Interference with Transforming Growth Factor-beta/ Smad3 Signaling Results in Accelerated Healing of Wounds in Previously Irradiated Skin

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2003 Nov 25

PMID 14633599

Citations 62

Authors

Kathleen C Flanders

Christopher D Major

Alidad Arabshahi

Ekinadese E Aburime

Miya H Okada

Makiko Fujii

Timothy D Blalock

Gregory S Schultz

Anastasia Sowers

Mario A Anzano

James B Mitchell

Angelo Russo

Anita B Roberts

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor (TGF)-beta regulates many aspects of wound repair including inflammation, chemotaxis, and deposition of extracellular matrix. We previously showed that epithelialization of incisional wounds is accelerated in mice null for Smad3, a key cytoplasmic mediator of TGF-beta signaling. Here, we investigated the effects of loss of Smad3 on healing of wounds in skin previously exposed to ionizing radiation, in which scarring fibrosis complicates healing. Cutaneous wounds made in Smad3-null mice 6 weeks after irradiation showed decreased wound widths, enhanced epithelialization, and reduced numbers of neutrophils and myofibroblasts compared to wounds in irradiated wild-type littermates. Differences in breaking strength of wild-type and Smad3-null wounds were not significant. As shown previously for neutrophils, chemotaxis of primary dermal fibroblasts to TGF-beta required Smad3, but differentiation of fibroblasts to myofibroblasts by TGF-beta was independent of Smad3. Previous irradiation-enhanced induction of connective tissue growth factor mRNA in wild-type, but not Smad3-null fibroblasts, suggested that this may contribute to the heightened scarring in irradiated wild-type skin as demonstrated by Picrosirius red staining. Overall, the data suggest that attenuation of Smad3 signaling might improve the healing of wounds in previously irradiated skin commensurate with an inhibition of fibrosis.

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