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Home / Equine Research Bank / PLoS One / Macrophage sub-populations and the lipoxin A4 receptor impli...
PloS one2012; 7(2); e32333; doi: 10.1371/journal.pone.0032333

Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair.

Abstract: Macrophages (Mφ) orchestrate inflammatory and reparatory processes in injured connective tissues but their role during different phases of tendon healing is not known. We investigated the contribution of different Mφ subsets in an equine model of naturally occurring tendon injury. Post mortem tissues were harvested from normal (uninjured), sub-acute (3-6 weeks post injury) and chronically injured (>3 months post injury) superficial digital flexor tendons. To determine if inflammation was present in injured tendons, Mφ sub-populations were quantified based on surface antigen expression of CD172a (pan Mφ), CD14(high)CD206(low) (pro-inflammatory M1Mφ), and CD206(high) (anti-inflammatory M2Mφ) to assess potential polarised phenotypes. In addition, the Lipoxin A(4) receptor (FPR2/ALX) was used as marker for resolving inflammation. Normal tendons were negative for both Mφ and FPR2/ALX. In contrast, M1Mφ predominated in sub-acute injury, whereas a potential phenotype-switch to M2Mφ polarity was seen in chronic injury. Furthermore, FPR2/ALX expression by tenocytes was significantly upregulated in sub-acute but not chronic injury. Expression of the FPR2/ALX ligand Annexin A1 was also significantly increased in sub-acute and chronic injuries in contrast to low level expression in normal tendons. The combination of reduced FPR2/ALX expression and persistence of the M2Mφ phenotype in chronic injury suggests a potential mechanism for incomplete resolution of inflammation after tendon injury. To investigate the effect of pro-inflammatory mediators on lipoxin A(4) (LXA(4)) production and FPR2/ALX expression in vitro, normal tendon explants were stimulated with interleukin-1 beta and prostaglandin E(2). Stimulation with either mediator induced LXA(4) release and maximal upregulation of FPR2/ALX expression after 72 hours. Taken together, our data suggests that although tenocytes are capable of mounting a protective mechanism to counteract inflammatory stimuli, this appears to be of insufficient duration and magnitude in natural tendon injury, which may potentiate chronic inflammation and fibrotic repair, as indicated by the presence of M2Mφ.
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Publication Date: 2012-02-22 PubMed ID: 22384219PubMed Central: PMC3284560DOI: 10.1371/journal.pone.0032333Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article focuses on understanding the role and proportions of certain macrophage sub-populations during various stages of tendon healing, using an equine model of naturally occurring tendon injury. The researchers also examine the role of the Lipoxin A4 receptor as a marker for resolving inflammation. The findings suggest that a key challenge in tendon repair is the insufficient counteraction of inflammatory stimuli leading to potential chronic inflammation and fibrotic repair.

Objective of the Research

  • The primary aim of this study was to investigate the interaction between different macrophage (Mφ) subsets during the stages of tendon healing. Macrophages are a type of white blood cell that plays a crucial role in repairing tissues and fighting infections. Specifically, the researchers sought to understand the contribution of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage sub-populations.
  • Another objective was to study the role of the Lipoxin A4 receptor (FPR2/ALX) as a marker for resolving inflammation during the healing process. Lipoxin A4 is a byproduct of the body’s inflammatory response, and its presence can suggest that the inflammation is being resolved or controlled.

Methodology

  • Tissue samples at various injury stages were taken from superficial digital flexor tendons of horses, collected post-mortem. Samples originated from normal (uninjured), sub-acute (3-6 weeks post injury), and chronic (>3 months post injury) states.
  • The researchers identified the macrophage subsets by their expression of surface antigens, CD172a, CD14(high)CD206(low) for M1, and CD206(high) for M2.
  • The presence and expression of the Lipoxin A4 receptor were used to gauge the status of inflammation resolution.
  • In addition, the research team studied the effect of inflammatory mediators, interleukin-1 beta, and prostaglandin E(2), on the production of Lipoxin A4 and expression of FPR2/ALX in normal tendon explants in vitro.

Results and Findings

  • In the sub-acute phase of injury, the M1 (pro-inflammatory) macrophages were predominant, highlighting an active inflammatory process. In the chronic injury state, however, a possible phenotype switch to M2 (anti-inflammatory) macrophages was observed.
  • The expression of the Lipoxin A4 receptor by tendon cells (tenocytes) was significantly upregulated in sub-acute injuries but not in chronic injuries. This suggests that inflammation might not be fully resolved in chronic injuries.
  • The expression of FPR2/ALX ligand Annexin A1 was significantly increased in sub-acute and chronic injuries, implying ongoing inflammation. This is contrasted with low-level expression in normal tendons.
  • Stimulation with either interleukin-1 beta or prostaglandin E(2) induced a release of Lipoxin A4 and an upregulation of FPR2/ALX expression demonstrating potential protective mechanisms initiated by tenocytes to counteract inflammatory stimuli.
  • The study concludes that although tenocytes could mount a protective mechanism against inflammation, this is typically not sufficient in a natural tendon injury, paving the way for potential chronic inflammation and fibrotic repair, as evidenced by the continuing presence of M2 macrophages.

Cite This Article

APA
Dakin SG, Werling D, Hibbert A, Abayasekara DR, Young NJ, Smith RK, Dudhia J. (2012). Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair. PLoS One, 7(2), e32333. https://doi.org/10.1371/journal.pone.0032333

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 7
Issue: 2
Pages: e32333
PII: e32333

Researcher Affiliations

Dakin, Stephanie Georgina
  • Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hatfield, United Kingdom. sdakin@rvc.ac.uk
Werling, Dirk
    Hibbert, Andrew
      Abayasekara, Dilkush Robert Ephrem
        Young, Natalie Jayne
          Smith, Roger Kenneth Whealands
            Dudhia, Jayesh

              MeSH Terms

              • Animals
              • Antigens, Differentiation / biosynthesis
              • Gene Expression Regulation
              • Horses
              • Image Processing, Computer-Assisted
              • Inflammation
              • Lectins, C-Type / biosynthesis
              • Lipopolysaccharide Receptors / biosynthesis
              • Lipoxins / metabolism
              • Macrophages / metabolism
              • Mannose Receptor
              • Mannose-Binding Lectins / biosynthesis
              • Microscopy, Fluorescence / methods
              • Models, Biological
              • Phenotype
              • Receptors, Cell Surface / biosynthesis
              • Receptors, Immunologic / biosynthesis
              • Receptors, Lipoxin / metabolism
              • Spleen / metabolism
              • Tendon Injuries / metabolism
              • Tendon Injuries / surgery
              • Tendons / metabolism
              • Tendons / surgery

              Grant Funding

              • BB/D524883/1 / Biotechnology and Biological Sciences Research Council
              • BB/F018258/1 / Biotechnology and Biological Sciences Research Council

              Conflict of Interest Statement

              SGD's PhD is funded by Biotechnology and Biological Sciences Research Council (BBSRC) UK and Ceva (France). This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The authors have declared that no other competing interests exist.

              References

              This article includes 82 references
              1. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes.. Clin J Sport Med 2005 May;15(3):133-5.
                pubmed: 15867554doi: 10.1097/01.jsm.0000165347.55638.23google scholar: lookup
              2. Welsh RP, Clodman J. Clinical survey of Achilles tendinitis in athletes.. Can Med Assoc J 1980 Jan 26;122(2):193-5.
                pmc: PMC1801770pubmed: 7363214
              3. Avella CS, Ely ER, Verheyen KL, Price JS, Wood JL, Smith RK. Ultrasonographic assessment of the superficial digital flexor tendons of National Hunt racehorses in training over two racing seasons.. Equine Vet J 2009 May;41(5):449-54.
                pubmed: 19642404doi: 10.2746/042516409x391042google scholar: lookup
              4. Järvinen M, Józsa L, Kannus P, Järvinen TL, Kvist M, Leadbetter W. Histopathological findings in chronic tendon disorders.. Scand J Med Sci Sports 1997 Apr;7(2):86-95.
                pubmed: 9211609doi: 10.1111/j.1600-0838.1997.tb00124.xgoogle scholar: lookup
              5. Józsa L, Réffy A, Kannus P, Demel S, Elek E. Pathological alterations in human tendons.. Arch Orthop Trauma Surg 1990;110(1):15-21.
                pubmed: 2288799doi: 10.1007/bf00431359google scholar: lookup
              6. Kannus P, Józsa L. Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients.. J Bone Joint Surg Am 1991 Dec;73(10):1507-25.
                pubmed: 1748700
              7. Alfredson H, Lorentzon R. Chronic tendon pain: no signs of chemical inflammation but high concentrations of the neurotransmitter glutamate. Implications for treatment?. Curr Drug Targets 2002 Feb;3(1):43-54.
                pubmed: 11899264doi: 10.2174/1389450023348028google scholar: lookup
              8. Aström M, Rausing A. Chronic Achilles tendinopathy. A survey of surgical and histopathologic findings.. Clin Orthop Relat Res 1995 Jul;(316):151-64.
                pubmed: 7634699
              9. Smith R, Schramme M. Tendon injury in the horse: current theories and therapies.. In Practice 2003;25:529–539.
              10. Silver IA, Brown PN, Goodship AE, Lanyon LE, McCullagh KG, Perry GC, Williams IF. A clinical and experimental study of tendon injury, healing and treatment in the horse.. Equine Vet J Suppl 1983 Jul;(1):1-43.
                pubmed: 9079042
              11. Crevier-Denoix N, Collobert C, Pourcelot P, Denoix JM, Sanaa M, Geiger D, Bernard N, Ribot X, Bortolussi C, Bousseau B. Mechanical properties of pathological equine superficial digital flexor tendons.. Equine Vet J Suppl 1997 May;(23):23-6.
                pubmed: 9354282doi: 10.1111/j.2042-3306.1997.tb05046.xgoogle scholar: lookup
              12. Millar NL, Hueber AJ, Reilly JH, Xu Y, Fazzi UG, Murrell GA, McInnes IB. Inflammation is present in early human tendinopathy.. Am J Sports Med 2010 Oct;38(10):2085-91.
                pubmed: 20595553doi: 10.1177/0363546510372613google scholar: lookup
              13. Marsolais D, Côté CH, Frenette J. Neutrophils and macrophages accumulate sequentially following Achilles tendon injury.. J Orthop Res 2001 Nov;19(6):1203-9.
                pubmed: 11781025doi: 10.1016/s0736-0266(01)00031-6google scholar: lookup
              14. Wong JK, Lui YH, Kapacee Z, Kadler KE, Ferguson MW, McGrouther DA. The cellular biology of flexor tendon adhesion formation: an old problem in a new paradigm.. Am J Pathol 2009 Nov;175(5):1938-51.
                pmc: PMC2774058pubmed: 19834058doi: 10.2353/ajpath.2009.090380google scholar: lookup
              15. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines.. Physiol Rev 2003 Jul;83(3):835-70.
                pubmed: 12843410doi: 10.1152/physrev.2003.83.3.835google scholar: lookup
              16. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA. Differential roles of macrophages in diverse phases of skin repair.. J Immunol 2010 Apr 1;184(7):3964-77.
                pubmed: 20176743doi: 10.4049/jimmunol.0903356google scholar: lookup
              17. Peters T, Sindrilaru A, Hinz B, Hinrichs R, Menke A, Al-Azzeh EA, Holzwarth K, Oreshkova T, Wang H, Kess D, Walzog B, Sulyok S, Sunderkötter C, Friedrich W, Wlaschek M, Krieg T, Scharffetter-Kochanek K. Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.. EMBO J 2005 Oct 5;24(19):3400-10.
                pmc: PMC1276170pubmed: 16148944doi: 10.1038/sj.emboj.7600809google scholar: lookup
              18. Nathan CF. Secretory products of macrophages.. J Clin Invest 1987 Feb;79(2):319-26.
                pmc: PMC424063pubmed: 3543052doi: 10.1172/jci112815google scholar: lookup
              19. Khan MH, Li Z, Wang JH. Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration.. Clin J Sport Med 2005 Jan;15(1):27-33.
                pubmed: 15654188doi: 10.1097/00042752-200501000-00006google scholar: lookup
              20. Langberg H, Skovgaard D, Karamouzis M, Bülow J, Kjaer M. Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans.. J Physiol 1999 Mar 15;515 ( Pt 3)(Pt 3):919-27.
                pmc: PMC2269174pubmed: 10066916doi: 10.1111/j.1469-7793.1999.919ab.xgoogle scholar: lookup
              21. Tsuzaki M, Guyton G, Garrett W, Archambault JM, Herzog W, Almekinders L, Bynum D, Yang X, Banes AJ. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells.. J Orthop Res 2003 Mar;21(2):256-64.
                pubmed: 12568957doi: 10.1016/s0736-0266(02)00141-9google scholar: lookup
              22. Yang G, Im HJ, Wang JH. Repetitive mechanical stretching modulates IL-1beta induced COX-2, MMP-1 expression, and PGE2 production in human patellar tendon fibroblasts.. Gene 2005 Dec 19;363:166-72.
                pmc: PMC2901527pubmed: 16226404doi: 10.1016/j.gene.2005.08.006google scholar: lookup
              23. Thampatty BP, Li H, Im HJ, Wang JH. EP4 receptor regulates collagen type-I, MMP-1, and MMP-3 gene expression in human tendon fibroblasts in response to IL-1 beta treatment.. Gene 2007 Jan 15;386(1-2):154-61.
                pmc: PMC1839868pubmed: 17046175doi: 10.1016/j.gene.2006.08.027google scholar: lookup
              24. Herrmann-Hoesing LM, Noh SM, Snekvik KR, White SN, Schneider DA, Truscott T, Knowles DP. Ovine progressive pneumonia virus capsid antigen as found in CD163- and CD172a-positive alveolar macrophages of persistently infected sheep.. Vet Pathol 2010 May;47(3):518-28.
                pubmed: 20382821doi: 10.1177/0300985809359605google scholar: lookup
              25. Ibrahim S, Saunders K, Kydd JH, Lunn DP, Steinbach F. Screening of anti-human leukocyte monoclonal antibodies for reactivity with equine leukocytes.. Vet Immunol Immunopathol 2007 Sep 15;119(1-2):63-80.
                pubmed: 17707518doi: 10.1016/j.vetimm.2007.06.034google scholar: lookup
              26. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.. J Exp Med 1992 Jul 1;176(1):287-92.
                pmc: PMC2119288pubmed: 1613462doi: 10.1084/jem.176.1.287google scholar: lookup
              27. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells.. Immunity 1999 Feb;10(2):137-42.
                pubmed: 10072066doi: 10.1016/s1074-7613(00)80014-xgoogle scholar: lookup
              28. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.. Trends Immunol 2002 Nov;23(11):549-55.
                pubmed: 12401408doi: 10.1016/s1471-4906(02)02302-5google scholar: lookup
              29. Gordon S. Alternative activation of macrophages.. Nat Rev Immunol 2003 Jan;3(1):23-35.
                pubmed: 12511873doi: 10.1038/nri978google scholar: lookup
              30. Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.. Cell Metab 2007 Aug;6(2):137-43.
                pubmed: 17681149doi: 10.1016/j.cmet.2007.06.010google scholar: lookup
              31. Smeekens SP, van de Veerdonk FL, Joosten LA, Jacobs L, Jansen T, Williams DL, van der Meer JW, Kullberg BJ, Netea MG. The classical CD14⁺⁺ CD16⁻ monocytes, but not the patrolling CD14⁺ CD16⁺ monocytes, promote Th17 responses to Candida albicans.. Eur J Immunol 2011 Oct;41(10):2915-24.
                pubmed: 21695694doi: 10.1002/eji.201141418google scholar: lookup
              32. Satoh N, Shimatsu A, Himeno A, Sasaki Y, Yamakage H, Yamada K, Suganami T, Ogawa Y. Unbalanced M1/M2 phenotype of peripheral blood monocytes in obese diabetic patients: effect of pioglitazone.. Diabetes Care 2010 Jan;33(1):e7.
                pubmed: 20040670doi: 10.2337/dc09-1315google scholar: lookup
              33. Raife TJ, Lager DJ, Kemp JD, Dick FR. Expression of CD24 (BA-1) predicts monocytic lineage in acute myeloid leukemia.. Am J Clin Pathol 1994 Mar;101(3):296-9.
                pubmed: 7510927doi: 10.1093/ajcp/101.3.296google scholar: lookup
              34. Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Györi G, Zlabinger GJ, Stulnig TM. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production.. Int J Obes (Lond) 2007 Sep;31(9):1420-8.
                pubmed: 17593905doi: 10.1038/sj.ijo.0803632google scholar: lookup
              35. Brancato SK, Albina JE. Wound macrophages as key regulators of repair: origin, phenotype, and function.. Am J Pathol 2011 Jan;178(1):19-25.
                pmc: PMC3069845pubmed: 21224038doi: 10.1016/j.ajpath.2010.08.003google scholar: lookup
              36. Stramer BM, Mori R, Martin P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair.. J Invest Dermatol 2007 May;127(5):1009-17.
                pubmed: 17435786doi: 10.1038/sj.jid.5700811google scholar: lookup
              37. Marsolais D, Côté CH, Frenette J. Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration.. Lab Invest 2003 Jul;83(7):991-9.
                pubmed: 12861039doi: 10.1097/01.lab.0000078688.07696.acgoogle scholar: lookup
              38. Magra M, Maffulli N. Nonsteroidal antiinflammatory drugs in tendinopathy: friend or foe.. Clin J Sport Med 2006 Jan;16(1):1-3.
                pubmed: 16377967doi: 10.1097/01.jsm.0000194764.27819.5dgoogle scholar: lookup
              39. Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes.. Proc Natl Acad Sci U S A 1984 Sep;81(17):5335-9.
                pmc: PMC391698pubmed: 6089195doi: 10.1073/pnas.81.17.5335google scholar: lookup
              40. Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.. Pharmacol Rev 2009 Jun;61(2):119-61.
                pmc: PMC2745437pubmed: 19498085doi: 10.1124/pr.109.001578google scholar: lookup
              41. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.. J Exp Med 2002 Oct 21;196(8):1025-37.
                pmc: PMC2194036pubmed: 12391014doi: 10.1084/jem.20020760google scholar: lookup
              42. Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh SF, Spite M. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.. J Exp Med 2009 Jan 16;206(1):15-23.
                pmc: PMC2626672pubmed: 19103881doi: 10.1084/jem.20081880google scholar: lookup
              43. Yang D, Chen Q, Le Y, Wang JM, Oppenheim JJ. Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages.. J Immunol 2001 Mar 15;166(6):4092-8.
                pubmed: 11238658doi: 10.4049/jimmunol.166.6.4092google scholar: lookup
              44. Serhan CN, Takano T, Chiang N, Gronert K, Clish CB. Formation of endogenous "antiinflammatory" lipid mediators by transcellular biosynthesis. Lipoxins and aspirin-triggered lipoxins inhibit neutrophil recruitment and vascular permeability.. Am J Respir Crit Care Med 2000 Feb;161(2 Pt 2):S95-S101.
                pubmed: 10673235doi: 10.1164/ajrccm.161.supplement_1.ltta-19google scholar: lookup
              45. Serhan CN, Chiang N. Lipid-derived mediators in endogenous anti-inflammation and resolution: lipoxins and aspirin-triggered 15-epi-lipoxins.. ScientificWorldJournal 2002 Jan 22;2:169-204.
                pmc: PMC6009744pubmed: 12806051doi: 10.1100/tsw.2002.81google scholar: lookup
              46. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery.. Nat Rev Drug Discov 2004 May;3(5):401-16.
                pubmed: 15136788doi: 10.1038/nrd1383google scholar: lookup
              47. Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor.. Nat Med 2002 Nov;8(11):1296-302.
                pmc: PMC2777269pubmed: 12368905doi: 10.1038/nm786google scholar: lookup
              48. Parente L, Solito E. Annexin 1: more than an anti-phospholipase protein.. Inflamm Res 2004 Apr;53(4):125-32.
                pubmed: 15060718doi: 10.1007/s00011-003-1235-zgoogle scholar: lookup
              49. Perretti M, Croxtall JD, Wheller SK, Goulding NJ, Hannon R, Flower RJ. Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration.. Nat Med 1996 Nov;2(11):1259-62.
                pubmed: 8898757doi: 10.1038/nm1196-1259google scholar: lookup
              50. Lim LH, Pervaiz S. Annexin 1: the new face of an old molecule.. FASEB J 2007 Apr;21(4):968-75.
                pubmed: 17215481doi: 10.1096/fj.06-7464revgoogle scholar: lookup
              51. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.. Nat Rev Immunol 2008 May;8(5):349-61.
                pmc: PMC2744593pubmed: 18437155doi: 10.1038/nri2294google scholar: lookup
              52. Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?. Am J Pathol 2010 Oct;177(4):1576-91.
                pmc: PMC2947253pubmed: 20813960doi: 10.2353/ajpath.2010.100322google scholar: lookup
              53. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution.. Nat Immunol 2001 Jul;2(7):612-9.
                pubmed: 11429545doi: 10.1038/89759google scholar: lookup
              54. Lui PP, Maffulli N, Rolf C, Smith RK. What are the validated animal models for tendinopathy?. Scand J Med Sci Sports 2011 Feb;21(1):3-17.
                pubmed: 20673247doi: 10.1111/j.1600-0838.2010.01164.xgoogle scholar: lookup
              55. Dowling BA, Dart AJ, Hodgson DR, Smith RK. Superficial digital flexor tendonitis in the horse.. Equine Vet J 2000 Sep;32(5):369-78.
                pubmed: 11037257doi: 10.2746/042516400777591138google scholar: lookup
              56. Möller A, Astron M, Westlin N. Increasing incidence of Achilles tendon rupture.. Acta Orthop Scand 1996 Oct;67(5):479-81.
                pubmed: 8948254doi: 10.3109/17453679608996672google scholar: lookup
              57. Maffulli N, Waterston SW, Squair J, Reaper J, Douglas AS. Changing incidence of Achilles tendon rupture in Scotland: a 15-year study.. Clin J Sport Med 1999 Jul;9(3):157-60.
                pubmed: 10512344doi: 10.1097/00042752-199907000-00007google scholar: lookup
              58. Dudhia J, Scott CM, Draper ER, Heinegård D, Pitsillides AA, Smith RK. Aging enhances a mechanically-induced reduction in tendon strength by an active process involving matrix metalloproteinase activity.. Aging Cell 2007 Aug;6(4):547-56.
                pubmed: 17578513doi: 10.1111/j.1474-9726.2007.00307.xgoogle scholar: lookup
              59. Smith RK, Goodship AE. The effect of early training and the adaptation and conditioning of skeletal tissues.. Vet Clin North Am Equine Pract 2008 Apr;24(1):37-51.
                pubmed: 18314035doi: 10.1016/j.cveq.2007.11.005google scholar: lookup
              60. Strocchi R, De Pasquale V, Guizzardi S, Govoni P, Facchini A, Raspanti M, Girolami M, Giannini S. Human Achilles tendon: morphological and morphometric variations as a function of age.. Foot Ankle 1991 Oct;12(2):100-4.
                pubmed: 1773989doi: 10.1177/107110079101200207google scholar: lookup
              61. Wilson AM, McGuigan MP, Su A, van Den Bogert AJ. Horses damp the spring in their step.. Nature 2001 Dec 20-27;414(6866):895-9.
                pubmed: 11780059doi: 10.1038/414895agoogle scholar: lookup
              62. Ker RF, Wang XT, Pike AV. Fatigue quality of mammalian tendons.. J Exp Biol 2000 Apr;203(Pt 8):1317-27.
                pubmed: 10729280doi: 10.1242/jeb.203.8.1317google scholar: lookup
              63. Williams IF, McCullagh KG, Goodship AE, Silver IA. Studies on the pathogenesis of equine tendonitis following collagenase injury.. Res Vet Sci 1984 May;36(3):326-38.
                pubmed: 6087432
              64. Dahlgren LA, van der Meulen MC, Bertram JE, Starrak GS, Nixon AJ. Insulin-like growth factor-I improves cellular and molecular aspects of healing in a collagenase-induced model of flexor tendinitis.. J Orthop Res 2002 Sep;20(5):910-9.
                pubmed: 12382953doi: 10.1016/s0736-0266(02)00009-8google scholar: lookup
              65. Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal cells in vivo.. Development 1997 Sep;124(18):3633-8.
                pubmed: 9342055doi: 10.1242/dev.124.18.3633google scholar: lookup
              66. Leibovich SJ, Wiseman DM. Macrophages, wound repair and angiogenesis.. Prog Clin Biol Res 1988;266:131-45.
                pubmed: 2454496
              67. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice.. Am J Pathol 2007 Mar;170(3):818-29.
                pmc: PMC1864893pubmed: 17322368doi: 10.2353/ajpath.2007.060547google scholar: lookup
              68. Nagaoka T, Kaburagi Y, Hamaguchi Y, Hasegawa M, Takehara K, Steeber DA, Tedder TF, Sato S. Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression.. Am J Pathol 2000 Jul;157(1):237-47.
                pmc: PMC1850195pubmed: 10880393doi: 10.1016/s0002-9440(10)64534-8google scholar: lookup
              69. Lawrence T, Gilroy DW. Chronic inflammation: a failure of resolution?. Int J Exp Pathol 2007 Apr;88(2):85-94.
                pmc: PMC2517296pubmed: 17408451doi: 10.1111/j.1365-2613.2006.00507.xgoogle scholar: lookup
              70. Chiang N, Serhan CN, Dahlén SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.. Pharmacol Rev 2006 Sep;58(3):463-87.
                pubmed: 16968948doi: 10.1124/pr.58.3.4google scholar: lookup
              71. Maderna P, Godson C. Lipoxins: resolutionary road.. Br J Pharmacol 2009 Oct;158(4):947-59.
                pmc: PMC2785518pubmed: 19785661doi: 10.1111/j.1476-5381.2009.00386.xgoogle scholar: lookup
              72. Leedom AJ, Sullivan AB, Dong B, Lau D, Gronert K. Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.. Am J Pathol 2010 Jan;176(1):74-84.
                pmc: PMC2797871pubmed: 20008149doi: 10.2353/ajpath.2010.090678google scholar: lookup
              73. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity.. Nat Rev Immunol 2011 Oct 25;11(11):750-61.
                pubmed: 22025054doi: 10.1038/nri3088google scholar: lookup
              74. Gavins FN, Sawmynaden P, Chatterjee BE, Perretti M. A twist in anti-inflammation: annexin 1 acts via the lipoxin A4 receptor.. Prostaglandins Leukot Essent Fatty Acids 2005 Sep-Oct;73(3-4):211-9.
                pubmed: 15982865doi: 10.1016/j.plefa.2005.05.008google scholar: lookup
              75. Arur S, Uche UE, Rezaul K, Fong M, Scranton V, Cowan AE, Mohler W, Han DK. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment.. Dev Cell 2003 Apr;4(4):587-98.
                pubmed: 12689596doi: 10.1016/s1534-5807(03)00090-xgoogle scholar: lookup
              76. Gronert K, Gewirtz A, Madara JL, Serhan CN. Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha-induced IL-8 release.. J Exp Med 1998 Apr 20;187(8):1285-94.
                pmc: PMC2212233pubmed: 9547339doi: 10.1084/jem.187.8.1285google scholar: lookup
              77. Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y, Shearer GM. Modulation of inflammation and immunity by cyclic AMP.. Science 1974 Apr 5;184(4132):19-28.
                pubmed: 4131281doi: 10.1126/science.184.4132.19google scholar: lookup
              78. Sims JE, Gayle MA, Slack JL, Alderson MR, Bird TA, Giri JG, Colotta F, Re F, Mantovani A, Shanebeck K. Interleukin 1 signaling occurs exclusively via the type I receptor.. Proc Natl Acad Sci U S A 1993 Jul 1;90(13):6155-9.
                pmc: PMC46886pubmed: 8327496doi: 10.1073/pnas.90.13.6155google scholar: lookup
              79. Bomsztyk K, Toivola B, Emery DW, Rooney JW, Dower SK, Rachie NA, Sibley CH. Role of cAMP in interleukin-1-induced kappa light chain gene expression in murine B cell line.. J Biol Chem 1990 Jun 5;265(16):9413-7.
                pubmed: 2160978
              80. Gilroy DW. Eicosanoids and the endogenous control of acute inflammatory resolution.. Int J Biochem Cell Biol 2010 Apr;42(4):524-8.
                pubmed: 20026423doi: 10.1016/j.biocel.2009.12.013google scholar: lookup
              81. Morris T, Stables M, Colville-Nash P, Newson J, Bellingan G, de Souza PM, Gilroy DW. Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways.. Proc Natl Acad Sci U S A 2010 May 11;107(19):8842-7.
                pmc: PMC2889345pubmed: 20421472doi: 10.1073/pnas.1000373107google scholar: lookup
              82. Romijn HJ, van Uum JF, Breedijk I, Emmering J, Radu I, Pool CW. Double immunolabeling of neuropeptides in the human hypothalamus as analyzed by confocal laser scanning fluorescence microscopy.. J Histochem Cytochem 1999 Feb;47(2):229-36.
                pubmed: 9889258doi: 10.1177/002215549904700211google scholar: lookup

              Citations

              This article has been cited 38 times.
              1. Lu J, Li H, Zhang Z, Xu R, Wang J, Jin H. Platelet-rich plasma in the pathologic processes of tendinopathy: a review of basic science studies.. Front Bioeng Biotechnol 2023;11:1187974.
                doi: 10.3389/fbioe.2023.1187974pubmed: 37545895google scholar: lookup
              2. Li Y, Wang X, Hu B, Sun Q, Wan M, Carr A, Liu S, Cao X. Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate peritendinous adhesion.. Bone Res 2023 May 8;11(1):24.
                doi: 10.1038/s41413-023-00252-1pubmed: 37156778google scholar: lookup
              3. Marr N, Zamboulis DE, Werling D, Felder AA, Dudhia J, Pitsillides AA, Thorpe CT. The tendon interfascicular basement membrane provides a vascular niche for CD146+ cell subpopulations.. Front Cell Dev Biol 2022;10:1094124.
                doi: 10.3389/fcell.2022.1094124pubmed: 36699014google scholar: lookup
              4. Smith EJ, Beaumont RE, McClellan A, Sze C, Palomino Lago E, Hazelgrove L, Dudhia J, Smith RKW, Guest DJ. Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors.. Cell Tissue Res 2023 Mar;391(3):523-544.
                doi: 10.1007/s00441-022-03726-6pubmed: 36543895google scholar: lookup
              5. Benage LG, Sweeney JD, Giers MB, Balasubramanian R. Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology.. Front Bioeng Biotechnol 2022;10:896336.
                doi: 10.3389/fbioe.2022.896336pubmed: 35910030google scholar: lookup
              6. Ellis I, Schnabel LV, Berglund AK. Defining the Profile: Characterizing Cytokines in Tendon Injury to Improve Clinical Therapy.. J Immunol Regen Med 2022 May;16.
                doi: 10.1016/j.regen.2022.100059pubmed: 35309714google scholar: lookup
              7. Yuan J, Lin F, Chen L, Chen W, Pan X, Bai Y, Cai Y, Lu H. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway.. Inflammopharmacology 2022 Apr;30(2):487-498.
                doi: 10.1007/s10787-022-00942-ypubmed: 35235107google scholar: lookup
              8. Russo V, El Khatib M, Prencipe G, Citeroni MR, Faydaver M, Mauro A, Berardinelli P, Cerveró-Varona A, Haidar-Montes AA, Turriani M, Di Giacinto O, Raspa M, Scavizzi F, Bonaventura F, Stöckl J, Barboni B. Tendon Immune Regeneration: Insights on the Synergetic Role of Stem and Immune Cells during Tendon Regeneration.. Cells 2022 Jan 27;11(3).
                doi: 10.3390/cells11030434pubmed: 35159244google scholar: lookup
              9. Chisari E, Rehak L, Khan WS, Maffulli N. Tendon healing is adversely affected by low-grade inflammation.. J Orthop Surg Res 2021 Dec 4;16(1):700.
                doi: 10.1186/s13018-021-02811-wpubmed: 34863223google scholar: lookup
              10. Lu V, Tennyson M, Zhang J, Khan W. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tendon and Ligament Repair-A Systematic Review of In Vivo Studies.. Cells 2021 Sep 27;10(10).
                doi: 10.3390/cells10102553pubmed: 34685532google scholar: lookup
              11. Marr N, Meeson R, Kelly EF, Fang Y, Peffers MJ, Pitsillides AA, Dudhia J, Thorpe CT. CD146 Delineates an Interfascicular Cell Sub-Population in Tendon That Is Recruited during Injury through Its Ligand Laminin-α4.. Int J Mol Sci 2021 Sep 8;22(18).
                doi: 10.3390/ijms22189729pubmed: 34575887google scholar: lookup
              12. Oreff GL, Fenu M, Vogl C, Ribitsch I, Jenner F. Species variations in tenocytes' response to inflammation require careful selection of animal models for tendon research.. Sci Rep 2021 Jun 14;11(1):12451.
                doi: 10.1038/s41598-021-91914-9pubmed: 34127759google scholar: lookup
              13. Markworth JF, Sugg KB, Sarver DC, Maddipati KR, Brooks SV. Local shifts in inflammatory and resolving lipid mediators in response to tendon overuse.. FASEB J 2021 Jun;35(6):e21655.
                doi: 10.1096/fj.202100078Rpubmed: 34042218google scholar: lookup
              14. Ribitsch I, Oreff GL, Jenner F. Regenerative Medicine for Equine Musculoskeletal Diseases.. Animals (Basel) 2021 Jan 19;11(1).
                doi: 10.3390/ani11010234pubmed: 33477808google scholar: lookup
              15. Tsai SL, Nödl MT, Galloway JL. Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies.. Dev Dyn 2021 Mar;250(3):393-413.
                doi: 10.1002/dvdy.269pubmed: 33169466google scholar: lookup
              16. Vinhas A, Almeida AF, Gonçalves AI, Rodrigues MT, Gomes ME. Magnetic Stimulation Drives Macrophage Polarization in Cell to-Cell Communication with IL-1β Primed Tendon Cells.. Int J Mol Sci 2020 Jul 30;21(15).
                doi: 10.3390/ijms21155441pubmed: 32751697google scholar: lookup
              17. Gracey E, Burssens A, Cambré I, Schett G, Lories R, McInnes IB, Asahara H, Elewaut D. Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis.. Nat Rev Rheumatol 2020 Apr;16(4):193-207.
                doi: 10.1038/s41584-019-0364-xpubmed: 32080619google scholar: lookup
              18. Xu HT, Lee CW, Li MY, Wang YF, Yung PS, Lee OK. The shift in macrophages polarisation after tendon injury: A systematic review.. J Orthop Translat 2020 Mar;21:24-34.
                doi: 10.1016/j.jot.2019.11.009pubmed: 32071872google scholar: lookup
              19. Jomaa G, Kwan CK, Fu SC, Ling SK, Chan KM, Yung PS, Rolf C. A systematic review of inflammatory cells and markers in human tendinopathy.. BMC Musculoskelet Disord 2020 Feb 6;21(1):78.
                doi: 10.1186/s12891-020-3094-ypubmed: 32028937google scholar: lookup
              20. Korolenko TA, Bgatova NP, Vetvicka V. Glucan and Mannan-Two Peas in a Pod.. Int J Mol Sci 2019 Jun 29;20(13).
                doi: 10.3390/ijms20133189pubmed: 31261851google scholar: lookup
              21. Nichols AEC, Best KT, Loiselle AE. The cellular basis of fibrotic tendon healing: challenges and opportunities.. Transl Res 2019 Jul;209:156-168.
                doi: 10.1016/j.trsl.2019.02.002pubmed: 30776336google scholar: lookup
              22. Brandt L, Schubert S, Scheibe P, Brehm W, Franzen J, Gross C, Burk J. Tenogenic Properties of Mesenchymal Progenitor Cells Are Compromised in an Inflammatory Environment.. Int J Mol Sci 2018 Aug 28;19(9).
                doi: 10.3390/ijms19092549pubmed: 30154348google scholar: lookup
              23. Tang C, Chen Y, Huang J, Zhao K, Chen X, Yin Z, Heng BC, Chen W, Shen W. The roles of inflammatory mediators and immunocytes in tendinopathy.. J Orthop Translat 2018 Jul;14:23-33.
                doi: 10.1016/j.jot.2018.03.003pubmed: 30035030google scholar: lookup
              24. Klatte-Schulz F, Minkwitz S, Schmock A, Bormann N, Kurtoglu A, Tsitsilonis S, Manegold S, Wildemann B. Different Achilles Tendon Pathologies Show Distinct Histological and Molecular Characteristics.. Int J Mol Sci 2018 Jan 30;19(2).
                doi: 10.3390/ijms19020404pubmed: 29385715google scholar: lookup
              25. Biasutti S, Dart A, Smith M, Blaker C, Clarke E, Jeffcott L, Little C. Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy.. PLoS One 2017;12(10):e0185282.
                doi: 10.1371/journal.pone.0185282pubmed: 29023489google scholar: lookup
              26. Stolk M, Klatte-Schulz F, Schmock A, Minkwitz S, Wildemann B, Seifert M. New insights into tenocyte-immune cell interplay in an in vitro model of inflammation.. Sci Rep 2017 Aug 29;7(1):9801.
                doi: 10.1038/s41598-017-09875-xpubmed: 28851983google scholar: lookup
              27. Watts AE, Millar NL, Platt J, Kitson SM, Akbar M, Rech R, Griffin J, Pool R, Hughes T, McInnes IB, Gilchrist DS. MicroRNA29a Treatment Improves Early Tendon Injury.. Mol Ther 2017 Oct 4;25(10):2415-2426.
                doi: 10.1016/j.ymthe.2017.07.015pubmed: 28822690google scholar: lookup
              28. Millar NL, Murrell GA, McInnes IB. Inflammatory mechanisms in tendinopathy - towards translation.. Nat Rev Rheumatol 2017 Jan 25;13(2):110-122.
                doi: 10.1038/nrrheum.2016.213pubmed: 28119539google scholar: lookup
              29. Linderman SW, Gelberman RH, Thomopoulos S, Shen H. Cell and Biologic-Based Treatment of Flexor Tendon Injuries.. Oper Tech Orthop 2016 Sep;26(3):206-215.
                doi: 10.1053/j.oto.2016.06.011pubmed: 28042226google scholar: lookup
              30. Hudgens JL, Sugg KB, Grekin JA, Gumucio JP, Bedi A, Mendias CL. Platelet-Rich Plasma Activates Proinflammatory Signaling Pathways and Induces Oxidative Stress in Tendon Fibroblasts.. Am J Sports Med 2016 Aug;44(8):1931-40.
                doi: 10.1177/0363546516637176pubmed: 27400714google scholar: lookup
              31. Dakin SG, Martinez FO, Yapp C, Wells G, Oppermann U, Dean BJ, Smith RD, Wheway K, Watkins B, Roche L, Carr AJ. Inflammation activation and resolution in human tendon disease.. Sci Transl Med 2015 Oct 28;7(311):311ra173.
                doi: 10.1126/scitranslmed.aac4269pubmed: 26511510google scholar: lookup
              32. Peffers MJ, Thorpe CT, Collins JA, Eong R, Wei TK, Screen HR, Clegg PD. Proteomic analysis reveals age-related changes in tendon matrix composition, with age- and injury-specific matrix fragmentation.. J Biol Chem 2014 Sep 12;289(37):25867-78.
                doi: 10.1074/jbc.M114.566554pubmed: 25077967google scholar: lookup
              33. Dakin SG, Dudhia J, Smith RK. Resolving an inflammatory concept: the importance of inflammation and resolution in tendinopathy.. Vet Immunol Immunopathol 2014 Apr 15;158(3-4):121-7.
                doi: 10.1016/j.vetimm.2014.01.007pubmed: 24556326google scholar: lookup
              34. Dakin SG, Smith RK, Heinegård D, Önnerfjord P, Khabut A, Dudhia J. Proteomic analysis of tendon extracellular matrix reveals disease stage-specific fragmentation and differential cleavage of COMP (cartilage oligomeric matrix protein).. J Biol Chem 2014 Feb 21;289(8):4919-27.
                doi: 10.1074/jbc.M113.511972pubmed: 24398684google scholar: lookup
              35. Smith RK, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy.. PLoS One 2013;8(9):e75697.
                doi: 10.1371/journal.pone.0075697pubmed: 24086616google scholar: lookup
              36. Zheng Y, Luo N, Mu D, Jiang P, Liu R, Sun H, Xiong S, Liu X, Wang L, Chu Y. Lipopolysaccharide regulates biosynthesis of cystathionine γ-lyase and hydrogen sulfide through Toll-like receptor-4/p38 and Toll-like receptor-4/NF-κB pathways in macrophages.. In Vitro Cell Dev Biol Anim 2013 Oct;49(9):679-88.
                doi: 10.1007/s11626-013-9659-4pubmed: 23877364google scholar: lookup
              37. Zhou HY, Hao JL, Bi MM, Wang S, Zhang H, Zhang WS. Molecular mechanism of the inhibition effect of Lipoxin A4 on corneal dissolving pathology process.. Int J Ophthalmol 2013;6(1):39-43.
                doi: 10.3980/j.issn.2222-3959.2013.01.08pubmed: 23550231google scholar: lookup
              38. Dakin SG, Dudhia J, Werling NJ, Werling D, Abayasekara DR, Smith RK. Inflamm-aging and arachadonic acid metabolite differences with stage of tendon disease.. PLoS One 2012;7(11):e48978.
                doi: 10.1371/journal.pone.0048978pubmed: 23155437google scholar: lookup
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