Topical Application of a Peptide Inhibitor of Transforming Growth Factor-β1 Ameliorates Bleomycin-Induced Skin Fibrosis

Abstract

Transforming growth factor-beta (TGF-beta) plays a crucial role in the pathogenesis of skin fibrotic diseases. Systemic TGF-beta inhibitors effectively inhibit fibrosis in different animal models; however, systemic inhibition of TGF-beta raises important safety issues because of the pleiotropic physiological effects of this factor. In this study, we have investigated whether topical application of P144 (a peptide inhibitor of TGF-beta1) ameliorates skin fibrosis in a well-characterized model of human scleroderma. C3H mice received daily subcutaneous injections of bleomycin for 4 wk, and were treated daily with either a lipogel containing P144 or control vehicle. Topical application of P144 significantly reduced skin fibrosis and soluble collagen content. Most importantly, in mice with established fibrosis, topical treatment with P144 lipogel for 2 wk significantly decreased skin fibrosis and soluble collagen content. Immunohistochemical studies in P144-treated mice revealed a remarkable suppression of connective tissue growth factor expression, fibroblast SMAD2/3 phosphorylation, and alpha-smooth muscle actin positive myofibroblast development, whereas mast cell and mononuclear cell infiltration was not modified. These data suggest that topical application of P144, a peptide inhibitor of TGF-beta1, is a feasible strategy to treat pathological skin scarring and skin fibrotic diseases for which there is no specific therapy.

Recombinant human anti–transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo‐controlled phase I/II trial of CAT‐192

“…There is a large body of indirect evidence implicating the overexpression of TGF␤ ligand or receptor in the pathogenesis of SSc (23), and several recent studies have demonstrated that blocking TGF␤ ligand may abrogate fibrosis in a number of mouse models (24). In addition, activation of TGF␤ signaling pathways constitutively in fibroblasts replicates many of the key histologic and biochemical features of established SSc (25).…”

Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage

“…[42][43][44][45] We show that intraperitoneal administration of these blocking peptides to mice exposed to PD fluid preserved the peritoneal morphology and function and decreased the accumulation of different subpopulations of "fibroblast-specific protein-1" (FSP-1) fibroblasts, especially of those co-expressing the mesothelial marker cytokeratin. These cells with intermediate phenotype (Cyto ϩ /FSP-1 ϩ ) displayed myofibroblastlike characteristics including fibrogenic capacity.…”

“…This dose of P17 was similar to that used in previous studies. [42][43][44][45] For quantitative RT-PCR analysis, mesothelial cells were lysed in TRI reagent (Ambion, Inc., Austin, TX), and RNA was extracted as per fabricant instructions. Complementary DNA was synthesized from 2 g of total RNA by reverse transcription (RNA PCR Core Kit, Applied Biosystems, Inc.).…”

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

“…Both cytokines are up-regulated in the skin of SSc patients and strongly stimulate matrix synthesis by dermal fibroblasts. Accordingly, blockade of TGF␤ or PDGF signaling has been shown to reduce the development of fibrosis in various experimental models (6)(7)(8)(9). However, substances that specifically inhibit PDGF pathways are not yet available for clinical application.…”