Development of endometrial fibrosis in the mare: factors involved in tissue remodelling and collagen deposition

Abstract

Age-related degeneration of the equine endometrium is an established and important cause of fertility problems in thoroughbred mares, causing great loss to the industry. As a part of the age-related endometrial degeneration complex, an excessive deposition of collagen leading to endometrial fibrosis is particularly important due to the limitations it causes to uterine function. The consequences include reduced efficacy of uterine defence mechanisms and a decrease in the uterine capacity for foetal nutrition. Extensive research into the process of fibrosis in other organs has shown that this condition results from the malfunction of physiological tissue repair mechanisms. These mechanisms revolve around tissue fibroblasts that due to continuous stimulation secrete excessive amounts of collagen and inhibit the activation of factors essential to the normal collagen degradation occurring in scar resolution. Among these factors are the MMPs, an enzyme family with the ability to degrade extracellular matrix components such as collagen during the normal repair mechanisms following tissue injury. The malfunction in the regulation of these enzymes is important in the development of fibrosis in the liver and other organs. In this study it was demonstrated that MMPs are involved in the acute uterine inflammatory response and that they were secreted by infiltrating inflammatory cells. The cellular mechanisms observed during endometritis in normal mares were comparable to the normal repair mechanisms known to be altered in the fibrosis of other organs. These enzymes were present in equine foetal fluids, and their regulation may be important in the process of abortion and stillbirth. It was demonstrated that inbreeding may be correlated with increased deposition of endometrial collagen in a study population of the Icelandic horse breed even though this breed appears to exhibit less severe endometrial degeneration than what is known in lighter breeds. It is likely that genetic predisposition leads to the disruption of normally self-limiting inflammatory and repair mechanisms in the endometrium, resulting in constant activation of collagen synthesis by local and infiltrating cells. This thesis has shown that tissue repair mechanisms involving MMPs are likely to be involved in endometrial fibrosis in the mare. An inherent alteration in these mechanisms may play a role in the pathogenesis of this condition, and might arise due to genetic predisposition. Further understanding of the pathways leading to excess collagen amounts in the endometrium may produce preventative measures, and even therapeutic targets.