Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis

Abstract

Background: Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPARγ ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. Methods: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- β (TGF-β) for 6 h. Results: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day –7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-α production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-β-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. Conclusion: These results suggest that activation of PPARγ ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-α, procollagen I and CTGF expression. Beneficial effects of this PPARγ ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARγ as a molecular target in fibroproliferative lung diseases.

Pioglitazone attenuates endotoxin-induced acute lung injury by reducing neutrophil recruitment

“…Consequently, PPAR-a and PPAR-c agonists may be helpful in the treatment of acute inflammatory diseases, such as ALI [13]. In this context, several studies have proven a beneficial role for PPAR-c agonists in models of allergic airway inflammation and bleomycin-induced ALI [14,15].…”

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts

“…PPAR␥ ligands, such as the thiazolidinedione (TZD) class of anti-diabetic drugs (e.g. pioglitazone, rosiglitazone, ciglitazone, and troglitazone), inhibit the expression of various inflammatory proteins like inducible nitric-oxide synthase, tumor necrosis factor-␣ (TNF␣), and matrix metallopeptidase (MMP9) in macrophages (37) and suppress the fibrosis of lung fibroblasts (35,38,39), dermal fibroblasts (40), and retinal pigment epithelial cells (41). The mechanism of action of PPAR␥ ligands is under investigation but involves both PPAR␥-dependent and PPAR␥-independent pathways (35).…”

Dysregulation of Claudin-5 in HIV-induced Interstitial Pneumonitis and Lung Vascular Injury. Protective Role of Peroxisome Proliferator–activated Receptor-γ

“…Pulmonary fibrosis and impaired lung function are the most serious complications of bleomycin treatment. In vivo studies showed that both natural and synthetic PPAR-g agonists suppressed bleomycininduced lung injury and fibrosis (43), and also inhibited inflammation, as well as skin and lung fibrosis in a murine model of scleroderma (44).…”