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Update on current research in laminitis
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Summary
Laminitis should be defined as pathological disintegration of the suspensory apparatus of the distal phalanx (SADP). If distal phalanx is not properly attached to the inside of the hoof, the weight of the horse and the forces of locomotion drive the bone down into the hoof capsule causing unrelenting pain in the feet and a characteristic lameness. The lamellar epidermal basal cell (LEBC) is the primary target of SADP disintegration and is the weak link in the hierarchy of tissues constituting the SADP. LEBCs may dis-attach from their underlying basement membrane or they may weaken and stretch leading to lamellar thinning and lengthening. The outcome is the DP pathologically descends towards the solar dermis. Dysregulation of the LBEC cytoskeleton and its associated cell adhesion complexes including cytolink protein depletion, attachment plaque degradation and cytoskeletal collapse explain this sudden LBEC stretching and SEL lengthening. Significant decreases in cytolink protein and gene expression and associated LBEC cytoskeletal disorganisation are reported in both HI- and CHO-induced laminitis. Since the LBEC, the cornerstone of the suspensory apparatus of the distal phalanx, is constantly loaded, it is now understandable why LBEC dysregulation leads to downwards dislocation of the distal phalanx and its attendant signs of clinical laminitis. The attack by laminitis on the LBEC that damages the lamellar cytoskeleton and cell adhesion complexes resembles changes occurring in skin cancer development. Anticancer drugs, currently in development, may be effective in preserving LEBC cell adhesion complexes and in turn the lamellae and the integrity of the SADP.
Introduction
Three main forms of laminitis are now recognised: sepsis-associated, endocrinopathic and supporting limb laminitis. Pathological disintegration of the suspensory apparatus of the distal phalanx (SADP) is the hallmark event of all laminitis pathology. Without the distal phalanx properly attached to the inside of the hoof, the weight of the horse and the forces of locomotion drive the bone down into the hoof capsule – sometimes slightly (with mild clinical signs) sometimes grossly (with severe clinical signs). There is unrelenting pain in the feet and a characteristic lameness.
Developmental phase
Laminitis has a developmental phase during which lamellar disintegration is triggered. This precedes foot pain onset (the acute phase). Interestingly despite long held historical views to the contrary perturbations in lamellar blood flow (ischaemia) play no role in the development of sepsis or HI related laminitis (supporting limb laminitis is a different matter). Using microdialysis probes inserted directly into the lamellar milieu our recent studies show increased lamellar perfusion (hyperaemia) during the development phase [1]. Thus there is no rationale for the use of vasodilator drug therapy during the development phase of laminitis. Changes in the lamellar epidermal basal cell (LEBC), observed in lamellar tissues from experimental and clinical cases of laminitis, show that the LEBC is the primary target of SADP disintegration. The LEBC, robust and trouble-free in the healthy horse, may be the weak link in the hierarchy of tissues constituting the SADP, an intact “chain” counteracting substantial physical forces that will fail should one “link” give way.
Lamellar epidermal basal cell pathology
SADP disintegration begins surprisingly early in the developmental phase of laminitis. Initially LEBCs may dis-attach from their underlying basement membrane. This well documented mechanism [2] is clearly seen in experimental models (e.g. alimentary carbohydrate overload) and in clinical cases of sepsis-related laminitis. The second way that LEBC impairment can lead to DP descent is weakening and stretching of LEBCs and secondary epidermal lamellae [3-5].This leads to SEL thinning and lengthening without wholesale dis-attachment from the BM but with the same net result – the DP pathologically descends towards the solar dermis. Profound loss of cell/cell and cell/basement membrane attachments destabilises the SADP’s ability to counteract the distracting forces of the horse’s weight and allows the DP to descend into the hoof capsule. Dysregulation of the LBEC cytoskeleton and its associated cell adhesion complexes including cytolink protein depletion, attachment plaque degradation and cytoskeletal collapse likely explain this sudden LBEC stretching and SEL lengthening. Significant decreases in cytolink protein and gene expression and associated LBEC cytoskeletal disorganisation have recently been reported in both HI- and CHO-induced laminitis [6; 7]. The LBEC is profoundly changed as laminitis-related pathology casts its shadow over the lamellar interface. Experimental models of equine laminitis and studies in other species have confirmed that aberrant cell signalling results in cell junction disassembly, loss of cell–cell and cell-matrix contacts and disruption in overall cell integrity. Ultimately, all this is due to disorganization of the physical inner framework of the cell, the cytoskeleton. Since the LBEC, the cornerstone of the suspensory apparatus of the distal phalanx, is constantly loaded, it is now understandable why LBEC dysregulation leads to downwards dislocation of the distal phalanx and its attendant signs of clinical laminitis [8].
Conclusion
Two seemingly disparate causes of laminitis (sepsis and hyperinsulinaemia) not only show similar histologic changes (e.g. stretching of the secondary epidermal lamellae), but also growth factor signalling associated with disruption of cell adhesion properties in other species [9]. The attack by laminitis on the LBEC that leads to loss of the protein components of the SEL cytoskeleton and cell adhesion complexes resembles changes occurring in skin cancer development. Anticancer drugs, currently in development, may be effective in preserving LEBC cell adhesion complexes and in turn SELs and the integrity of the SADP.
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- Get unlimited access to books, proceedings and journals.
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[1] Medina-Torres, C.E., Underwood, C., et al. (2016) Microdialysis measurements of lamellar perfusion and energy metabolism during the development of laminitis in the oligofructose model. Equine Vet. J. 48, 246-252.
[2] Pollitt, C.C. (1996) Basement membrane pathology: a feature of acute equine laminitis. Equine Vet J. 28, 38-46.
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