Doctoral Dissertations

Date of Award

12-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Nicholas Frank

Committee Members

Stephen Kania, Robert Moore, Robert Donnell, Michael Karlstad

Abstract

Laminitis is a crippling disease of horses that can result in chronic lameness and debilitation, and sometimes warrants euthanasia. It is a complication of inflammatory conditions such as gastrointestinal disease, and also occurs in obese, insulin-resistant horses with Equine Metabolic Syndrome (EMS). Inflammation and insulin resistance are risk factors for laminitis, and these mechanisms might converge to induce laminitis in susceptible animals.

Systemic inflammation is often attributed to endotoxemia, although circulating endotoxin concentrations are not commonly measured in the clinical setting. Although a theoretic basis exists for endotoxemia in the pathogenesis of laminitis, administration of endotoxin alone does not induce the condition. This could be related to differences between experimental models and naturally occurring disease.

Studies presented in this dissertation address the overall hypothesis that systemic inflammation causes laminitis and new experimental models can be developed to better represent clinical disease. Associations between systemic inflammation and laminitis were first established by measuring blood inflammatory cytokine expression during a laminitis induction model. A clinically relevant endotoxin model that induced laminitis was then sought, but endotoxin administration alone was insufficient to cause laminitis and endotoxin tolerance developed. Endotoxemia was therefore evaluated in conjunction with predisposing factors such as obesity. In horses with EMS, endotoxin infusion caused exaggerated inflammatory responses, and derangements in glucose homeostasis were more pronounced. Laminitis, however, did not develop. Repeated inflammatory events are implicated in the pathogenesis of sepsis-associated organ failure, so a final study was performed to test whether preexisting endotoxemia increased the risk of laminitis during subsequent carbohydrate overload-induced systemic inflammation. This did not occur, however systemic inflammation was more pronounced in horses that developed laminitis compared to non-responders, and tissues rather than circulating leukocytes appeared to be the major source of inflammatory mediators.

Our results do not support a role for endotoxin as the causal agent of laminitis, even when combined with predisposing factors. Tissues appear to be an important source of inflammatory mediators, therefore their role in laminitis should be further characterized. Additionally, future investigations should determine whether exaggerated inflammatory responses and loss of glycemic control increase the risk of laminitis in horses with EMS.

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