%0 Journal Article
%T The PPAR¦Ă Agonist Rosiglitazone Is Antifibrotic for Scleroderma Lung Fibroblasts: Mechanisms of Action and Differential Racial Effects
%A Galina S. Bogatkevich
%A Kristin B. Highland
%A Tanjina Akter
%A Richard M. Silver
%J Pulmonary Medicine
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/545172
%X We present novel data demonstrating that the expression of PPAR¦Ă is reduced in lung fibroblasts from black SSc-ILD patients as compared to white patients. Activating PPAR¦Ă with the agonist rosiglitazone increased the expression of MMP-1 and inhibited collagen type I in lung fibroblasts isolated from white, but not black, SSc-ILD patients. Blocking the c-Met receptor abolishes rosiglitazone's effects on collagen and MMP-1 in lung fibroblasts isolated from white SSc-ILD patients, while augmenting the expression of the c-Met receptor in fibroblasts from black SSc-ILD patients replicates the effects of rosiglitazone seen in whites. We conclude that PPAR¦Ă agonists warrant consideration as potential antifibrotic drugs in patients with SSc-ILD. Differential therapeutic effects might be anticipated especially relative to racial differences and the functional expression of the c-Met receptor. 1. Introduction PPAR¦Ă is a ligand-dependent transcription factor belonging to the nuclear steroid/retinoid/vitamin D receptor superfamily that plays a pivotal role in the regulation of adipogenesis, insulin sensitivity, glucose homeostasis, and immune response (reviewed in [1, 2]). Activation of PPAR¦Ă inhibits the proinflammatory effects of lipopolysaccharide and various cytokines on immune cells. PPAR¦Ă is detectable in normal lung where it is expressed in epithelial cells, smooth muscle cells, and alveolar macrophages [3¨C5]. Reduced PPAR¦Ă nuclear protein and gene expression has been demonstrated in dermal fibroblasts and in lung and skin biopsies from patients with SSc [6, 7], and in alveolar macrophages of patients with sarcoidosis and pulmonary alveolar proteinosis [4, 8], suggesting that insufficient PPAR¦Ă activity may contribute to ongoing dysregulated inflammation and fibrosis. In normal skin fibroblasts, ligand activation of cellular PPAR¦Ă has been shown to reduce basal collagen gene expression and abrogate TGF-¦Â-induced stimulation [9]. PPAR¦Ă ligands also abrogate TGF-¦Â-induced expression of ¦Á-SMA, a marker of myofibroblasts, and suppress stimulation of Smad-dependent transcriptional responses to TGF-¦Â [9]. Recently, Kapoor et al. demonstrated that a loss of PPAR¦Ă in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis [10]. Activating PPAR¦Ă with rosiglitazone was shown to alleviate the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts [6] and to attenuate inflammation, dermal fibrosis, and subcutaneous lipoatrophy in a murine model of scleroderma [11], suggesting that PPAR¦Ă ligands may be considered as
%U http://www.hindawi.com/journals/pm/2012/545172/