A review of cellular and molecular mechanisms in endocrinopathic, sepsis‐related and supporting limb equine laminitis

Abstract

Equine laminitis has both fascinated and frustrated veterinary researchers and clinicians for many years. The recognition that many ponies suffering from pasture‐associated laminitis have an insulin‐dysregulated phenotype (endocrinopathic laminitis, EL) and that prolonged insulin and glucose infusions can experimentally induce laminar pathology and functional failure are seminal discoveries in this field. Researchers have studied the molecular basis for disease pathogenesis in models of EL, sepsis‐related laminitis and supporting limb laminitis and generated much data over the last 15 years. This review attempts to synthesise those data, drawing comparisons between models and naturally occurring laminitis. A hypothesis is proposed that the basal epithelial cell stress is a central event in each category of laminitis. Furthermore, in naturally occurring pasture‐associated laminitis, pathways that predominate in each type of laminitis contribute to laminar lamellar pathology to varying extents. Based on the molecular mechanisms determined in experimental models, interactions between these pathways are identified.

Consequences of adiponectin deficiency: Can they be related to the pathophysiology of laminitis?

“…Whilst hypoxia is a potential stressor on the metabolically active lamellar EBCs, most of the work using experimental models of SRL and EL has failed to demonstrate reduced perfusion or metabolic stress typical of hypoxia (increased lactate to pyruvate ratio, e.g. ; see Table 5 in Reference [1]).…”

“…In vivo , apoptosis of kidney epithelial cells was higher in the knockout mice compared with wild type both under normal conditions and following induction of ischaemic injury in these mice. Apoptosis in the basal lamellar epithelial cells has been shown to occur in both naturally occurring laminitis (see Table 1 in Reference[1]) and in the developmental phase of EL and SRL models of laminitis (see Tables 1 and 2 in Reference [1]). 14 Hypoadiponectinaemia associated with increased laminitis risk could contribute to this increased susceptibility of lamellar epithelial basal cells (EBCs) to apoptosis.…”

“…In the comprehensive review of laminitis molecular pathology (naturally occurring and experimental models) published in this issue, 1 the frequent finding of hypoadiponectinaemia as a neglected, potentially modifiable predisposing factor in naturally occurring laminitis was highlighted. There is much evidence from other species that adiponectin deficiency (relative or absolute) is an important factor predisposing to some of the complications of type‐2 diabetes.…”

“…In addition to the strong evidence that low adiponectin levels is a consistent risk factor associated with laminitis development and occurs concomitantly with the insulin dysregulation (ID) phenotype (see Elliott and Bailey 2023 1 ), evidence from euglycaemic hyperinsulinaemic clamp (EHC) and sepsis‐related laminitis (SRL) models of laminitis suggests signalling factors on the mTOR1C pathway, such as ribosomal S6 protein (RS6P) and AKt, are highly upregulated in the developmental phases (see Supplementary Table 2 in Reference [1]). In pasture‐associated laminitis where ID and hypoadiponectinaemia are clear risk factors, the degree of activation of the mTORC1 pathway could be exacerbated as a result of a chronic imbalance of the counter‐regulatory AMP‐kinase pathway, activation of which is reduced with the relative deficiency of adiponectin.…”

“…In pasture‐associated laminitis where ID and hypoadiponectinaemia are clear risk factors, the degree of activation of the mTORC1 pathway could be exacerbated as a result of a chronic imbalance of the counter‐regulatory AMP‐kinase pathway, activation of which is reduced with the relative deficiency of adiponectin. Activation of the mTORC1 pathway in pasture‐associated laminitis is likely contributed by both insulin activation of insulin‐like growth factor‐1 (IGF‐1) receptors and growth factor pathway activation resulting from platelet stimulation by lipopolysaccharide released from the gut as a result of carbohydrate overload (see Figure 4 in Reference[1]). The only model in which AMP‐kinase activation has been studied is the dietary challenge model of endocrinopathic laminitis (EL) where phosphorylated AMP‐kinase was reduced in the lamellae of lean ponies fed a high carbohydrate diet for 7 days 6 .…”