We present novel data demonstrating that the expression of PPARγ is reduced in lung fibroblasts from black SSc-ILD patients as compared to white patients. Activating PPARγ 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 PPARγ 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 PPARγ 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 PPARγ inhibits the proinflammatory effects of lipopolysaccharide and various cytokines on immune cells. PPARγ is detectable in normal lung where it is expressed in epithelial cells, smooth muscle cells, and alveolar macrophages [3–5]. Reduced PPARγ 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 PPARγ activity may contribute to ongoing dysregulated inflammation and fibrosis. In normal skin fibroblasts, ligand activation of cellular PPARγ has been shown to reduce basal collagen gene expression and abrogate TGF-β-induced stimulation [9]. PPARγ ligands also abrogate TGF-β-induced expression of α-SMA, a marker of myofibroblasts, and suppress stimulation of Smad-dependent transcriptional responses to TGF-β [9]. Recently, Kapoor et al. demonstrated that a loss of PPARγ in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis [10]. Activating PPARγ 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 PPARγ ligands may be considered as
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