Anatomy and Neuroscience - Theses
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ItemMorphological and functional consequences of ischemia/reperfusion injury in the enteric nervous system( 2011)Of all organs, the intestine is possibly the most susceptible to the damaging effects of ischemia and reperfusion (I/R) injury. I/R injury to the intestine occurs following shock, sepsis, vascular surgery, strangulation ileus, embolism, intestinal obstruction, necrotising enterocolitis and small intestine transplantation. I/R injury that occurs during intestinal transplantation is particularly relevant because small intestinal transplantation is being increasingly applied; it has become a treatment of choice for patients with short bowel syndrome who are on total parenteral nutrition and who have developed life-threatening complications. Studies of the consequences and mechanisms of I/R in the intestine have concentrated on damage to the epithelium and the breakdown of the mucosal barrier. However, I/R also affects enteric neurons, changing their properties and even causing their death. At the time I began my project, almost all studies of effects of I/R on enteric neurons have used only morphological methods, or markers of apoptosis, to document changes. My work has identified a selectivity of effects on nitric oxide synthase (NOS) neurons and on intrinsic primary afferent neurons (IPANs) following I/R. Following I/R, NOS neurons became swollen, and their dendrites were distorted, while IPANs shrank and showed signs of distortion of the surface membrane. In addition to the changes in cell morphology, my work has also developed further measures of effects of I/R on enteric neurons, including detection of neuronal apoptosis, the nitrosylation of proteins in enteric neurons and smooth muscle cells, and the translocation to the nucleus of the mRNA-binding protein, Hu. I have also made the first studies of the physiological consequences of intestinal I/R properties in enteric neurons by recording from enteric neurons with intracellular microelectrodes. Furthermore, I have shown that nNOS plays a protective role following intestinal I/R injury since the deletion of nNOS resulted in markedly more I/R-induced damage. Finally, this study showed that damage to the mucosa and muscle recovers quickly after I/R, but that changes in neurons persist. This suggests that neuronal damage may be involved in long-term functional changes after intestinal I/R. During my project, I had the opportunity to study the involvement of enteric neurons in intestinal dysfunction following I/R injury. By investigating the specificity of effects on different classes of neurons and the ways in which properties of the neurons are altered, strategies for coping with deleterious effects of the neuronal changes can possibly be identified. My work provides quantitative methods to assess neuronal responses to I/R injury, and thus a basis for assessing the effectiveness of protective strategies.