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Pirfenidone Attenuates The Profibrotic Contractile Phenotype Of Human Dermal Myofibroblasts
Adrienne R. Wells, Kai P. Leung.
US Army Institute of Surgical Research, Fort Sam Houston, TX, USA.

BACKGROUND - Burn injury often results in thick, inflexible hypertrophic scarring with debilitating contractures if occurring across craniofacial regions and joints. This scarring develops from dysregulated wound healing with reduced extracellular matrix turnover, increased matrix production, and the persistence of profibrotic contractile myofibroblasts. These cells are transformed from normal fibroblasts by exposure to transforming growth factor beta 1 (TGF-β1). F-actin stress fibers populated with alpha smooth muscle actin (α-SMA) confer substantial contractile properties to differentiated myofibroblasts. Pirfenidone (Pf), an FDA-approved antifibrotic, significantly reduces the transdifferentiation of normal human dermal fibroblasts (NHDF) into myofibroblasts as shown in vitro with concurrent TGF-β1/Pf treatment. Here we tested the in vitro effects of Pf on the profibrotic phenotype and contractility of established myofibroblasts in 3D collagen lattices and 2D culture conditions. METHODS - NHDF were differentiated into myofibroblasts by 3-5 day TGF-β1 treament. A single dose of Pf was administered and samples were collected over time for immunocytochemistry, Western blot and qRT-PCR. F-actin stress fibers and α-SMA expression were quantified in confocal images. Cell contractility was assessed by treating stressed myofibroblast populated collagen lattices with Pf and measuring the area after release. RESULTS - Pf treatment of established myofibroblasts reduced F-actin and α-SMA in contractile stress fibers. Pf treatment also returned to normal the reduced levels of matrix metalloproteinase gene expression (MMP1) found in myofibroblasts. Finally, Pf treatment reduced collagen lattice contraction. CONCLUSIONS - Pf is a potent antifibrotic with the potential to mitigate excess ECM accumulation and contraction in scars by modulating the structure and function of myofibroblast cells. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government. This work is in part funded through the Congressionally Directed Medical Research Programs, U.S. Army Medical Research and Materiel Command W81XWH-15-2-0083 and the Naval Medical Research Center's Advanced Medical Development program (MIPRN3239815MHX040).

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