THE ROLE OF INFLAMMATORY CYTOKINES IN WOUND-HEALING - ACCELERATED HEALING IN ENDOTOXIN-RESISTANT MICE

The role of cytokines in normal wound healing remains poorly defined. In vitro, tumor necrosis factor alpha (TNF-alpha) decreases collagen a ccumulation, perhaps by increasing collagenase activity. The current s tudy was undertaken to test the hypothesis that cytokines impair wound healing and collagen production. Wounds in C3H/HeJ (J) mice, which ar e characterized by a genetic defect in macrophage production of TNF an d other cytokines in response to endotoxin, were compared with wounds in normal endotoxin-sensitive C3H/HeN (N) mice. Methods: TNF (by murin e ELISA) and collagenolytic activity (CA by in vivo labelled collagen fibril degradation assay) were measured in wound fluid from silicone r eservoirs on post-wounding days 1, 3, and 5 (n = 5 per group). Hydroxy proline (HOP, nmol/mg sponge) incorporation (by HPLC) in polyvinylalco hol sponges and breaking strength (BS, as determined by tensiometry) i n linear wounds were assessed on days 5, 7, 10, and 14 (n = 5 per grou p). The data demonstrate significantly increased BS at 5 and 7 days in endotoxin-resistant J mice compared with that in endotoxin-sensitive N mice. An early, significant reduction in TNF production in J mice co rresponded with a significant increase in CA on day 1, increased colla gen production at day 7, and increased procollagen gene transcription at early time points. Conclusion. The reduced production of inflammato ry cytokines including TNF in the wound fluid of J mice corresponded w ith an early improvement in wound tensile strength. An accelerated acc umulation of collagen in the wounds of J mice, perhaps resulting from a significant decrease in collagenolytic activity or increased collage n production, are potential mechanisms. The data suggest that cytokine s produced in normal healing of clean wounds may contribute to a delay in increased tensile strength.