Transport of circulating IGF-I and LR3IGF-I from blood to extracellular wound fluid sites in rats

Abstract

Significant levels of IGF-I are found in wound fluid. The contribution that systemic IGF-I makes to the total IGF-I pool in wounds and the influence of IGF binding proteins (IGFBPs) on the delivery of systemic IGF-I to these wound sites has not been established. In the present series of experiments, we have shown that IGF-I flux across a model endothelial cell barrier is decreased in the presence of IGFBPs, whereas flux of Long R3IGF-I (LR3IGF- I, an IGF-I analogue with low affinity for IGFBPs) is unaffected. On the basis of these findings, the transport of IGF-I and LR3IGF-I from blood to extracellular wound fluid was assessed. Wound chambers were implanted subcutaneously in the backs of adult male rats and left in place for 14 days. A single i.v. bolus of either 125I-IGF-I or 125I-LR3IGF-I (10 x 106 c.p.m.) was administered via a jugular catheter and wound fluid and plasma samples taken at sequential time points between 5 and 240 min. 125I- LR3IGF-I was removed from the circulation more rapidly than 125I-IGF-I in both sham control and chamber implanted rats. Although implantation of the chambers did not alter the pharmacokinetic parameters of 125I-IGF-I, significant increases in the steady state volume of distribution, clearance rate and half-life were recorded for 125I-LR3IGF-I. In addition, significantly more intact 125I-LR3IGF-I was recovered in wound fluid than 125I-IGF-I at each time point, although only 0.08% of administered 125I-LR3IGF-I was recovered per ml of wound fluid at 240 min. Compared with plasma, a greater proportion of wound fluid IGF-I radioactivity had distributed to the lower molecular weight IGFBPs or existed as free peptide. However, a small amount of wound fluid 125I-IGF-I was detected in the 150 kDa region 30 min after injection. A greater proportion of 125I-LR3IGF-I was associated with the lower molecular weight IGFBPs or existed as free peptide in both wound fluid and plasma. These data point to the importance of IGFBPs in determining the pharmacokinetic parameters of IGF-I in an extracellular fluid-expanded state. They also suggest only a minor role for endocrine IGF-I in surface wound repair.