The role of sialylated-alpha-1 antitrypsin in resolution of acute and chronic inflammation

Alpha-1-antitrypsin (AAT) deficiency (AATD) is a hereditary disorder that results in the rapid progression of lung disease, especially in smokers. Specific treatment for this disorder is available in the form of weekly intravenous injections of AAT. This is referred to as augmentation therapy and studies have shown that augmentation therapy restores the concentration of AAT in the blood and slows down the course of lung disease. AAT is produced by liver cells and as it is being made a variety of sugars are attached to the core protein. The process of adding sugars to AAT is called glycosylation. This results in the formation of different forms of AAT, depending on what type of sugar is attached and also how much is attached. These different sugar-coated forms of AAT are referred to as glycoforms. Recently we published data demonstrating that blood from patients, as they are recovering from pneumonia, has high levels of a specific glycoform of AAT, called sialylated-AAT (S-AAT). Now we want to build on this solid foundation of work, and we aim to understand whether this phenomenon is specific to pneumonia or if S-AAT is produced upon resolution of other acute and also chronic diseases. This innovative research project will recruit patients with acute and chronic infections to confirm the production of S-AAT during resolution of inflammation. We will challenge the hypothesis that S-AAT is very effective at modulating activity of a range of inflammatory molecules and therefore aids in clearance of inflammation leading to a healthy body. We will employ knock-out cells to understand how S-AAT is produced, and in vivo murine and in vitro cell studies to confirm the anti-inflammatory effect of S-AAT. The significant effect that changes in glycosylation can have raises the question of whether S-AAT can be considered for the manufacture of a new AAT augmentation product with enhanced anti-inflammatory properties.

Award Date
28 June 2018
Award Value
Principal Investigator
Dr Emer Reeves
Host Institution
Royal College of Surgeons in Ireland
MRCG-HRB Joint Funding Scheme