Trinity College Dublin: New hope for Chronic Obstructive Pulmonary Disease: World COPD Day 2021

To coincide with World COPD Day today, Dr Suzanne Cloonan, Associate Professor in Respiratory Medicine in Trinity’s School of Medicine and Tallaght University Hospital (TUH) describes her laboratory’s research investigating how cellular iron metabolism is regulated in the lungs of patients with COPD, and how dysregulation of iron uptake, release, or turnover contributes to the disease process.

Chronic Obstructive Pulmonary Disease (COPD) is a lung disease that makes it increasingly hard to breathe. It affects 440,000 people in Ireland and 170 million people worldwide. It is the fourth leading cause of death in Ireland. COPD is characterised by obstructed airflow from the lungs typically caused by exposure to cigarette smoke, but made worse by genetic factors, host responses, and infection. It is difficult to diagnose this condition in the early stages and doctors have few therapeutic treatment options.

There have not been many breakthroughs in therapy in decades, meaning COPD remains an irreversible and relentlessly progressive disease.

The role of iron in COPD
Excessive iron build up in the lungs is thought to be a major factor in COPD. Dr Cloonan’s research team believe they have identified the culprit for the excess which is a gene they previously found to increase patients’ susceptibility to the progressive lung disease. This gene, called IRP2 is tasked with regulating iron uptake in cells. The team’s discovery was significant because it validates the results of a 2009 study that implicated IRP2 in the disease’s development and demonstrates how the gene supports COPD. The findings also illustrate that IRP2 may be a powerful therapeutic target. Dr Cloonan described the lab’s focus:

We want to figure out where in the lung this iron accumulates and how this excess of iron affects the development of COPD. We are asking the following questions: Where does this iron come from given that cigarette smoke contains very little iron? What cells types are important in iron accumulation in the lung? Does having more iron promote the growth of bad bacteria rendering COPD patients more susceptible to infection?

Dr Cloonan’s team also aim to find out how iron is transported into and out of the mitochondrion (mitochondria are the ‘powerhouse’ of the cell). Mitoferrin-2 and mitoferrin 1 are mitochondrial membrane proteins that are thought to be involved in iron transport across the mitochondrial inner membrane into the mitochondrial matrix. The researchers investigate how these transporters contribute to normal mitochondrial function, metabolism and dynamics in the cell and how they co-ordinate with other aspects of cellular iron regulation.

The team also investigates how disturbances in iron metabolism underlie and drive alveolar macrophage-associated immune system disarray in COPD. Their research focuses on iron uptake, turnover, metabolism and export in alveolar macrophages and how these normal homeostatic processes are essential for the innate immune response to infection.

Research collaborations
Dr Cloonan collaborates with TUH’s Professor Seamus Donnelly (Professor of Respiratory and Interstitial Disease) and St James Hospital’s Professor Joseph Keane (Professor of Medicine). She highlights the crucial input from post-doctoral researchers Dr Claire Healy and Dr Niamh Williams in her laboratory. Dr Cloonan is part of a multi-centre study of COPD aiming to better classify patients for clinical trials:

We worked closely with SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study). SPIROMICS is a USA-based multi-centre longitudinal observational study of chronic COPD. SPIROMICS was designed to guide future development of therapies for COPD by providing robust criteria for subclassifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, and identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials.

Patient education on COPD
Creating awareness of COPD, along with engagement with patients and clinicians, is a core focus for Dr Cloonan and her team. Key groups include the Irish Thoracic Society and COPD Support Ireland. She explains how patient and public involvement is a crucial part of her work:

My partnership with key COPD groups allows for the provision of education, the gathering of information about specific COPD patient populations in Ireland, and providing a forum whereby patients can provide inputs into any research activities. I aim to build awareness for COPD research resulting in patients who are better informed and who understand the need for scientific research, enhancing patient morale and building a partnership between patient, science, and industry to ultimately develop novel therapeutic avenues for this disease.

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