The effect of continuous digital hypothermia on lamellar energy metabolism and perfusion during laminitis development in two experimental models

Abstract

Background Continuous digital hypothermia (CDH) prevents lamellar failure in the euglycaemic hyperinsulinaemic clamp (EHC) and oligofructose (OF) laminitis models, but the mechanisms remain unclear. Objectives To evaluate the effects of CDH on lamellar energy metabolism and perfusion in healthy horses and during EHC and OF laminitis models. Study design In vivo experiment. Methods Archived samples were used from Standardbred geldings that received no treatment (CON) (n = 8) or underwent EHC (n = 8) or OF (n = 6) laminitis models. Both forelimbs were instrumented with a lamellar microdialysis system, and one forelimb was cooled (CDH) with the other maintained at ambient temperature (AMB). Microdialysate was collected every 6 hours and analysed for glucose, lactate and pyruvate concentrations and lactate to pyruvate ratio (L:P). Microdialysis urea clearance was used to estimate lamellar tissue perfusion. Data were analysed using a mixed‐effects linear regression model. Results Glucose did not change in CDH limbs relative to AMB in CON (P = .3), EHC (P = .3) or OF (P = .6) groups. There was a decrease in lactate (P < .001) and pyruvate (P < .01) in CDH limbs relative to AMB in all groups. L:P decreased in CON CDH relative to CON AMB (P < .001) but was not different in EHC (P = .6) and OF (P = .07) groups. Urea clearance decreased in CDH limbs relative to AMB in CON (P = .002) and EHC (P < .001), but not in OF (P = .4). Main limitations The EHC model may not mimic natural endocrinopathic laminitis. Conclusions CDH caused a marked decrease in lamellar glucose metabolism (CON, EHC and OF) and perfusion (CON and EHC) without affecting lamellar glucose concentration. Although cellular energy failure is not a primary pathophysiological event in EHC and OF laminitis models, CDH may act by limiting energy supply to pathologic cellular processes whilst preserving those critical to lamellar homoeostasis.

Lamellar perfusion and energy metabolism in a preferential weight bearing model

“…Recently, a novel, nonpainful model utilising a platform shoe insert was successfully used to induce preferential weight bearing (PWB) for 48 hours, causing lamellar signalling changes (increased expression of hypoxia-inducible factor-1 alpha) suggestive of ischaemia. 11 By combining this model with tissue microdialysis, a technique that can detect temporal changes in lamellar perfusion and metabolism, [12][13][14][15][16][17] the objective of the current study was to investigate the effects of PWB on lamellar perfusion and energy balance.…”

A review of cellular and molecular mechanisms in endocrinopathic, sepsis‐related and supporting limb equine laminitis

“…Such evidence was not found in sampling sub‐lamellar fluid. In a further study, where dialysis probes were placed in the lamellar tissue and microdialysis used to study lamellar metabolism during OF‐laminitis and EHC‐laminitis induction under ambient temperature and continuous digital hypothermia, some evidence of nonischaemic oxidative energy failure was identified between 24 and 36 h of induction as evidenced by a marked increase in the lactate to pyruvate ratio in both models 76 . The late occurrence of this change in the lamellar microdialysates suggests energy failure is unlikely to be a primary pathophysiological event in either EHC or OF model of laminitis but could be a complication of the primary pathology which is benefited by continuous digital hypothermia.…”

Studies on the pathogenesis of insulin-induced laminitis in horses

“…Lamellar mRNA concentrations of chemokines CXCL6 and CXCL8 were decreased in CDH limbs in the current study, which may have limited lamellar leukocyte infiltration. Indeed CDH has many other therapeutic effects on various cellular pathways that are not necessarily independent of inflammatory events; for example, it has been demonstrated that CDH reduces lamellar perfusion and lamellar energy metabolism both in normal horses and horses undergoing the EHC [271]. Importantly, it has been noted that signaling pathways responsible for nutrient sensing and metabolism, including AMPK and mTOR, intersect with inflammatory pathways and therefore may influence each other in the EHC model [36].…”