Alleviation of pulmonary fibrosis by the dual PPAR agonist saroglitazar and breast milk mesenchymal stem cells via modulating TGFß/SMAD pathway.
Seba Hassan AttiaSara F SaadawySamaa M El-MahrokyMahitab M NageebPublished in: Naunyn-Schmiedeberg's archives of pharmacology (2024)
Pulmonary fibrosis (PF) is a complex disorder with high morbidity and mortality. Limited efficacies of the available drugs drive researchers to seek for new therapies. Saroglitazar (Saro), a full (PPAR α/γ) agonist, is devoid of known PPAR-mediated adverse effects. Breast milk mesenchymal stem cells (BrMSCs) are contemplated to be the ideal cell type harboring differentiation/anti-inflammatory/immunosuppressive properties. Accordingly, our aims were to investigate the potential roles of Saro and/or BrMSCs in PF and to spot their underlying protective mechanisms. In this study, PF was induced by bleomycin (BLM) via intratracheal instillation. Treatment started 14 days later. Animals were treated with oral saroglitazar (3 mg/kg daily) or intraperitoneal single BrMSCs injection (0.5 ml phosphate buffer saline (PBS) containing 2 × 10 7 cells) or their combination with same previous doses. At the work end, 24 h following the 6 weeks of treatment period, the levels of oxidative (MDA, SOD), inflammatory (IL-1ß, IL-10), and profibrotic markers (TGF-ß, αSMA) were assessed. The autophagy-related genes (LC3, Beclin) and the expression of PPAR-α/γ and SMAD-3/7 were evaluated. Furthermore, immunohistochemical and histological work were evaluated. Our study revealed marked lung injury influenced by BLM with severe oxidative/inflammatory/fibrotic damage, autophagy inhibition, and deteriorated lung histology. Saro and BrMSCs repaired the lung structure worsened by BLM. Treatments greatly declined the oxidative/inflammatory markers. The pro-fibrotic TGF-ß, αSMA, and SMAD-3 were decreased. Contrarily, autophagy markers were increased. SMAD-7 and PPAR α/γ were activated denoting their pivotal antifibrotic roles. Co-administration of Saro and BrMSCs revealed the top results. Our findings support the study hypothesis that Saro and BrMSCs can be proposed as potential treatments for IPF.
Keyphrases
- pulmonary fibrosis
- transforming growth factor
- mesenchymal stem cells
- epithelial mesenchymal transition
- oxidative stress
- signaling pathway
- insulin resistance
- cell death
- idiopathic pulmonary fibrosis
- endoplasmic reticulum stress
- anti inflammatory
- induced apoptosis
- bone marrow
- physical activity
- cell cycle arrest
- single cell
- type diabetes
- skeletal muscle
- simultaneous determination
- high resolution
- smoking cessation
- human health