title: Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing.
abstract: OBJECTIVE
  The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound healing, we investigated rate of healing, leukocyte infiltration, and expression of cytokines, interleukin-8 and interleukin-6, and neuropeptides, substance P, and neuropeptide Y.
  
  
  METHODS
  Diabetes was induced in New Zealand White rabbits by administering alloxan while control rabbits received saline. Ten days later, animals in both groups underwent surgery. One ear served as a sham, and the other was made ischemic (ligation of central+rostral arteries) or neuroischemic (ischemia+ resection of central+rostral nerves). Four 6-mm punch biopsy wounds were created in both ears and wound healing was followed for 10 days using computerized planimetry.
  
  
  RESULTS
  Nondiabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high proinflammatory cytokine expression, both indicators of chronic proinflammatory state, and low neuropeptide expression were seen in preinjury diabetic skin. Postinjury, in diabetic wounds, the M1/M2 ratio remained high, the reactive increase in cytokine expression was low, and neuropeptide expression was further decreased in neuroischemic wounds.
  
  
  CONCLUSIONS
  This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount postinjury cytokine response as well as a diminished neuropeptide expression, contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound-healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes.
authors.affiliation: Department of Surgery, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Pradhan Nabzdyk
authors.forename: Sarada
authors.initials: S
authors.lastname: Kuchibhotla
authors.forename: Patrick
authors.initials: P
authors.lastname: Guthrie
authors.forename: Maggie
authors.initials: M
authors.lastname: Chun
authors.forename: Michael E
authors.initials: ME
authors.lastname: Auster
authors.forename: Christoph
authors.initials: C
authors.lastname: Nabzdyk
authors.forename: Steven
authors.initials: S
authors.lastname: Deso
authors.forename: Nicholas
authors.initials: N
authors.lastname: Andersen
authors.forename: Charalambos
authors.initials: C
authors.lastname: Gnardellis
authors.forename: Frank W
authors.initials: FW
authors.lastname: LoGerfo
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D007511:Ischemia / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012883:Skin Ulcer / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D009479:Neuropeptides