FGF protection and inhibition of human neutrophil elastase by carboxymethyl benzylamide sulfonate dextran derivatives

Abstract

Several derivatized dextrans (DxD) containing defined percentage of carboxymethyl, carboxymethyl benzylamide and carboxymethyl benzylamide sulfonate 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 ability to interact with, stabilise and protect the heparin-binding growth factor of the fibroblast growth factor family against trypsin digestion (Tardieu et al., J. Cell. Physiol. 1992; 150: 94). The wound healing action of these DxD was explained by postulating that the endogenously released heparin-binding growth factors could be protected within the wound. To further understand the action of these DxD on tissue repair, we have studied their effect on the human neutrophil elastase (HNE) activity, one of the proteases involved in wound repair. These DxD inhibited HNE in an hyperbolic non-competitive manner. Extent of HNE inhibition by DxD increased with their molecular weight and benzylamide sulfonate substitution levels. One DxD, RGTI1, was the best inhibitor (Kl 40 pM) and efficiently inhibited FGF-2 proteolysis by HNE, restoring its growth-promoting activity towards human skin fibroblasts. The data contribute to a better understanding of the wound-healing property and anti-inflammatory activity of these polymers.