Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR-gamma as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-gamma in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-gamma agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-gamma agonists, including a constitutively active PPAR-gamma construct (VP16-PPAR-gamma), inhibit the ability of transforming growth factor-beta1 to induce myofibroblast differentiation and collagen secretion. PPAR-gamma agonists also inhibit fibrosis in a murine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR-gamma is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-gamma ligands as novel therapeutic agents for fibrotic lung diseases.

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce fibrosis in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-β (TGF-β) signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy.

Alveolar macrophages abundantly express PPAR-γ, with both natural and synthetic agonists maintaining the cell in a quiescent state hyporesponsive to antigen stimulation. Conversely, agonists upregulate expression and function of the cell-surface receptor CD36, which mediates phagocytosis of lipids, apoptotic neutrophils, and other unopsonized materials. These effects led us to investigate the actions of PPAR-γ agonists on the Fcγ receptor, which mediates phagocytosis of particles opsonized by binding of immunoglobulin G antibodies. We found that troglitazone, rosiglitazone, and 15-deoxy-Δ12,14-prostaglandin J2 increase the ability of alveolar, but not peritoneal, macrophages to carry out phagocytosis mediated by the Fcγ receptor. Receptor expression was not altered but activation of the downstream signaling proteins Syk, ERK-1, and ERK-2 was observed. Although it was previously known that PPAR-γ ligands stimulate phagocytosis of unopsonized materials, this is the first demonstration that they stimulate phagocytosis of opsonized materials as well.

Development of effective therapeutics for chronic wounds remains a formidable clinical challenge. Deficiency of growth factors is of paramount importance among the multitude of factors contributing to the pathogenesis of diabetic wounds. Clinical interest has been witnessed in the past for exogenous applications of platelet derived growth factor B (PDGF-B) in chronic nonhealing wounds. However, accomplishing even modest favorable clinical effects in such topical applications requires large and repeated doses of PDGF-B proteins. Chronic wounds are being increasingly circumvented by gene therapy approach and to this end, cationic liposomes are emerging as promising nonviral carriers for delivering various growth factors encoding therapeutic genes to wound beds. However, as in case of topical application of growth factors, all the prior studies on the use of cationic liposomes in nonviral gene therapy of wounds involved repeated injections of cationic liposome:cDNA complexes over several weeks for ensuring complete wound healing. Herein, we show that a single subcutaneous administration of an electrostatic complex of rhPDGF-B plasmid, integrin receptor selective RGDK-lipopeptide 1 and cholesterol (as auxiliary lipid) is capable of healing wounds in streptozotocin-induced diabetic Sprague-Dawley rats (as model of chronic wounds). Western blot analysis revealed significant expression of rhPDGF-B in mouse fibroblast cells transfected with RGDK-lipopeptide 1:rhPDGF-B lipoplex. The transfection efficiencies of the RGDK-lipopeptide 1 in mouse and human fibroblast cells preincubated with various monoclonal anti-integrin receptor antibodies support the notion that the cellular uptake of the RGDK-lipopeptide 1:DNA complexes in fibroblast cells is likely to be selectively mediated by alpha5beta1 integrin receptors. Findings in the histopathological stainings using both hematoxylin and eosin (H & E) as well as Masson's Trichrome staining revealed a significantly higher degree of epithelization, keratization, fibrocollagenation and blood vessel formation in rats treated with RGDK-lipopeptide 1:rhPDGF compared to those in rats treated with vehicle alone.