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Title: The amelioration of transplantation associated ischaemia reperfusion injury by the novel heme oxygenase-1 inducer heme arginate
Author: Beesley, Matthew Frederick
ISNI:       0000 0004 6425 3699
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2014
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A kidney transplant is the optimum treatment for patients with renal failure, both prolonging life and improving its quality (Parfrey, 2000. Wolfe, 1999). Transplanting an organ subjects it to Ischaemia reperfusion injury (IRI) as the vascular supply is temporarily disrupted and then reinstated. IRI is a risk factor for delayed graft function (DGF) (Bronzatto, 2009), which prejudices both short and long-term graft survival (Ojo, 1997). The severity of IRI has also been linked with early changes within the renal microvasculature that correlate with subsequent impaired organ function and DGF following transplantation (Schmitz, 2008). At the current time there are no specific treatments for IRI. Heme oxygenase-1 (HO-1) is a 32kDa enzyme that catalyses the breakdown of Heme molecules to Biliverdin, Carbon monoxide and free Iron. Studies suggest that induction of HO-1 prior to surgery may be beneficial by reducing the severity of injury in animal models of IRI and transplantation (Amersi, 1999. Tullius 2002). The majority of such studies utilise heavy metal protoporphyrins as HO-1 inducing agents. These substances are highly toxic, preventing their use in clinical practice. Heme arginate (HA) is a clinically licensed drug used in humans for the treatment of porphyria. It is well tolerated, with a minimal side effect profile (Mustajoki, 2003). It has also been shown that HA can induce HO-1 in healthy human volunteers (Doberer, 2010). The principal aims of this thesis are to determine whether the administration of HA can confer protection within in vitro and in vivo models of IRI and renal isograft transplantation. I assess the structural integrity of the microvasculature and evaluate changes in the inflammatory cell populations following transplantation and IRI to determine whether these correlate with the degree of renal tubular injury observed. Initial In vitro experiments demonstrate the potential for HA to induce HO-1 in a murine cardiac endothelial cell line (MCEC-1). I subsequently develop and characterise an in vitro model that simulates the changes in gaseous tensions encountered during IRI in vivo, and show that MCEC-1 cells that are pre-treated with HA are significantly protected against exposure to these adverse conditions (n=3, p < 0.05). In subsequent in vivo experiments, HA administration was shown to up-regulate functional HO-1 within murine renal tissue. Mice that were pre-treated with HA 24 hours prior to surgery showed significant preservation of renal tubules and renal function (creatinine) in a murine model of renal IRI (n=8, p < 0.05). In a series of murine renal isograft transplants, HA pre-treatment of organ donors resulted in significant protection of renal tubules against IRI (n=10, p < 0.05). An apparent, but statistically insignificant, trend toward protection of renal tubules was also observed in organ recipients that were pre-treated with HA (n=10, p=0.21). Further experiments are necessary to clarify the underlying mechanisms responsible for the apparent protective effects of HA against tubular injury in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available