title: Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat.
abstract: OBJECTIVE
  Chemokines are major promoters of repair and may regulate nerve ingrowth that is essential in tendon healing. The purpose of this study was to assess the temporal occurrence of different chemokines during Achilles tendon healing in relation to sensory nerve regeneration. Chemokine presence in tendon healing has not been studied previously.
  
  
  METHODS
  Chemokine expression, nerve regeneration, angiogenesis and inflammatory cell occurrence during healing of Achilles tendon rupture in the rat were studied by immunohistochemistry and histology including semiquantitative assessment. Markers for chemokines (CCL5, CCL2, CCL3, CXCL10), nerves (PGP-9.5) and sensory neuropeptide substance P (SP) were analysed at different time points (1 day-16 weeks) post-rupture.
  
  
  RESULTS
  In intact tendons (controls) immunoreactivity to all chemokines, PGP-9.5 and SP were confined to the tendon surroundings. After rupture, there was rapid increase in the tendon proper of the chemokines studied, all exhibiting their peak expression at week 1. Subsequently, at weeks 2-6, emerging inflammatory cells and maximum sprouting of PGP-/SP-positive nerves were observed close to newly formed blood vessels within the tendon proper, while chemokine expression already decreased. During weeks 6-8, PGP-/SP-positive nerves withdrew from the rupture site and relocated together with the chemokines in the surrounding tendon.
  
  
  CONCLUSIONS
  Early chemokine expression in the healing tendon precedes ingrowth of new nerves, angiogenesis and emergence of inflammatory cells. The fine-tuned temporal and spatial appearance of chemokines suggests a chemoattractant role for inflammatory cell migration and possibly also a role in angiogenesis and neurogenesis. Chemokines may thus exhibit vital targets for biological modulation of tendon repair.
authors.affiliation: Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden, anders.stalman@ki.se.
authors.forename: A
authors.initials: A
authors.lastname: Stålman
authors.forename: D
authors.initials: D
authors.lastname: Bring
authors.forename: P W
authors.initials: PW
authors.lastname: Ackermann
mesh_terms: D000125:Achilles Tendon / Q000276:immunology / Q000293:injuries / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054405:Chemokine CCL3 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012421:Rupture; D013373:Substance P / Q000096:biosynthesis; D013708:Tendon Injuries / Q000276:immunology / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis; D014945:Wound Healing / Q000502:physiology
chemical_list: D015415:Biomarkers; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D018925:Chemokines; C091326:Cxcl10 protein, rat; C482860:UCHL1 protein, human; D013373:Substance P; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase