Causes of lamellar attachment failure in different forms of laminitis
In each form of laminitis, a combination of epithelial cell adhesion loss and epithelial cell stretch weakens the lamellar attachment (Figure 1).
Endocrinopathic laminitis is dominated by cell stretch, whereas SRL and SLL are dominated by adhesion loss.
A question of vital importance to our understanding is whether this attachment failure occurs as a result of:
- Specific cellular signaling event that is common to all forms of laminitis
- Insult-specific alterations in epithelial cell homeostasis that lead to a common endpoint due to the unique and immense physical stresses on the lamellar epithelium
The van Eps laboratory is taking a multidisciplinary approach to examining structural, molecular and physiologic events during laminitis development to answer this fundamental question.
Is cellular energy failure a consistent feature?
The maintenance of lamellar epithelial adhesion and cytoskeletal dynamics required to withstand the immense mechanical stress within the equine hoof is an energy consuming process. Using our recently developed tissue microdialysis system capable of assessing lamellar perfusion and energy balance in vivo, we have demonstrated a relatively high rate of glucose consumption and lactate production within the lamellae.
As lamellar epithelial cells are highly dependent on glucose as an energy substrate and there is no means for local storage of glycogen in the lamellar tissue, lamellar epidermal glucose uptake must be matched by constant delivery via the blood to maintain function.
However, our microdialysis urea clearance data demonstrate that even the normal lamellar dermis is relatively poorly perfused compared with the adjacent sublamellar dermis or skin, making it inherently prone to energy imbalances secondary to perfusion or metabolic derangement.
The van Eps lab has therefore focused on determining whether this contributes to the development of different forms of laminitis.
Evidence for ischemia only in supporting-limb laminitis
While perfusion derangements have long been implicated in different forms of laminitis, direct evidence has been lacking. Imaging studies show an effect of limb loading on vascular contrast fill.
Using the lamellar tissue microdialysis technique described above, we have demonstrated a unique relationship between limb load cycling and lamellar perfusion. We have new data demonstrating the importance of load and load cycling on perfusion and also suggesting an important role for ischemia in SLL.
The Van Eps lab is now focusing on methods to prevent perfusion failure specifically in SLL.
About non-ischemic energy failure
Disturbances of energy metabolism despite adequate blood perfusion have been increasingly recognized in the pathophysiology of human sepsis-related organ failure and after traumatic brain injury. Although lamellar ischemia was not a feature of SRL (OF model), we have new evidence of non-ischemic oxidative energy failure later in laminitis development in this model, characterized by an increase in microdialysate L:P ratio (without decreased pyruvate or urea clearance), consistent with non-ischemic energy failure. Controlling this may help to prevent progression in SRL.
Preventing lamellar attachment failure using therapeutic hypothermia
The van Eps laboratory has demonstrated the protective effect of continuous digital hypothermia in several experimental studies of SRL and it has translated into an effective clinical preventative. In their early studies, they found hypothermia dramatically inhibited transcription of inflammatory mediators in lamellar tissue when applied prophylactically.
However, while protective effects were still observed when hypothermia was applied later in the SRL model, inhibition of inflammation was no longer observed.
Furthermore, while the Van Eps laboratory found that hypothermia protected against the non-ischemic energy dysregulation noted in the SRL model, it also has a remarkable protective effect in the hyperinsulinemic clamp model of endocrinopathic laminitis, where there is no evidence of energy dysregulation.
Thus, continued studies evaluating the specific effects of hypothermia are required to help unlock the important mechanistic pathways in SRL and endocrinopathic laminitis.
The Holy Grail- discovery of a common pathway leading to all types of laminitis
Together with collaborators at the Ohio State University, Dr. van Eps and coworkers are examining cellular pathways that appear to be common to all forms of laminitis which may result in therapeutic targets for pharmacologic intervention in laminitis.
Dr. van Eps’ research is supported by the Grayson Jockey Club Research Foundation.
Hopster, K & W. van Eps, A. (2018). Pain management for laminitis in the horse. Equine Veterinary Education. 10.1111/eve.12910. https://onlinelibrary.wiley.com/doi/full/10.1111/eve.12910
Dern, K., van Eps, A., Wittum, T., Watts, M., Pollitt, C. and Belknap, J. (2018) Effect of Continuous Digital Hypothermia on Lamellar Inflammatory Signaling When Applied at a Clinically-Relevant Timepoint in the Oligofructose Laminitis Model. J Vet Intern Med 32, 450-458.
Dern, K., Watts, M., Werle, B., van Eps, A., Pollitt, C. and Belknap, J. (2017) Effect of Delayed Digital Hypothermia on Lamellar Inflammatory Signaling in the Oligofructose Laminitis Model. J Vet Intern Med 31, 575-581.
Gardner, A.K., van Eps, A.W., Watts, M.R., Burns, T.A. and Belknap, J.K. (2017) A novel model to assess lamellar signaling relevant to preferential weight bearing in the horse. Vet J 221, 62-67.
Medina-Torres, C.E., Pollitt, C.C., Underwood, C., Castro-Olivera, E.M., Collins, S.N., Allavena, R.E., Richardson, D.W. and van Eps, A.W. (2014) Equine lamellar energy metabolism studied using tissue microdialysis. Vet J.
Medina-Torres, C.E., Underwood, C., Pollitt, C.C., Castro-Olivera, E.M., Hodson, M.P., Richardson, D.W. and van Eps, A.W. (2015) Microdialysis measurements of equine lamellar perfusion and energy metabolism in response to physical and pharmacological manipulations of blood flow. Equine Vet J.
Medina-Torres, C.E., Underwood, C., Pollitt, C.C., Castro-Olivera, E.M., Hodson, M.P., Richardson, D.W. and van Eps, A.W. (2016) The effect of weightbearing and limb load cycling on equine lamellar perfusion and energy metabolism measured using tissue microdialysis. Equine Vet J 48, 114-119.
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Underwood, C., Pollitt, C.C., Metselaar, J.M., Laverman, P., van Bloois, L., van den Hoven, J.M., Storm, G. and van Eps, A.W. (2015) Distribution of technetium-99m PEG-liposomes during oligofructose-induced laminitis development in horses. Vet J 206, 218-225.
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van Eps, A.W., Leise, B.S., Watts, M., Pollitt, C.C. and Belknap, J.K. (2012) Digital hypothermia inhibits early lamellar inflammatory signalling in the oligofructose laminitis model. Equine Vet J 44, 230-237.
van Eps, A.W. and Orsini, J.A. (2016) A comparison of seven methods for continuous therapeutic cooling of the equine digit. Equine Vet J 48, 120-124.
van Eps, A.W. and Pollitt, C.C. (2009) Equine laminitis model: Cryotherapy reduces the severity of lesions evaluated seven days after induction with oligofructose. Equine Vet J 41, 741-746.
van Eps, A.W., Pollitt, C.C., Underwood, C., Medina-Torres, C.E., Goodwin, W.A. and Belknap, J.K. (2013) Continuous digital hypothermia initiated after the onset of lameness prevents lamellar failure in the oligofructose laminitis model. Equine Vet J.