5053189_monash_120067.pdf (2.34 MB)
Activin A: expression and potential sources in cardiopulmonary bypass and myocardial ischaemia-reperfusion injury
thesisposted on 2017-10-06, 05:44 authored by Chen, Yi
Activin A, a member of the transforming growth factor-β superfamily of regulatory proteins, has been implicated in both acute and chronic inflammation. Neutralising its biological effects using follistatin, a naturally occurring high affinity binding protein, has been associated with improved outcomes in animal models of inflammatory conditions such as endotoxaemia, inflammatory bowel disease, asthma and renal ischaemia-reperfusion injury. Cardiac surgery is associated with a generalised non- specific inflammatory response and this is largely an effect of cardiopulmonary bypass and myocardial ischaemia-reperfusion injury. In this thesis, the release pattern of activin A and follistatin in the setting of cardiopulmonary bypass and myocardial ischaemia-reperfusion was studied. Cardiopulmonary bypass was associated with a biphasic pattern of activin A release. Follistatin was also robustly released by cardiopulmonary bypass and the serum levels correlated with serum interleukin-6 levels. Activin A expression was increased in myocardial ischaemia-reperfusion and pre-treatment with follistatin reduced infarct size associated with ischaemia-reperfusion. Lastly, neutrophils were identified as a potential source of preformed activin A in acute inflammation. Tumour necrosis factor-α was able to stimulate the release of activin A from neutrophils via a p38 MAP kinase dependent pathway. Overall, this thesis has provided data to support the hypothesis that the activin A/follistatin axis is involved in the inflammatory response to cardiopulmonary bypass and myocardial ischaemia-reperfusion. Circulating neutrophils may be a potential source of preformed activin A in the setting of acute inflammation. Follistatin may have therapeutic potential in ameliorating myocardial ischaemia-reperfusion injury.