Differential Protective Actions of Dulaglutide and Dexamethasone in Methotrexate Induced Pulmonary Fibrosis: Relationship with AMPK and Beclin-1 Levels.

Background and

Objectives

Pulmonary fibrosis (PF) is a life-threatening respiratory disorder involving complex pathophysiological mechanisms such as inflammation, collagen deposition, and epithelial cell injury. Methotrexate (MTX), a chemotherapeutic and immunosuppressive agent, is frequently associated with pulmonary toxicity, representing a significant adverse effect with unpredictable outcomes. Thus, the current study investigates the possible protective effect of dulaglutide (DUL) against MTX-induced lung injury.

Methods

Sixty male Wistar rats were allocated into six groups: group 1 served as a control group, group 2 received MTX (14 mg/kg/week, p.o) for 2 weeks, group 3 was treated with MTX treatment (14 mg/kg/week, p.o) prior to dexamethasone (DEXA) (0.5 mg/kg/week i.p), Groups 4-5 were treated concurrently with MTX (14 mg/kg/week, p.o) and DUL at doses of 0.05 and 0.1 mg/kg/week, s.c. and Group 6 received DUL (0.1 mg/kg/week, s.c.) only. Animals were sacrificed on day 15 for histopathological and biochemical assessments.

Results

Our data demonstrated that MTX markedly increased some oxidative stress markers, inflammatory biomarkers and fibrotic and apoptotic indicators, alongside a significant decrease in Beclin-1 and Adenosine Monophosphate Activated Protein Kinase (AMPK) levels. DUL administration significantly ameliorated these alternations in a dose-dependent manner, with histopathological findings corroborating biochemical data through Hematoxylin & Eosin (H&E) and Mason's Trichrome (MTC) staining.

Conclusions

DUL confers significant protection against MTX-induced pulmonary fibrosis, likely through its antioxidant, anti-inflammatory, and anti-apoptotic properties, which are associated with the restoration of total AMPK and Beclin-1 levels. This highlights its therapeutic potential in preventing drug-induced lung toxicity.