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- 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 microL/day, i.p., and 15 mL/day, i.v.). TNF rats received TNF i.p. (100 microg/kg per day) and saline i.v. (15 mL/day). TNF+IL-1ra rats received TNF i.p. (100 microg/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.


CONCLUSIONS
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.
Maish
G O
GO
Department of Surgery, Pennsylvania State University, College of Medicine, Hershey 17033, USA.
Shumate
M L
ML
Ehrlich
H P
HP
Vary
T C
TC
Cooney
R N
RN
D000005:Abdomen / Q000601:surgery; D000704:Analysis of Variance; D000818:Animals; D003094:Collagen / Q000378:metabolism; D006097:Granulation Tissue / Q000378:metabolism; D006909:Hydroxyproline / Q000032:analysis; D007262:Infusions, Intravenous; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000276:immunology
D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D006909:Hydroxyproline