ABSTRACT
Liver fibrosis is considered an epidemic health problem due to different insults that lead to death. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is one of the newer anti-diabetic drugs used to manage type 2 diabetes mellitus (T2DM). DAPA exerted beneficial effects in many human and rat models due to its antioxidant, anti-inflammatory and antifibrotic activities. AIM: Due to previously reported capabilities related to DAPA, we designed this study to clarify the beneficial role of DAPA in liver fibrosis triggered by common bile duct ligation (CBL) in male rats. METHODS: For 14 or 28 days after CBL procedures, DAPA was administered to the rats orally at a dose of 10 mg/kg once daily. The effects of DAPA were evaluated by assaying liver enzymes, hepatic oxidant/antioxidant parameters, serum levels of tumor necrotic factor alpha (TNF-α), and AMP-activated protein kinase (AMPK). In addition, we measured the hepatic expression of fibrosis regulator-related genes along with evaluating liver histological changes. KEY FINDINGS: DAPA successfully decreased hepatic enzymes and malondialdehyde levels, increased superoxide dismutase activity, elevated catalase levels, decreased serum levels of TNF-α, elevated serum levels of AMPK, decreased liver hydroxyproline content, upregulated Sirt1/PGC1α/FoxO1 liver gene expressions, down-regulated fibronectin-1 (Fn-1), collagen-1 genes in liver tissues, and improved the damaged liver tissues. Deteriorated biochemical parameters and histological liver insults associated with CBL were more pronounced after 28 days, but DAPA administration for 14 and 28 days showed significant improvement in most parameters and reflected positively in the histological structures of the liver. SIGNIFICANCE: The significance of this study lies in the observation that DAPA mitigated CBL-induced liver fibrosis in rats, most likely due to its antioxidant, anti-inflammatory, and antifibrotic effects. These results suggest that DAPA's beneficial impact on liver fibrosis might be attributed to its interaction with the Sirt1/AMPK/PGC1α/FoxO1 pathway, indicating a potential mechanistic action for future exploration.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation ß-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. AIMS: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. MAIN METHODS: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. KEY FINDINGS: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. SIGNIFICANCE: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.
