Interleukin-1 Receptor Antagonist Attenuates Tumor Necrosis Factor-Induced Alterations in Wound Breaking Strength

BACKGROUND:Tumor necrosis factor (TNF) is an important mediator of impaired wound healing during sepsis. To determine whether the inhibitory effects of systemic TNF on wound healing are mediated directly by TNF or by means of the induction of interleukin-1 (IL-1), we investigated the effects of TNF and interleukin-1 receptor antagonist (IL-1ra) on wound healing in healthy rats. METHODS:Male Sprague-Dawley rats were anesthetized, and jugular catheters were placed. After recovery of 48 hours, osmotic minipumps were inserted into the peritoneal cavity and polyvinyl alcohol implants were placed subcutaneously. Control rats were infused with saline (24 μL/day, i.p., and 15 mL/day, i.v.). TNF rats received TNF i.p. (100 μg/kg per day) and saline i.v. (15 mL/day). TNF+IL-1ra rats received TNF i.p. (100 μg/kg per day) and IL-1ra i.v. (2 mg/kg per day;15 mL/day). All animals were pair fed to the TNF group. On day 6, the wounds were harvested. The breaking strength of the abdominal incision was measured. Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol implant histology from 1 to 4 in a blinded manner. Collagen deposition in polyvinyl alcohol implants was quantified by hydroxyproline assay. RESULTS:TNF decreased the breaking strength of incisional wounds to 40% of control levels (p < 0.001). IL-1ra restored the breaking strength of incisions from TNF-infused animals to 80% of control levels. Similar reductions in granulation tissue penetration, quality, and hydroxyproline content were observed in TNF-treated animals and were partially ameliorated by IL-1ra. CONCLUSION:IL-1ra significantly attenuates the inhibitory effects of systemic TNF on wound healing. These results suggest that the inhibitory effects of TNF on cutaneous tissue repair are mediated in part by IL-1.