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Journal of veterinary internal medicine2017; 32(1); 450-458; doi: 10.1111/jvim.15027

Effect of Continuous Digital Hypothermia on Lamellar Inflammatory Signaling When Applied at a Clinically-Relevant Timepoint in the Oligofructose Laminitis Model.

Abstract: Although continuous digital hypothermia (CDH) protects lamellae from injury in the oligofructose (OF) model of sepsis-related laminitis (SRL), conflicting results exist from these studies regarding effects of CDH on lamellar inflammatory events. Objective: To determine the effect of CDH on lamellar inflammatory events in normal and OF-treated horses when instituted at a clinically relevant time point (onset of clinical signs of sepsis in this model). Methods: Standardbred geldings (n = 15) aged 3-11 years were used. Methods: In a randomized, controlled discovery study, animals were administered either OF (OF group, n = 8) or water (CON group, n = 8) by nasogastric tube and CDH was initiated in one forelimb (ICE) 12 hours later. Lamellar tissue samples were collected 24 hours after initiation of CDH (ICE and ambient [AMB] forelimbs). Lamellar mRNA concentrations of inflammatory mediators and lamellar leukocyte numbers were assessed using qPCR and immunohistochemistry, respectively; values from four sample groups (CON AMB, OF AMB, CON ICE, and OF ICE) were analyzed using mixed model linear regression. Results: Although lamellar mRNA concentrations of multiple inflammatory mediators (IL-1β, IL-6, CXCL1, MCP2, COX-2) were increased after OF administration (OF AMB group versus CON AMB; P < 0.05), only 2 inflammatory mediators (IL-6 and COX-2) and lamellar leukocyte numbers were decreased with CDH (OF ICE versus OF AMB; P < 0.05). Conclusions: Continuous digital hypothermia initiated at a time point similar to that commonly used clinically (clinical onset of sepsis) resulted in a more focused inhibition of inflammatory signaling.
Publication Date: 2017-12-27 PubMed ID: 29282770PubMed Central: PMC5787192DOI: 10.1111/jvim.15027Google Scholar: Lookup
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  • Journal Article
  • Randomized Controlled Trial

Summary

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The research focuses on the effect of continuous digital hypothermia (CDH) on inflammatory signals within the hoof structure of horses during the onset of sepsis-related laminitis, a common horse disease. The study found that the application of CDH at clinically relevant times reduced select inflammation markers and leukocyte numbers.

Methods

  • 15 Standardbred geldings aged 3-11 years were used in the study, which was randomized and controlled.
  • The horses were administered oligofructose (OF) to induce sepsis-related laminitis or water as a control via a nasogastric tube.
  • 12 hours later, CDH was applied to one forelimb, labelling it as the “ICE” group. The other forelimb, exposed to ambient conditions, was the “AMB” group.
  • 24 hours after the initiation of CDH, samples of lamellar tissue (the sensitive tissue inside the hoof) were collected from both the ICE and AMB groups.
  • The samples were assessed for mRNA concentrations of inflammatory mediators and lamellar leukocyte numbers using a technique known as quantitative polymerase chain reaction (qPCR) and immunohistochemistry, respectively.

Results

  • The lamellar mRNA concentrations of several inflammatory mediators were found to be increased in the OF AMB group, indicating the successful induction of inflammation typically seen in sepsis-related laminitis.
  • However, applying CDH (in the OF ICE group) resulted in reduced levels of two specific inflammatory mediators, IL-6 and COX-2, as well as a decrease in lamellar leukocyte numbers, demonstrating the anti-inflammatory effects of CDH.

Conclusions

  • The study concluded that the application of CDH at a clinically relevant time (onset of clinical signs of sepsis) resulted in a more focused inhibition of inflammatory signaling.
  • This research supports the use of CDH as a strategy to control inflammation in the laminitis model, but also suggests that its effects are somewhat specific, as not all inflammatory markers showed significant reduction.

Cite This Article

APA
Dern K, van Eps A, Wittum T, Watts M, Pollitt C, Belknap J. (2017). 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(1), 450-458. https://doi.org/10.1111/jvim.15027

Publication

ISSN: 1939-1676
NlmUniqueID: 8708660
Country: United States
Language: English
Volume: 32
Issue: 1
Pages: 450-458

Researcher Affiliations

Dern, K
  • Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA.
van Eps, A
  • Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Qld, Australia.
Wittum, T
  • Department of Veterinary Preventive Medicine, Ohio State University, Columbus, OH, USA.
Watts, M
  • Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA.
Pollitt, C
  • Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Qld, Australia.
Belknap, J
  • Department of Veterinary Clinical Sciences, Ohio State University, Columbus, OH, USA.

MeSH Terms

  • Animals
  • Cytokines / metabolism
  • Foot Diseases / pathology
  • Foot Diseases / therapy
  • Foot Diseases / veterinary
  • Hoof and Claw / pathology
  • Horse Diseases / pathology
  • Horse Diseases / therapy
  • Horses
  • Hypothermia, Induced / veterinary
  • Inflammation / therapy
  • Inflammation / veterinary
  • Leukocytes / pathology
  • Male
  • Oligosaccharides / administration & dosage
  • Oligosaccharides / toxicity
  • RNA, Messenger
  • Signal Transduction

Conflict of Interest Statement

Authors declare no conflict of interest.

References

This article includes 56 references
  1. Eades SC. Sepsis‐related laminitis. In: Belknap JK, ed. Equine Laminitis. Ames, IA: Wiley Blackwell; 2017:191–195.
  2. Minnick PD, Brown CM, Braselton WE. The induction of equine laminitis with an aqueous extract of the heartwood of black walnut (Juglans nigra). Vet Hum Toxicol 1987;29:230–233.
    pubmed: 3604042
  3. Garner HE, Coffman JR, Hahn AW. Equine laminitis of alimentary origin: An experimental model. Am J Vet Res 1975;36:441–444.
    pubmed: 1124880
  4. van Eps AW, Pollitt CC. Equine laminitis induced with oligofructose. Equine Vet J 2006;38:203–208.
    pubmed: 16706272
  5. Leise BS, Watts MR, Roy S. Use of laser capture microdissection for the assessment of equine laminar basal epithelial cell signaling in the early stages of laminitis. Equine Vet J 2015;47:478–488.
    pmc: PMC4771185pubmed: 24750316
  6. Leise BS, Watts M, Tanhoff E. Laminar regulation of STAT1 and STAT3 in black walnut extract and carbohydrate overload induced models of laminitis. J Vet Intern Med 2012;26:996–1004.
    pubmed: 22805114
  7. Leise BS, Faleiros RR, Watts M. Laminar inflammatory gene expression in the carbohydrate overload model of equine laminitis. Equine Vet J 2011;43:54–61.
    pubmed: 21143634
  8. Faleiros RR, Leise BS, Watts M. Laminar chemokine mRNA concentrations in horses with carbohydrate overload‐induced laminitis. Vet Immunol Immunopathol 2011;144:45–51.
    pubmed: 21889804
  9. Faleiros RR, Johnson PJ, Nuovo GJ. Laminar leukocyte accumulation in horses with carbohydrate overload‐induced laminitis. J Vet Intern Med 2011;25:107–115.
    pubmed: 21143304
  10. Faleiros RR, Leise BB, Westerman T. In vivo and in vitro evidence of the involvement of CXCL1, a keratinocyte‐derived chemokine, in equine laminitis. J Vet Intern Med 2009;23:1086–1096.
    pubmed: 19572911
  11. Loftus JP, Black SJ, Pettigrew A. Early laminar events involving endothelial activation in horses with black walnut‐ induced laminitis. Am J Vet Res 2007;68:1205–1211.
    pubmed: 17975975
  12. Black SJ, Lunn DP, Yin C. Leukocyte emigration in the early stages of laminitis. Vet Immunol Immunopathol 2006;109:161–166.
    pubmed: 16169600
  13. Blikslager AT, Yin C, Cochran AM. Cyclooxygenase expression in the early stages of equine laminitis: A cytologic study. J Vet Intern Med 2006;20:1191–1196.
    pubmed: 17063715
  14. Riggs LM, Franck T, Moore JN. Neutrophil myeloperoxidase measurements in plasma, laminar tissue, and skin of horses given black walnut extract. Am J Vet Res 2007;68:81–86.
    pubmed: 17199423
  15. Faleiros RR, Nuovo GJ, Flechtner AD. Presence of mononuclear cells in normal and affected laminae from the black walnut extract model of laminitis. Equine Vet J 2011;43:45–53.
    pubmed: 21143633
  16. Faleiros RR, Nuovo GJ, Belknap JK. Calprotectin in myeloid and epithelial cells of laminae from horses with black walnut extract‐induced laminitis. J Vet Intern Med 2009;23:174–181.
    pubmed: 19175737
  17. Kullmann A, Holcombe SJ, Hurcombe SD. Prophylactic digital cryotherapy is associated with decreased incidence of laminitis in horses diagnosed with colitis. Equine Vet J 2014;46:554–559.
    pubmed: 23927380
  18. Van Eps AW, Pollitt CC. Equine laminitis model: Cryotherapy reduces the severity of lesions evaluated seven days after induction with oligofructose. Equine Vet J 2009;41:741–746.
    pubmed: 20095220
  19. van Eps AW, Pollitt CC, Underwood C. Continuous digital hypothermia initiated after the onset of lameness prevents lamellar failure in the oligofructose laminitis model. Equine Vet J 2014;46:625–630.
    pubmed: 24004323
  20. van Eps AW, Leise BS, Watts M. Digital hypothermia inhibits early lamellar inflammatory signalling in the oligofructose laminitis model. Equine Vet J 2012;44:230–237.
    pubmed: 21895750
  21. Dern K, Watts M, Werle B. Effect of delayed digital hypothermia on lamellar inflammatory signaling in the oligofructose laminitis model. J Vet Intern Med 2017;31:575–581.
    pmc: PMC5354059pubmed: 28145603
  22. Godman JD, Burns TA, Kelly CS. The effect of hypothermia on influx of leukocytes in the digital lamellae of horses with oligofructose‐induced laminitis. Vet Immunol Immunopathol 2016;178:22–28.
    pubmed: 27496739
  23. Obel N. Studies of the Histopathology of Acute Laminitis. Almgvist and Wilcsells Bottrykeri Ab Uppsala; 1948. Thesis.
  24. Pollitt CC. Basement membrane pathology: A feature of acute equine laminitis. Equine Vet J 1996;28:38–46.
    pubmed: 8565952
  25. Vandesompele J, De Preter K, Pattyn F. Accurate normalization of real‐time quantitative RT‐PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3:1–11.
    pmc: PMC126239pubmed: 12184808
  26. van Eps AW. Therapeutic hypothermia (cryotherapy) to prevent and treat acute laminitis. Vet Clin North Am Equine Pract 2010;26:125–133.
    pubmed: 20381741
  27. Umbro I, Gentile G, Tinti F. Recent advances in pathophysiology and biomarkers of sepsis‐induced acute kidney injury. J Infect 2016;72:131–142.
    pubmed: 26702738
  28. Wiersinga WJ, Leopold SJ, Cranendonk DR. Host innate immune responses to sepsis. Virulence 2014;5:36–44.
    pmc: PMC3916381pubmed: 23774844
  29. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004;202:145–156.
    pubmed: 14743496
  30. Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL‐6 blockade for cytokine storm. Immunotherapy 2016;8:959–970.
    pubmed: 27381687
  31. de Laat MA, van Eps AW, McGowan CM. Equine laminitis: Comparative histopathology 48 hours after experimental induction with insulin or alimentary oligofructose in standardbred horses. J Comp Pathol 2011;145:399–409.
    pubmed: 21429503
  32. Belknap JK, Giguere S, Pettigrew A. Lamellar pro‐inflammatory cytokine expression patterns in laminitis at the developmental stage and at the onset of lameness: Innate vs. adaptive immune response. Equine Vet J 2007;39:42–47.
    pubmed: 17228594
  33. Fontaine GL, Belknap JK, Allen D. Expression of interleukin‐1beta in the digital laminae of horses in the prodromal stage of experimentally induced laminitis. Am J Vet Res 2001;62:714–720.
    pubmed: 11341391
  34. van Eps AW, Pollitt CC. Equine laminitis: Cryotherapy reduces the severity of the acute lesion. Equine Vet J 2004;36:255–260.
    pubmed: 15147134
  35. Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti‐inflammatory drugs on sepsis. Intensive Care Med 2012;38:1249–1257.
    pubmed: 22531881
  36. Leme FOP, Bonna FAB, Marval CA. Histopathology of the ditital laminae from horses with acute induced laminitis treated with ketoprophen, phenylbutazone, and flunixin meglumine. Arq Bras Med Vet Zoo 2010;62:241–250.
  37. Medina‐Torres CE, Underwood C, Pollitt CC. Microdialysis measurements of lamellar perfusion and energy metabolism during the development of laminitis in the oligofructose model. Equine Vet J 2016;48:246–252.
    pubmed: 25586365
  38. Housby JN, Cahill CM, Chu B. Non‐steroidal anti‐inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999;11:347–358.
    pubmed: 10328874
  39. Sagi SA, Weggen S, Eriksen J. The non‐cyclooxygenase targets of non‐steroidal anti‐inflammatory drugs, lipoxygenases, peroxisome proliferator‐activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production. J Biol Chem 2003;278:31825–31830.
    pubmed: 12805355
  40. Waguespack RW, Kemppainen RJ, Cochran A. Increased expression of MAIL, a cytokine‐associated nuclear protein, in the prodromal stage of black walnut‐induced laminitis. Equine Vet J 2004;36:285–291.
    pubmed: 15147139
  41. Lorente L, Martin MM, Perez‐Cejas A. Association between interleukin‐6 promoter polymorphism (‐174 G/C), serum interleukin‐6 levels and mortality in severe septic patients. Int J Mol Sci 2016;17:1861.
    pmc: PMC5133861pubmed: 27834822
  42. Harbarth S, Holeckova K, Froidevaux C. Diagnostic value of procalcitonin, interleukin‐6, and interleukin‐8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001;164:396–402.
    pubmed: 11500339
  43. Gaini S, Koldkjaer OG, Pedersen C. Procalcitonin, lipopolysaccharide‐binding protein, interleukin‐6 and C‐reactive protein in community‐acquired infections and sepsis: A prospective study. Crit Care 2006;10:R53.
    pmc: PMC1550885pubmed: 16569262
  44. Scheller J, Garbers C, Rose‐John S. Interleukin‐6: From basic biology to selective blockade of pro‐inflammatory activities. Semin Immunol 2014;26:2–12.
    pubmed: 24325804
  45. Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL‐6) immunotherapy. Cold Spring Harb Perspect Biol 2017;a028456.
    pmc: PMC6071487pubmed: 28778870
  46. Chalaris A, Schmidt‐Arras D, Yamamoto K. Interleukin‐6 trans‐signaling and colonic cancer associated with inflammatory bowel disease. Dig Dis 2012;30:492–499.
    pubmed: 23108305
  47. Bollrath J, Phesse TJ, von Burstin VA. gp130‐mediated Stat3 activation in enterocytes regulates cell survival and cell‐cycle progression during colitis‐associated tumorigenesis. Cancer Cell 2009;15:91–102.
    pubmed: 19185844
  48. Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL‐6 mediated involvement. Cancer Lett 2016;375:51–61.
    pubmed: 26945971
  49. de Laat MA, Patterson‐Kane JC, Pollitt CC. Histological and morphometric lesions in the pre‐clinical, developmental phase of insulin‐induced laminitis in Standardbred horses. Vet J 2013;195:305–312.
    pubmed: 22884985
  50. Carter RA, Shekk V, de Laat MA. Novel keratins identified by quantitative proteomic analysis as the major cytoskeletal proteins of equine (Equus caballus) hoof lamellar tissue. J Anim Sci 2010;88:3843–3855.
    pubmed: 20622188
  51. French KR, Pollitt CC. Equine laminitis: Cleavage of laminin 5 associated with basement membrane dysadhesion. Equine Vet J 2004;36:242–247.
    pubmed: 15147132
  52. French KR, Pollitt CC. Equine laminitis: Loss of hemidesmosomes in hoof secondary epidermal lamellae correlates to dose in an oligofructose induction model: An ultrastructural study. Equine Vet J 2004;36:230–235.
    pubmed: 15147130
  53. Wang L, Pawlak EA, Johnson PJ. Impact of laminitis on the canonical Wnt signaling pathway in basal epithelial cells of the equine digital laminae. PLoS One 2013;8:e56025.
    pmc: PMC3566061pubmed: 23405249
  54. Savagner P. Epithelial‐mesenchymal transitions: From cell plasticity to concept elasticity. Curr Top Dev Biol 2015;112:273–300.
    pubmed: 25733143
  55. Thiem S, Pierce TP, Palmieri M. mTORC1 inhibition restricts inflammation‐associated gastrointestinal tumorigenesis in mice. J Clin Invest 2013;123:767–781.
    pmc: PMC3561832pubmed: 23321674
  56. Lane HE, Burns TA, Hegedus OC. Lamellar events related to insulin‐like growth factor‐1 receptor signalling in two models relevant to endocrinopathic laminitis. Equine Vet J 2017;19:643–654.
    pubmed: 28078757