Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils andmacrophages during the late phase of repair

Chemokines are seen as the stimuli that largely control leukocyte migration . To assess whether the severely impaired process of cutaneous repair obser ved in genetically diabetic db/db mice is associated with a dysregulated in filtration of immune cells, we determined the expressional kinetics for the murine growth-regulated oncogene/melanoma growth stimulatory activity homo log macrophage inflammatory protein-2, and the macrophage chemoattractant p rotein-1, respectively. Wound repair in db/db mice was characterized by a s ustained inflammatory response and a prolonged expression of macrophage inf lammatory protein-2 and macrophage chemoattractant protein-1. Immuno-histoc hemistry revealed that keratinocytes at the wound margins expressed macroph age chemoattractant protein-1, whereas macrophage inflammatory protein-2 im munopositive signals were observed only in keratinocytes of hair follicles located adjacent to the wound site. Inactivation studies using neutralizing antibodies against macrophage chemoattractant protein-1 or macrophage infl ammatory protein-2 indicated that sustained expression of these chemokines participated in a prolonged presence of neutrophils and macrophages at the wound site during diabetic repair. Furthermore, our data provide evidence t hat late infiltration (day 13 after injury) of neutrophils and macrophages into wounds in db/db mice was associated with a simultaneous downregulation of mRNA for receptors specific for macrophage inflammatory protein-2 and m acrophage chemoattractant protein-1 in these animals.