Stefanutti, G.; (2011) Novel experimental therapies for intestinal ischaemia and reperfusion injury. Doctoral thesis , UCL (University College London).

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Abstract

Intestinal ischaemia and reperfusion (I/R) contributes to the pathogenesis of numerous clinical conditions in all age groups. Many of these diseases, including neonatal necrotizing enterocolitis (NEC), result in significant morbidity and mortality through multiple organ dysfunction, and available treatment is currently limited to supporting vital functions. My aims were: to investigate novel therapeutic strategies such as moderate hypothermia and peroxynitrite decomposition catalyst FeTMPyP [5,10,15,20- tetrakis(N-methyl-4'-pyridyl)porphyrinato iron (III)] in experimental models of adult and infant intestinal I/R; and to characterise the inflammatory process in human NEC, evaluating its relationship with clinical outcome. In an adult rat model, total-body moderate hypothermia applied throughout ischaemia and reperfusion counteracts oxidative stress in both the intestine and distant organs. This suggests that hypothermia could be beneficial as a preventative measure when intestinal ischaemia can be foreseen. However, in clinical practice therapy can usually be commenced only after ischaemia has occurred. In two sets of experiments, I showed that rescue hypothermia applied after mesenteric ischaemia improves outcome in both adult and neonatal rats, and this benefit is maintained after rewarming. Hypothermic protection could result from prevention of multiple organ dysfunction through several different pathways, including modulation of hepatic phosphoenergetics, pulmonary inflammatory infiltrate, cardiac energy metabolism, and systemic oxidative stress. Administration of peroxynitrite decomposition catalyst FeTMPyP as a rescue therapy at reperfusion also exerts a protective effect in neonatal rats, possibly via inhibition of adhesion molecule expression, leukocyte recruitment, and lipid peroxidation in the intestine, leading to prevention of systemic oxidative stress. In a study conducted on human specimens from neonates with NEC, tissue injury seems to be mediated via increased expression of endothelial adhesion molecules ICAM-1 and P-Selectin, leading to macrophage and neutrophil infiltration. Endothelial E-Selectin is expressed exclusively in NEC patients, and appears to be a marker of rapidly evolving disease and distant organ failure.

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