The evaluation of the avb6 integrin as a biomarkers and therapeutic target for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease where the fine, delicate structure of the lungs is replace by a hard, concrete-like substance called fibrous matrix. This prevents the normal functions of the lung, such as the transfer of oxygen from the air to the body, it also leads to irritation and persistent cough. The speed at which this concrete-like matrix is deposited in the lung varies between different people, but ultimately leads to death. Unfortunately it is difficult to predict who will get worse quickly, and who will get worse slowly. Furthermore, there are no treatments that can improve the outlook for people with IPF at the current time. The aim of this study is to develop a biological test that can predict which people with IPF are going to have slowly progressive disease compared with rapidly progressive disease. More importantly these biological tests will hopefully be able to be used to show whether a current, or new treatment, is working in an individual patient. This information will help patients plan their future when the receive a diagnosis of IPF and will help in the development of new treatments for this condition, which are so urgently sought.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown aetiology. The pathogenesis of IPF is thought to be due to abnormal repair following alveolar epithelial injury within the lung. Current estimates suggest 4500 new cases of IPF each year in the UK, with median survival around 3 years. Furthermore, there has been a progressive increase in the incidence of IPF since the early 1980s. Considerable disease heterogeneity exists both in terms of clinical presentation and survival. However, there are no treatments that reduce the mortality or morbidity, although candidate treatments are emerging.
The aim of this proposal is to evaluate the alphavbeta6 integrin, which has an established role in the pathogenesis of fibrogenesis, as a potential biomarker in IPF. We will use immunohistochemistry from historical and prospective data sets as well as serum and lavage studies to evaluate alphavbeta6 integrin expression and downstream TGFbeta activation. We will develop a radiolabelled imaging strategy to permit real-time assessement of alphavbeta6 integrin expression which can then be followed longitudinally to assesss disease progression or response to therapy.
Specifically we aim to: 1) immunotype (alphavbeta6; alphaSMA, PAI-1, HGF) histological samples from patients undergoing surgical biopsies, to accurately determine patients with a poor prognosis compared with other fibrotic lung diseases; 2) develop non-invasive radioimaging (PET/CT and SPECT/CT) of pulmonary alphavbeta6 integrin levels to monitor the presence and progression of pulmonary fibrosis; 3) evaluate bronchoalveolar lavage and serum makers of alphavbeta6 integrin mediated TGFbeta activation in patients with IPF.
Initial studies will be performed in historical samples from patients with a diagnosis of lung fibrosis to determine whether . The cohort will be recruited within the established clinical network of centres in the whole Trent region, and will aim to recruit up to 225participants. At the time of diagnosis participants will be phenotyped in detail and the cohort will be followed for an average of 2.5 years (range 1 to 4 years). During this time we expect nearly 50% of our cohort to die. We will then determine which factors most accurately predict survival.
The results of this study will provide information regarding prognosis and disease progression in IPF. This information will be used to help plan the timing of therapeutic interventions such as lung transplantation as well as design of efficient clinical trials to alleviate the suffering of patients who suffer from this devastating disease.