Matrix-binding motifs and peptide mimetics as modulators of wound healing and fibrogenesis

摘要

Fibrogenesis can be regarded as a continuous wound-healing process which results in scar formation. In this process the extracellular matrix (ECM) itself directs cellular migration, proliferation and fibrogenic activation or deactivation. The ECM provides specific signals to cells via in part defined oligopeptide sequences or structural domains, resulting either in stress activation, with a resultant fibrogenic response, or in stress relaxation, with a fibrolytic response of fibroblasts, myofibroblasts or hepatic stellate cells. Signal transduction by the ECM converges with that by growth factors or cytokines, and usually only this cosignalling results in the observed growth factor response. ECM molecules also play a prominent role in the regulation of angiogenesis, and collagen-derived peptides can modulate the availability and activity of certain growth factors and matrix metalloproteinases (MMPs) that are stored on the surface of collagen molecules. Identification of the interactive sites allows the development and in vivo application of antifibrotic and antiangiogenic strategies which are based on ECM-derived biomodulatory peptides or peptide sequences. The use of combinatorial chemistry has already led to nonpeptidic organic analogues that allow oral application of such agents with an extended biological half life. Finally, certain peptides can be used to target activation-induced cellular receptors such as certain integrins that are preferentially expressed on the fibrogenic cells.