-Hayward TK, Quint JK, Thomas CM, Tudhope SJ, Wedzicha JA, Barnes PJ, Donnelly LE. Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J. 2010 May;35(5):1039-47. doi: 10.1183/09031936.00036709. Epub 2009 Nov 6.

  PMID: 19897561 BACKGROUND

• Bewley MA, Preston JA, Mohasin M, Marriott HM, Budd RC, Swales J, Collini P, Greaves DR, Craig RW, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Shapiro SD, Whyte MKB, Dockrell DH. Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages. Am J Respir Crit Care Med. 2017 Oct 1;196(7):845-855. doi: 10.1164/rccm.201608-1714OC.

  PMID: 28557543 BACKGROUND

• Bewley MA, Budd RC, Ryan E, Cole J, Collini P, Marshall J, Kolsum U, Beech G, Emes RD, Tcherniaeva I, Berbers GAM, Walmsley SR, Donaldson G, Wedzicha JA, Kilty I, Rumsey W, Sanchez Y, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Whyte MKB, Dockrell DH; COPDMAP. Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists. Am J Respir Crit Care Med. 2018 Sep 15;198(6):739-750. doi: 10.1164/rccm.201705-0903OC.

  PMID: 29547002 BACKGROUND

• Belchamber KBR, Singh R, Batista CM, Whyte MK, Dockrell DH, Kilty I, Robinson MJ, Wedzicha JA, Barnes PJ, Donnelly LE; COPD-MAP consortium. Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages. Eur Respir J. 2019 Oct 10;54(4):1802244. doi: 10.1183/13993003.02244-2018. Print 2019 Oct.

  PMID: 31320451 BACKGROUND

• Mills EL, Kelly B, O'Neill LAJ. Mitochondria are the powerhouses of immunity. Nat Immunol. 2017 Apr 18;18(5):488-498. doi: 10.1038/ni.3704.

  PMID: 28418387 BACKGROUND

• Sadiku P, Willson JA, Ryan EM, Sammut D, Coelho P, Watts ER, Grecian R, Young JM, Bewley M, Arienti S, Mirchandani AS, Sanchez Garcia MA, Morrison T, Zhang A, Reyes L, Griessler T, Jheeta P, Paterson GG, Graham CJ, Thomson JP, Baillie K, Thompson AAR, Morgan JM, Acosta-Sanchez A, Darde VM, Duran J, Guinovart JJ, Rodriguez-Blanco G, Von Kriegsheim A, Meehan RR, Mazzone M, Dockrell DH, Ghesquiere B, Carmeliet P, Whyte MKB, Walmsley SR. Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis. Cell Metab. 2021 Feb 2;33(2):411-423.e4. doi: 10.1016/j.cmet.2020.11.016. Epub 2020 Dec 10.

  PMID: 33306983 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Immune cells from bronchoalveolar lavage obtained by bronchoscopy and peripheral blood mononuclear cells/neutrophils obtained from peripheral blood.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Bronchoscopy; Specimen Handling; Blood Donation

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Diagnostic Techniques, Respiratory System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative; Pulmonary Surgical Procedures; Thoracic Surgical Procedures; Clinical Laboratory Techniques; Investigative Techniques; Tissue and Organ Procurement; Health Services; Health Care Facilities Workforce and Services

Study Officials

• David H Dockrell, MD

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David H Dockrell, MD

CONTACT

+441312426213; David.Dockrell@ed.ac.uk

Sarah Walmsley, MD

CONTACT

Sarah.Walmsley@ed.ac.uk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2023
• First Posted: February 24, 2023
• Study Start: May 11, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): February 10, 2028
• Last Updated: June 11, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will become available upon publication of results at the end of the study.
• Access Criteria: IPD will be shared directly with other researchers for analysis of cohort data upon request from the Principal Investigator.

Locations

GB (2)