Defining the anti-fibrotic mechanisms of prostacyclin drugs in pulmonary fibrosis

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Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which healthy lung tissue is replaced by scar tissue. The lungs become stiff and lose their ability to transfer oxygen from the atmosphere to the blood. The disease is termed "idiopathic" as the cause is unknown. IPF is the fourth leading cause of death from a respiratory illness in the UK. The condition is more common in men, particularly affecting those over the age of 70. 32,500 people were living with the condition as per the last available data recorded in 2012. This number is rising and is predicted to continue to do so. The average survival is poor with a life expectancy of only three years from the time of diagnosis. This is comparable to the worst cancers. Symptoms of IPF include progressive shortness of breath and dry cough. In the later stages, the blood pressure in the arteries of the lungs can also rise, putting strain on the heart and circulation (termed pulmonary hypertension) leading to heart failure and fluid retention.The current understanding of what happens on a microscopic level in IPF is as follows: cells which line the airways in the lungs are damaged (by, for example, smoke inhalation or a virus) and the normal repair process that would follow this damage does so in an uncontrolled manner and produces large amounts of scar tissue. This may happen because an individual carries a set of genes making them more susceptible. Unfortunately, there is a lack of effective treatments for the condition. Two drugs are approved in the UK - Pirfenidone and Nintedanib - but both have only been proven to slow the scarring process down and come with a number of side effects. No treatments are available which can stop or reverse the scarring. In a recent clinical trial, a drug called Treprostinil was shown to improve both the high blood pressure in the lungs but also reduce the stiffness of the lung tissue in patients with lung scarring. Treprostinil belongs to a class of drugs known as prostacyclins which naturally occur in the body and have important functions in maintaining blood pressure and also blood clotting. They have long been used to treat pulmonary hypertension. Precisely how Treprostinil and other available prostacyclin drugs improve lung scarring is less well understood and possibly represent an exciting new treatment for IPF.Understanding how prostacyclin drugs work in IPF will help to better establish how these agents can be best used to treat the condition. My research proposal is to better define how prostacyclin drugs act within individual cells found in the lungs which are involved in fibrosis. My three aims are as follows: 1) Confirm how prostacyclin drugs interact with relevant cells - for example by establishing which receptors these agents combine with and what effect this has on the machinery inside the cells. I will test this in cells obtained from humans and mice. 2) Establish what effect prostacyclin drugs have on the generation of scar tissue - for example, do prostacyclin drugs reduce the amount of fibrotic tissue generated and is this effect most pronounced in a specific cell? 3) Test whether combining different prostacyclin drugs and other agents which act within the cells can be used to maximize any beneficial effect seen.The information gained from these experiments will have helped explain how these drugs work and importantly how they can potentially benefit patients with IPF.