The pivotal role of alpha-1 antitrypsin (AAT) in maintaining a protease-anti-protease balance has been extensively studied and within the lung AAT plays an essential role in protecting the alveolar matrix from destruction by proteolytic enzymes. AAT deficiency (AATD) is a congenital condition that provides us with clear evidence for the physiological and clinical importance of AAT.
Research into the diverse functions of AAT has revealed that AAT possesses immune regulatory and anti-inflammatory properties, independent of its anti-protease activity. Adding to this field, we have recently published that during the acute inflammatory process of community acquired pneumonia (CAP) the circulating AAT molecule differs due to variations in its glycosylation pattern and that AAT glycans containing 4 sialic acids appeared during the resolution phase of CAP. Moreover, our preliminary data of this proposal highlights the role of sialylation in the anti-inflammatory activity of AAT, as during the resolving phase of infection there was a significant increase in circulating levels of CXCL8 and CXCL7 complexed to sialylated negative glycoforms of AAT (S-AAT). This binding event led to enhanced inhibition of CXCR1 and CXCR2-engagement, which may serve to prevent further migration of cells to epithelial surfaces and decrease the potential for neutrophil-mediated damage.
This project aims to recruit patients with common short term acute infections, and individuals during an exacerbation of chronic lifelong airways disease, to challenge the hypothesis that production of S-AAT is the body’s attempt to resolve inflammation. We will utilize an armoury of in vivo, ex vivo and in vitro assays to confirm the enhanced anti-inflammatory properties of S-AAT, and to prove that production of S-AAT is essential for dampening down inflammation. It is expected that the data will raise possibilities for the future application of a more sialylated form of AAT as augmentation therapy in AATD individuals and its potential use as a potent anti-inflammatory agent in inflammatory conditions such as chronic obstructive pulmonary disease (COPD).
