Page 525 - Adams and Stashak's Lameness in Horses, 7th Edition

Lameness of the Distal Limb 491

epithelial cells interfacing with the lamellar dermis, and inserted into the lamellar tissue to assess lamellar events
parabasal epithelial cells on the interior of each second- in the oligofructose model, lamellar perfusion does not
VetBooks.ir similarly to skin epithelial cells, with basal epithelial cells similar dysfunction of mitochondrial respiration as
appear to change, whereas metabolite changes suggest a
ary epidermal lamella. These cells appear to function
reported in models of human sepsis. Due to histologic
attaching to the matrix fibers of the underlying basement
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membrane (continuous with the matrix fibers of the der- evidence of lamellar stretching and dysadhesion in the
mal lamellae) primarily via the same protein complexes oligofructose model of SRL, and electron microscopic
present in the basal epithelial layer in the skin: hemides- evidence of cytoskeletal and hemidesmosome disarray, 32,43
mosomes. The lamellar epithelial cells also have an intri- it is likely that dysregulation of both cytoskeletal dynam-
cate cytoskeleton, likely providing the same “stiffness” to ics and adhesion dynamics is playing a role in lamellar
the lamellar cells as is reported in epithelial cells in other failure in SRL. Although earlier reports proposed that
species. In lamellar failure in laminitis, it is likely that matrix breakdown by matrix metalloproteases (MMPs)
dysregulation of epithelial cytoskeletal dynamics leads to may play an important role in lamellar failure, 31,42,52,59
lamellar stretching of the epidermal lamellae, whereas the lack of presence of activated forms of MMPs of inter-
dysregulation of hemidesmosome complexes (attached est and the lack of efficacy of potent a protease inhibitor
48
to the intermediate filament aspect of the cytoskeleton) as a treatment for laminitis in the oligofructose model
appears to lead to dysadhesion of the lamellar basal epi- decrease the likelihood of proteases playing the central
thelial cells from the basement membrane and therefore event in lamellar failure (Underwood and Pollitt, unpub-
to separation of the epidermal and dermal lamellae. lished data). Finally, the same lamellar growth factor‐
related signaling (possibly through the proinflammatory
cytokine IL‐6) as discussed with endocrinopathic lami-
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nitis has been documented to occur in the carbohydrate
PATHOGENESIS: PATHOPHYSIOLOGIC models of SRL (Belknap laboratory, unpublished data)
CONSIDERATIONS and may play an important role in lamellar epithelial cell
dysregulation and lamellar failure.
The delineation of the three general types of laminitis In endocrinopathic laminitis, including both meta-
has allowed more focused investigations into systemic bolic syndrome and pituitary pars intermedia dysfunc-
and local lamellar events occurring in these different tion (PPID), both clinical and experimental studies
types of the disease. Additionally, the availability of indicate that hyperinsulinemia (commonly termed
state‐of‐the‐art research tools to assess lamellar events insulin dysregulation) is the primary factor inducing
has allowed rapid advancement of knowledge over the lamellar failure. In a study of horses diagnosed with
last decade. Finally, although we have had models of PPID, laminitis only occurred in those animals with
SRL for several decades, we have only recently devel- hyperinsulinemia. In equine metabolic syndrome
39
oped experimental models of endocrinopathic laminitis (EMS), the term “insulin resistance” has been taken
and SLL. from the human medical literature on metabolic syn-
Experimental models for SRL include both carbohy- drome in which obesity leads to a poorer systemic
drate overload models and the black walnut extract response to insulin, most likely due to inflammatory
model. These models were developed in order to closely mediators released from the excessive adipose tissue. In
emulate the clinical cases of laminitis caused by either EMS, this obesity‐related systemic inflammation has
consumption of excessive carbohydrate or of black wal- not been conclusively demonstrated; it appears that the
nut shavings (used for bedding). The first CHO overload main risk factor for laminitis may be a propensity
model established included the gastric administration of toward hyperinsulinemia upon ingestion of carbohy-
a mixture of corn starch and wood flour (commonly drate independent of actual insulin resistance. The role
termed the starch gruel model). 34,35 Today, this starch hyperinsulinemia plays in lamellar failure is well sup-
gruel model has largely been replaced by the oligofruc- ported by the most commonly used experimental
tose model in which a gastric bolus of oligofructose in model for endocrinopathic laminitis, the euglycemic
solution is administered. 21,22,53 Whereas the black walnut hyperinsulinemic clamp (EHC) model. In this model,
extract model was useful for examining early events in elevated blood insulin levels (in the presence of normal
the disease process, 7,47 the fact that most animals did blood glucose concentrations) lead to the same histo-
not progress to structural lamellar failure somewhat logic changes to the lamellae as observed in clinical
decreased the clinical relevance of (and interest in) the cases of endocrinopathic laminitis. 39,43 In regard to the
7
model. Using these models, a profound inflammatory cause of lamellar failure due to hyperinsulinemia, it has
response was detailed in the lamellar tissue (much greater recently been reported that the lamellar epithelial cells
than other tissues in the body). 7,46,47 Interestingly, similar in the EHC model of endocrinopathic laminitis undergo
inflammatory events were discovered as occur in organ the same growth factor‐related signaling shown to dis-
injury in human sepsis, including the extravasation of rupt normal cytoskeletal and adhesion dynamics in
leukocytes into the lamellar tissue 26,28,29 and the marked cancer biology when epithelial cells transform into
increased expression of inflammatory mediators/enzymes cancer cells (termed epithelial‐to‐mesenchymal transi-
in the lamellar tissue including cytokines, chemokine, 27,30 tion). In both clinical cases of endocrinopathic lami-
44
46
and cyclooxygenase (COX)‐2. 46,70 Although lamellar nitis and in the EHC model, the lamellae do not
ischemia due to decreased blood flow has been purported commonly undergo the dramatic dysadhesion/separa-
as the cause for lamellar failure in SRL, conflicting results tion of the lamellar basal epidermal cells from the
are present in the literature, primarily due to the lack of underlying dermal lamellae that commonly leads to
a technique to accurately assess lamellar perfusion. In rapid structural failure in SRL. Instead, lamellar
43
recent investigations in which a microdialysis probe is stretching plays a more prominent role, likely due to