Equine laminitis. New insights into the pathogenesis. A review

Laminitis is typical of Ungulates but it is especially significant in horses. The most prevalent clinical signs (≥70%) are difficulty turning and a short/stilted or lame walk. Very severe, highly acute laminitis cause the third phalanx to detach from the hoof wall and to drop ventrally inside the hoof, 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) sepsis /SIRS (systemic inflammatory response syndrome) related laminitis; 2) endocrinopatic laminitis; 3) pasture-associated laminitis; 4) supporting limb laminitis, experimentally linked to hoof lamellar hypoxia. Type 1 correlates with sepsis from Gram-negative polymicrobial bacteria (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 digital lamellar expression of a variety of inflammatory mediators and with activation of extracellular matrix metalloproteinases (MMPs). The most common form of laminitis, endocrinopatic laminitis (type 2), may occurr secondary to metabolic diseases (equine metabolic syndrome, Cushing’s disease), usually in obese horses and ponies, and is exacerbated in animals that graze lush pastures (type 3 laminitis). The unifying pathogenic factor in types 2 and 3 laminitis, is hyperinsulinemia with insulin toxicity. The main failure in these cases is the 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 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. The lamellae are sparsely populated with insulin receptors (insR), whereas IGF-1 receptors (IGF-1R) are abundant. However 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.