The PPAR-gamma agonist pioglitazone alleviates bleomycin-induced lung fibrosis in male BALB/c mice
Keywords:
pulmonary fibrosis, inflammation, bleomycin, pioglitazone, PPARGAbstract
Background: Many transcription factors may be involved in the pathogenesis of pulmonary fibrosis (PF). One such factor is PPARG. The PPARG agonist, pioglitazone (PG), has demonstrated general lung protective activity in animal models and is considered a promising therapeutic agent for fibrotic intervention. This study aimed to investigate the effect of PG on the expression of connective tissue remodeling genes in the lungs using bleomycin (BLM)-induced lung fibrosis (BIF).
Methods: The study was conducted on male BALB/c mice. PF was induced by pretreatment with bleomycin sulfate and cyclophosphamide. The mice were randomly divided into 3 groups: the first group was administered BLM at a dose of 0.15 U/kg in 50 µl of sterile saline (0.9% NaCl), and the second group was administered 50 µl of saline. The third group was not induced with pulmonary fibrosis and served as a control group. On the 4th day of the experiment, animals from the first and second groups were randomly divided into animals that received PG orally at a dose of 20 mg/kg or saline (40 µl) for 14 days. 4-hydroxyproline was determined in right lung tissue samples. Gene expression was determined using real-time PCR.
Results: PG administration to BIF mice resulted in a significant reduction and normalization of the total number of BAL cells, fibrosis score, mRNA expression of genes associated with connective tissue – Col1a1 (P=0.0466), Col3a1 (P=0.0053), Mmp2 (P=0.0006), Tgfb2 (P=0.0459), and Tgfb3 (P=0.0017), as well as mRNA of genes regulating lung connective tissue inflammation and fibrosis – Mrc1 (P=0.0263), Edn1 (P=0.0012), Pparg (P=0.0044), Nr1d1 (P=0.0053) and Fn1 (P=0.0125).
Conclusions: PPARG activation by PG alleviates BIF by decreasing collagen deposition, Col1a1 and Col3a1 mRNA expression, remodeling of lung tissue (decreasing Mmp2, Edn1, and Fn1 mRNA), and M2-specific profibrotic macrophage Mrc1 mRNA.
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