FGF PROTECTION AND INHIBITION OF HUMAN NEUTROPHIL ELASTASE BY CARBOXYMETHYL BENZYLAMIDE SULFONATE DEXTRAN DERIVATIVES

Several derivatized dextrans (DxD) containing defined percentage of ca rboxymethyl, carboxymethyl benzylamide and carboxymethyl benzylamide s ulfonate groups have been shown to stimulate tissue repair in various in vivo models including skin, bone, muscle and cornea. These selected DxD were also shown to mimic heparin or heparan sulfate by their abil ity to interact with, stabilise and protect the heparin-binding growth factor of the fibroblast growth factor family against trypsin digesti on (Tardieu et al., J. Cell. Physiol. 1992; 150: 94). The wound healin g action of these DxD was explained by postulating that the endogenous ly released heparin-binding growth factors could be protected within t he wound. To further understand the action of these DxD on tissue repa ir, we have studied their effect on the human neutrophil elastase (HNE ) activity, one of the proteases involved in wound repair. These DxD i nhibited HNE in an hyperbolic non-competitive manner. Extent of HNE in hibition by DxD increased with their molecular weight and benzylamide sulfonate substitution levels. One DxD, RGT11, was the best inhibitor (K-i 40 pM) and efficiently inhibited FGF-2 proteolysis by HNE, restor ing its growth-promoting activity towards human skin fibroblasts. The data contribute to a better understanding of the wound-healing propert y and anti-inflammatory activity of these polymers.