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 R(3)IGF-I (LR(3)
IGF-I, an
IGF-I analogue with low affinity for IGFBPs) is unaffected. On the basis of these findings, the transport of
IGF-I and
LR(3)IGF-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 (125)I-IGF-I or (125)I-LR(3)IGF-I (10x10(6) 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. (125)I-LR(3)IGF-I was removed from the circulation more rapidly than (125)I-IGF-I in both
sham control and chamber implanted rats. Although implantation of the chambers did not alter the pharmacokinetic parameters of (125)I-IGF-I, significant increases in the steady state volume of distribution, clearance rate and half-life were recorded for (125)I-LR(3)IGF-I. In addition, significantly more intact (125)I-LR(3)IGF-I was recovered in
wound fluid than (125)I-IGF-I at each time point, although only 0.08% of administered (125)I-LR(3)IGF-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 (125)I-IGF-I was detected in the 150 kDa region 30 min after injection. A greater proportion of (125)I-LR(3)IGF-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.