Lung selective dysregulation of the CXCR7/CXCL12 biological axis: a novel pathomechanism in human pulmonary vascular disease

Lead Researcher:

Dr Christine Costello

Award Date:

1 January 2013

Host Institution:

University College Dublin

Scheme:

Health Research Award

Summary:

Chronic lung diseases including asthma, cystic fibrosis and occupational lung diseases are amongst the commonest causes of death and disability worldwide. In Ireland, respiratory diseases impose a particularly heavy burden; Ireland has the highest death rate from respiratory disease in western Europe. Faced with this large and increasing burden of disease, our present treatment options are limited. Bronchodilator therapy is essentially palliative, while anti-inflammatory therapies including glucocorticoids are associated with significant side effects during long-term use. Thus there is a pressing need to identify new targets that could lead to improved therapeutic options for chronic lung disease patients. Regional hypoxia (low oxygen) occurs in the majority of patients with significant lung disease, and is implicated as an important stimulus for pulmonary vascular remodelling. These changes in vessels ultimately lead to an increase in blood pressure (termed pulmonary hypertension), which can significantly worsen outcome for patients. We previously carried out a study to determine which proteins cause these lung-selective hypoxic responsive changes. We discovered that a receptor for the potent pro-angiogenic (causes blood vessel growth) protein CXCL12, namely CXCR7, was significantly increased in the lung (but not in other organs) in response to low oxygen. We next showed that CXCL12 levels were significantly higher in the blood of pulmonary hypertensive patients and CXCR7 was also elevated in the grossly remodelled vessels of these patients. Taken together, these findings strongly suggest that signalling via CXCR7 may be particularly important in the lung disease. In the present proposal, we propose to use a combination of cell and animal experiments, along with clinically relevant human samples, to examine how signalling via CXCR7 effects the growth of blood vessels in the lung. The end goal of this proposal is to identify if this pathway represents a new target for therapeutic intervention for chronic lung diseases.