The role of activin A and follistatin in the acute phase and reperfusion responses during lung transplantation — ASN Events

The role of activin A and follistatin in the acute phase and reperfusion responses during lung transplantation (#61)

David M De Kretser 1 , Mark P Hedger 1 , Greg Snell 2 , Tom Kotsimbos 3 , Nicole Mifsud 3 , David Phillips 4 , Robyn O'Hehir 3
  1. Monash University, Clayton, Vic, Australia
  2. Lung Transplant Unit, Alfred Hospital, Melbourne, Victoria, Australia
  3. Dept of Allergy, Immunology & Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia
  4. Paranta Biosciences, Melbourne, Victoria, Australia

Organ transplantation requires that the organ be subjected to anoxia during transport and surgical implantation prior to revascularisation. Organ reperfusion results in an ischaemia reperfusion injury (IRI) that can compromise subsequent transplant function. IRI causes an inflammatory response activated via the Toll-like Receptor-4 (TLR4)1 . Since the proinflammatory cytokine activin A is stimulated via the TLR4 pathway in mouse models of sepsis 2 , we undertook studies to determine if activin A was a regulator of inflammation in IRI during lung transplantation. Activin A and its binding protein follistatin were measured by a specific ELISA and radioimmunoassay respectively, in serum samples collected from 48 patients undergoing lung transplantation just prior to the induction of anaesthesia, at about 2 hrs into the surgical procedure representing a time-point about 30 mins before lung reperfusion and also at 15 mins, 2hrs, 8hrs and 24 hrs after initiation of transplant reperfusion. 

Basal serum levels of activin A (236 +/- 36 pg/ml) were elevated above normal levels in men and women (~160pg/ml), probably related to the lung pathology requiring a transplant (eg cystic fibrosis, pulmonary hypertension).

Serum activin A levels increased between basal and peak levels in the 2hr samples (844+/-100 pg/ml), consistent with the acute phase response to surgery. The activin A levels remain elevated at the start of the reperfusion phase and decline to normal levels at 24 hrs. The substantial activin A increase associated with transplant surgery is a likely driver of inflammation that may cause primary graft dysfunction. While follistatin increases from basal 12.6 +/- 1.0ng/ml to 30.0 +/- 7.9 ng/ml in the 2hr sample, further elevation of follistatin levels during this period, through its capacity to bind and neutralise the bioactivity of activin A, may diminish the impact of IRI thereby improving graft function and organ survival. 

  1. 1Eltzschig HK & Eckle T. Ischemia and reperfusion- from mechanism to translation. Nat Med 2011;17:1391-1401.
  2. 2Jones KL et al. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci USA 2007;104:16239-16244.