Equine laminitis, new insights into the pathogenesis: A review
Laminitis, a widespread sporadic pododermatitis, is typical of Ungulates but it is especially significant in horses. The most prevalent owner‐reported clinical signs (≥70%) are difficulty turning and a short/stilted or lame walk. Affected horses may have recurrent episodes and sometimes have to be euthanized due to permanent hoof damage. Very severe, highly acute laminitis cause the third phalanx to detach from the hoof wall and to drop ventrally inside the hoof. Ventral deviation, in a flexor direction, of the third phalanx, is favoured both by the destruction of the dermal-epidermal junction, as well as by a hyperplasia of the epidermal laminae that produce a horny growth (keraphylocele) acting as a wedge.
Four main risk factors correspond to four types of laminitis: 1) diseases involving sepsis or endotoxaemia [sepsis‐/SIRS (systemic inflammatory response syndrome)‐related laminitis]; 2) protracted trauma (load-bearing laminitis, supporting limb laminitis): 3) metabolic diseases from endocrine origin (endocrinopatic laminitis); 4) lush pastures (pasture-associated laminitis) especially in foals. Cases of type 1 correlate with sepsis from Gram-negative polymicrobial bacteria, and include postpartum metritis with retained placenta, colic (proximal enteritis, volvulus) and enterocolitis. The systemic inflammatory events that occur in type 1 laminitis coincide with marked increase in lamellar expression of a variety of inflammatory mediators and with activation of extracellular matrix metalloproteinases (MMPs). In the type 2 laminitis, mainly linked to bearing excessive weight on a limb for long periods, experimental results have suggested that severe lamellar hypoxia may occur.
Endocrinopatic laminitis (type 3), the most common form encountered in equine veterinary practice, may occurr secondary to metabolic diseases (equine metabolic syndrome, Cushing's disease), usually in obese horses and foals, and is exacerbated in animals that graze lush pastures (type 4 laminitis). The unifying pathogenic factor in types 3 and 4 laminitis, is hyperinsulinemia with insulin toxicity. The main failure in these cases is the disruption of the structural integrity of the dermo-epidermal bond of the lamellae, i.e. loss of the adherence of the basal epithelial cells in the epidermal lamellae to the underlying dermal lamellae through the separation of the dermo-epidermal attachment at the basement membrane (BM) level. The distinction between primary or secondary BM pathology may be very difficult to make. However in the current view the early and key cytomorphological pathology points to lamellar cell stretching, suggesting cytoskeletal deformation with weakening and elongation of the lamellar epithelial cells, which translate into alteration of their tensegrity. These events may well induce some secondary alteration in the structure and/or elasticity of the BM, with cytoskeletal disengagement and loss of the hemidesmosomes and thus a further relaxation of the lamellae followed by loss of adhesion of the layer of basal epithelial lamellar cells with the underlying BM. EGFR (Epithelial grow factor receptor) was found as unlikely pathogenic factor in insulin-associated early laminitis pathophysiology, but it might play a role in epidermal hyperplasia-repair. The lamellae are sparsely populated with insulin receptors (insR), whereas IGF-1 receptors (IGF-1R) are abundant. However research findings suggest that insulin is unlikely to directly bind and to activate equine IGF-1R in vivo, even at high physiological concentrations. An indirect mechanism through which insulin could activate IGF-1R should be envisaged in the displacing IGF-1 from IGF-binding proteins (IGFBPs) such as IGFBP7 or fragments of IGFBP3, thereby increasing free IGF-1 concentrations, or in a direct action on a very small population of lamellar InsR. However that may be, whether there is a direct hormonal influence on cellular cytoskeletal mechanics of the potentially crucial lamellar cell stretching will likely necessitate new experimentation.