INVIVO EFFECTS OF SYSTEMIC INSULIN-LIKE GROWTH FACTOR-I ALONE AND COMPLEXED WITH INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-3 ON CORTICOSTEROID SUPPRESSED WOUNDS

Glucocorticoids are known to decrease wound healing by inhibiting the inflammatory response and collagen synthesis. In patients on steroids requiring emergency surgery, a safe agent that can be administered systemically is needed to reverse the deleterious effects of corticosteroids. TGF-beta and PDGF work topically but are not candidates for systemic administration. IGF-I and IGF-I:BP-3 are logical choices for systemic administration to improve wound healing. Both have been found in our laboratory to repair the corticosteroid-induced defect in wound healing when applied topically; the IGF-I:BP-3 complex gave significantly better results than IGF-I alone. Therefore, we asked whether these agents administered systemically could reverse the impaired wound healing caused by corticosteroids and whether the IGF-I:BP-3 complex was superior. Sprague-Dawley rats 350 g had 4 Hunt-Schilling wire mesh wound cylinders implanted s.c. on the back. Depo-Medrol (8 mg) was given s.c. at the time of surgery. Experimental rats were given daily s.c. injections of IGF-I or IGF-I:BP-3 (supplied by Celtrix Pharm, Santa Clara, CA) in PBS and 0.1% rat serum albumin, pH 6.0. The groups were: vehicle; IGF-I 125 mug/d; IGF-I:BP-3 complex containing 125 mug IGF-I/d. On post-op. day 17, the tissue in the wound cylinders was harvested and dried at 37-degrees-C. Dry weight, DNA, total protein, and hydroxyproline (collagen) contents were obtained by our published procedures. Wound cylinder dry weight, DNA, total protein and hydroxyproline were increased by IGF-I 250%, 340%, 200% and 205%, respectively, over controls. However, the most striking results came from the IGF-I:BP-3 treated group which improved dry weight, DNA, total protein, and hydroxyproline contents, respectively, 360%, 450%, 320%, and 250% over controls and 146%, 130%, 160% and 120% over the best IGF-I response. Both IGF-I and the IGF-I:BP-3 complex reversed the effects of steroids. The greatest improvement was given by the IGF-I:BP-3 complex which was significantly more effective than an equivalent amount of IGF-I alone. The complex of BP-3 with IGF-I may enhance the effect of IGF-I on wound healing by the following mechanisms: 1) preventing the down-regulation of receptors; 2) protecting IGF-I from degradation by wound proteases; 3) increasing the residence time of IGF-I in the wound environment; 4) targeting IGF-I to the wound; and 5) facilitating the presentation of IGF-I to its receptor. This experiment demonstrates that a systemically administered growth factor can enhance wound healing and repair the defect induced by corticosteroids. The IGF-I:BP-3 complex in this experiment was observed to have a greater effect than IGF-I alone and should be safer than IGF-I. The complex may also be useful to correct other catabolic states.