Elements of pathogenesis and pathophysiology in experimentally-induced and naturally acquired equine laminitis
Equine laminitis is a crippling disease affecting up to 1% of horses in USA. Treatments are typically unsuccessful, due to a lack of effective therapeutics, which reflects our lack of understanding of the pathophysiology of the disease. There are three prominent theories regarding the initial events leading to lamellar pathology: ischemia-reperfusion (I/R) injury, alterations in laminar metabolism and systemic inflammation. It is considered that matrix metalloproteinases (MMP) may contribute to tissue damage, irrespective of events governing the onset of laminitis. Two experimental models of laminitis were utilized, the black walnut extract (BWE) model, and the carbohydrate overload model (CHO). These model systems were used to examine the contributions of I/R, inflammation and MMPs to the development of laminitis. In the BWE model, we found no biochemical indicators of I/R injury, namely no conversion of xanthine dehydrogenase to xanthine oxidase. As early as 1.5 hours post-BWE administration, there was accumulation of proMMP-9, infiltration of neutrophils into the laminae and induction of genes encoding proinflammatory cytokines (e.g IL-1β, IL-8 and IL-6).
Concentrations of proMMP-9 increased over time through to Obel grade 1 lameness (OG1), while proMMP-2 and MMP-2 did not change relative to controls. In CHO-induced laminitis, levels of proMMP-2 and MMP-2 remained similar to controls through OG1, but there was a significant accumulation of MMP-2 at later stages of the disease. ProMMP-9 was detectable as early as OG1, and was highly elevated at Obel grade 3 lameness (OG3). MMP-9 and MMP-2 were elevated to varying degrees in naturally acquired laminitis depending on the phase of the disease examined, being highest in animals with aggravated chronic laminitis. Lamellar ProMMP-9 correlated positively with myeloid cells, the majority of which are neutrophils during the stages of laminitis investigated. Despite the increases in gelatinase levels, all of which were shown by SDS-PAGE and zymography, there was no overall increase in native gelatinase activity relative to controls, suggesting association of MMP with tissue inhibitors of MMP (TIMPs). These results suggest that inflammation may play a role in the development of pathology in laminitis but raise questions regarding the contributions of MMP-9 and MMp-2 to tissue damage.
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