Phloridzin mitigates bleomycin-elicited lung fibrosis in Wistar rats: The interplay between antioxidant defenses, inflammatory processes, transforming growth factor beta 1, and autophagy

Pulmonary fibrosis is a serious complication that limits the clinical use of bleomycin (BLM). This study investigated the protective role of phloridzin (PZ) against BLM-induced pulmonary fibrosis in rats. In a rat model of BLM-elicited lung fibrosis, PZ was administered daily at two dose levels for 35 days, beginning 7 days before BLM treatment. PZ significantly reduced the elevated total leukocyte count, neutrophil and lymphocyte percentages, and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid (BALF), while increasing BALF macrophage levels. It also lowered malondialdehyde and increased glutathione concentrations. Furthermore, PZ pre-treatment suppressed transforming growth factor-beta 1, interleukin-1β, and nuclear factor-kappa B, while reducing cleaved caspase-3 expression and restoring beclin-1 tissue levels. Histopathological analysis confirmed these protective effects. Taken together, PZ mitigated oxidative stress, inflammation, and apoptosis, while supporting autophagic activity, thereby demonstrating a strong protective effect against BLM-induced lung fibrosis. Importantly, this work provides the first evidence that PZ may counteract multiple pathological mechanisms of BLM-elicited lung toxicity, positioning it as a promising candidate for therapeutic intervention in drug-induced pulmonary fibrosis.