Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia.
Abstract: The euglycemic hyperinsulinemic clamp model (EHC) of equine endocrinopathic laminitis induces rapid loss of lamellar tissue integrity, disrupts keratinocyte functions, and induces inflammation similar to natural disease. Continuous digital hypothermia (CDH) blocks tissue damage in this experimental model, allowing identification of specific genes or molecular pathways contributing to disease initiation or early progression. Archived lamellar tissues (8 horses, 48 h EHC treatment, including CDH-treated front limbs) were used to measure relative expression levels of genes encoding keratin 17 (KRT17), a stress-induced intermediate filament protein, and genes upregulated downstream of keratin 17 and/or interleukin 17A (IL-17A), as mediators of inflammation. Compared to front or hind limbs at ambient temperature, CDH resulted in significantly lower expression of KRT17, CCL2, CxCL8, PTGS2 (encoding COX2), IL6, TNFα, S100A8 and MMP1. By immunofluorescence, COX2 was robustly expressed in lamellar keratinocytes from ambient limbs, but not in CDH-treated limbs. Genes not significantly reduced by CDH were IL17A, DEFB4B, S100A9 and MMP9. Overall, 8 of 12 genes were expressed at lower levels in the CDH-treated limb. These 8 genes are expressed by wounded or stress-activated keratinocytes in human disease or mouse models, highlighting the role of keratinocytes in equine laminitis.
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
Publication Date: 2021-09-21 PubMed ID: 34562796DOI: 10.1016/j.vetimm.2021.110326Google Scholar: Lookup
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Summary
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The research article investigates the effects of Continuous Digital Hypothermia (CDH) on the expression of inflammatory pathway mediators in horses suffering from laminitis, a painful and life-threatening hoof condition. It shows that CDH lowers the expression of certain proteins and genes, potentially reducing inflammation and damage associated with laminitis.
Understanding the Research Topic & Objective
- The main purpose of this research was to understand the effect of Continuous Digital Hypothermia (CDH), a therapeutic cooling treatment, on the expression of specific genes linked with inflammation in equine laminitis, a painful and debilitating disease affecting horse hooves.
- This study utilized an euglycemic hyperinsulinemic clamp model (EHC), which is a widely used model to induce laminitis experimentally. The EHC model effectively replicates several disease symptoms including the rapid loss of lamellar tissue integrity, disruption of keratinocyte functions, and induction of inflammation.
- The researchers aimed to identify how CDH impacts this process, focusing specifically on two key mediators: keratin 17 (KRT17), a protein expressed under stress conditions, and several genes that are regulated by KRT17 and/or interleukin 17A (IL-17A), another key player in inflammation response.
Methodology and Findings
- The researchers used archival lamellar tissues from 8 horses, all of which had undergone 48 hours of EHC treatment. In some instances, the horses’ front limbs were also treated with CDH.
- They discovered that, compared to the limbs kept at ambient temperature, those treated with CDH showed significantly lower expression of KRT17, COX2, and certain other genes (CCL2, CxCL8, PTGS2, IL6, TNFα, S100A8, and MMP1) that play roles in inflammation response.
- CDH treatment did not reduce the expression of four specific genes: IL17A, DEFB4B, S100A9, and MMP9.
- Overall, 8 of the 12 genes examined were expressed at lower levels in the CDH-treated limbs. Notably, these 8 genes are typically expressed by wounded or stress-activated keratinocytes in human diseases or mouse models, suggesting a similar role of keratinocytes in equine laminitis.
Significance of the Study
- This study shows promising results that CDH treatment can reduce the expression of certain genes involved in inflammation and stress response in equine laminitis, potentially reducing tissue damage and inflammation associated with the disease.
- These findings shed light on the molecular processes underlying equine laminitis, and may pave the way for further research to develop more effective treatments for this condition in horses.
Cite This Article
APA
Cassimeris L, Armstrong C, Burger QC, Stokes S, van Eps A, Galantino-Homer H.
(2021).
Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia.
Vet Immunol Immunopathol, 241, 110326.
https://doi.org/10.1016/j.vetimm.2021.110326 Publication
Researcher Affiliations
- 111 Research Dr., Department of Biological Sciences, Lehigh University, Bethlehem, PA, 18015, USA. Electronic address: lc07@lehigh.edu.
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA.
- 111 Research Dr., Department of Biological Sciences, Lehigh University, Bethlehem, PA, 18015, USA.
- Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA.
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA.
MeSH Terms
- Animals
- Horse Diseases / therapy
- Horses
- Hyperinsulinism / complications
- Hyperinsulinism / veterinary
- Hypothermia / veterinary
- Inflammation Mediators / metabolism
- Keratin-17 / metabolism
- Lameness, Animal / etiology
- Lameness, Animal / therapy
Citations
This article has been cited 5 times.- Underberg BA, Van der Vekens E, Drews B, Kaessmeyer S. Cyclooxygenase-2 and von Willebrand factor-an immunohistochemical study of the equine foot with and without laminitis, post-mortem perfused with paraffin oil. Front Vet Sci 2025;12:1673415.
- Zamith Cunha R, Gobbo F, Morini M, Zannoni A, Mainardi C, D'arpe L, Gramenzi A, Chiocchetti R. Distribution of endocannabinoid system receptors in the equine hoof: dysregulation as a potential therapeutic target for laminitis. Histochem Cell Biol 2025 Jul 1;163(1):71.
- Tuniyazi M, Tang R, Hu X, Zhang N, Shen P. Efficacy of Carbonate Buffer Mixture in Preventing Hoof Lamella Injury Associated with Subacute Ruminal Acidosis in Dairy Goats. Vet Sci 2024 Aug 27;11(9).
- Burns TA, Watts MR, Belknap JK, van Eps AW. Digital lamellar inflammatory signaling in an experimental model of equine preferential weight bearing. J Vet Intern Med 2023 Mar;37(2):681-688.
- Sundberg JP, Galantino-Homer H, Fairfield H, Ward-Bailey PF, Harris BS, Berry M, Pratt CH, Gott NE, Bechtold LS, Kaplan PR, Durbin-Johnson BP, Rocke DM, Rice RH. Witch Nails (Krt90whnl): A spontaneous mouse mutation affecting nail growth and development. PLoS One 2022;17(11):e0277284.
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