Disease progression in IPF is associated with alveolar epithelial damage followed by the development of areas of fibroblast proliferation and differentiation. Tissue damage leads to increased matrix deposition, and ultimately severe derangement of gas exchange units. Loss of alveolar function leads to impaired ventilation, decreased lung function and both systemic and local tissue hypoxia.

There are two main projects related to inflammatory gene expression in the lung.

The first is focused upon understanding the transcriptional regulation of the macrophage migration inhibitory factor (MIF) gene. Dr Baugh's team recently described a functional tetranucleotide-repeat element in the MIF promoter that correlates with disease severity in inflammatory disease such as rheumatoid arthritis, and are seeking to elucidate the mechanism by which this polymorphism affects gene expression.

Extending from these studies on the regulation of MIF expression the second main research project is based upon the effects of hypoxia on pro-inflammatory gene expression in primary human lung fibroblasts derived from patients with various respiratory pathologies. The lungs are exquisitely sensitive to changes in atmospheric and blood oxygen levels and normally respond in order to maintain health of the organism. In some inflammatory lung diseases, however, it is believed that abnormal responses to hypoxia may contribute to exacerbated inflammation and aberrant tissue remodelling. We are particularly interested in elucidating mechanisms by which hypoxia may drive aberrant remodelling in diseases such as IPF. 

Professor Peter Kelly (UCD Associate Professor of Neurology and Consultant Neurologist at the Mater Misericordiae University Hospital) is leading research into prediction of early stroke recurrence.  His group have developed a diagnostic imaging test to measure plaque inflammation and in a small clinical study comprising 60 stroke patients, have shown a significant association between plaque inflammation in the carotid artery and the 13 patients who had a recurrent stroke.

“At the moment 20 out of every 100 patients who suffer a mini-stroke will have another stroke within 90 days. The risk is frontloaded in the week immediately following the mini-stroke, and a recurrence is usually far more profound and debilitating. This research describes a way to determine those patients who are most at risk by measuring the level of plaque inflammation in the carotid artery. We used a diagnostic imaging device known as PET-CT to gauge levels of inflammation, which then shows up on the scan as a bright spot. We were able to set a threshold whereby the level of brightness corresponds to the highest stroke risk – thereby predicting the likelihood of a recurrent stroke for high risk patients,” said Professor Kelly.

Current international guidelines recommend that patients who present following a mini-stroke routinely undergo a number of diagnostic tests, one of which involves a carotid ultrasound to determine the extent to which the carotid artery has narrowed. However, this approach is limited in its effectiveness. The findings from Professor Kelly and his team point to plaque inflammation – not just narrowing - as the primary predictor of recurrent stroke.

“This could fundamentally change the way in which we target and treat patients who present following a mini-stroke. It means that we may be able to significantly reduce the number of people who suffer a second stroke during the high risk period by identifying and treating them more quickly. Further down the line, we can use these findings in trials by inventing drugs that attack and reduce levels of inflammation in the carotid artery.” said Professor Kelly.

“It’s important also to send the message that early diagnosis and treatment can only be effective if people recognise and act on the warning signs from the Irish Heart Foundation’s FAST campaign. A mini-stroke usually manifests itself in temporary and transient symptoms like slurred speech, loss of feeling in the limbs or blurred vision. People often ignore the symptoms because they usually disappear quickly, but a mini-stroke is a shot across the bow and should be treated as a medical emergency,” said Professor Kelly.

Chronic obstructive lung diseases – most commonly caused by smoking - affect over 100,000 people in Ireland and present life-threatening complications such as emphysema and chronic bronchitis. Chronic obstructive lung diseases make it hard to empty air out of the lungs. This is because the airways get smaller leading to airflow obstruction. Chronic lung diseases include chronic bronchitis, emphysema or a combination of both conditions. Symptoms of chronic lung disease include shortness of breath, cough and sputum (phlegm) production. It is estimated that over 100,000 people suffer from the disease in Ireland. It is estimated that by 2020, chronic obstructive lung disease will be the third most common cause of death worldwide, primarily due to increased rates of smoking in the developing world.

Most people with chronic lung diseases are smokers or have smoked in the past and are over 35. Chronic lung disease can also be caused by working or living for many years in an environment where there is exposure to smoke, dust or other fumes.

Chronic bronchitis is caused by inflammation and increased mucus (phlegm) in the breathing tubes (airways). Because of the swelling and extra mucus the inside of the breathing tubes become smaller causing obstruction in airflow.

Emphysema is caused by damage to the air sacs (alveoli) of the lung. Normally there are more than 300 million air sacs in the lungs. If the walls of the air sacs are damaged they lose their elasticity and trap air. This causes extra air to remain in the lungs after you breathe out. The extra effort required to breathe results in shortness of breath.

Professor Paul McLoughlin (UCD Professor of Physiology) and his research group at the UCD Conway Institute lead research into the identification of potential new treatment for these condition. According to findings published in Circulation it may be possible to target and regulate a protein that contributes to pulmonary hypertension - high blood pressure in the arteries of the lung – a disabling and potentially fatal complication for patients suffering from chronic obstructive lung disease.

Professor McLoughlin notes that

“diseases such as emphysema, chronic bronchitis and fibrosis of the lungs cause abnormally low levels of oxygen in the lung. When the lung is starved of oxygen, blood pressure in the arteries of the lung increases which damages blood vessels and makes it more difficult for the heart to pump blood, leading in many cases to heart failure and premature death”

While investigating the factors that contribute to high blood pressure in the arteries, the group found that when oxygen levels in the lung are reduced, the body produces elevated quantities of a protein called gremlin – suggesting a link between elevated levels of gremlin and pulmonary hypertension.

Further investigations showed that mice whose genes had been mutated to reduce gremlin were protected against pulmonary hypertension, even when in a low oxygen environment similar to that found in lung disease. The heart was also protected and the damage to blood vessels in the lung was less severe. 

Further research showed that gremlin was elevated in the lungs of patients with pulmonary hypertension, confirming a key role for the protein in damaging the blood vessels of the lung.

“These research findings suggest the potential for additional novel treatments of patients by designing drugs that block the actions of gremlin in the lung”,

said Professor McLoughlin.