Bioactive interleukin-8 is expressed in wounds and enhances wound healing

Background, Wound healing is a sequential biological process that involves the integration of chemotaxis of neutrophils, mitosis and migration of kera tinocytes, and remodeling of the scar, all of which are regulated by specif ic soluble mediators. To modulate wound healing specific mediators have to be identified and functionally characterized. Therefore we addressed this s tudy on the polymorphonuclear leukocyte (PMN) attractant interleukin-8 (IL- 8) and its function in epidermal wound healing. Materials and methods. Peptide purification, bioassays for PMN chemotaxis, and sequential IL-8 measurements were performed on human wound fluid from b urn blisters and skin graft donor sites, Histology for IL-8 immunoreactivit y was included. In vitro human keratinocytes were assayed for proliferation , migration, and integrin expression after IL-8 treatment. Wounding experim ents with topical IL-8 were performed in a chimeric mouse model. Results. IL-8 was found to be the major bioactive chemoattractant for PMNs in human blister and skin graft donor site wound fluids (mean levels rangin g from 173 ng/ml Postoperative Day (POD) 1 to 2130 ng/ml (POD 5)). Released intracellular epidermal IL-8 immunoreactivity at the wound edge was consid ered as an immediate source of IL-8 while NH2-terminal analysis revealed th e 77-amino-acid residue form as a second source of IL-8 possibly PMN derive d. In vitro experiments on the effect of recombinant human (rh) IL-8 on ker atinocyte proliferation revealed a rise in cell number (4.8-fold, ED50 = 0. 6 ng/ml), which was accompanied by an increase in cells in S phase and over expression of the integrin subunit alpha 6. In vivo topically applied IL-8 (1 mu g/ml) on human skin grafts in a chimeric mouse model enhanced reepith elialization in IL-8 treated animals over controls due to elevated numbers of mitotic keratinocytes. Wound contraction was significantly diminished by topical IL-8. Conclusions. These results indicate the sequential function of endogenous I L-8 in all phases of human wound healing. Topical IL-8 may be useful in imp aired wound healing. (C) 2000 Academic Press.