Abstract
Pulmonary fibrosis (PF) remains a devastating disease. Copper (Cu), an essential trace element, has been implicated in fibrotic processes in various organs, including the lungs. This study investigated the potential protective effects of trientine (TRI), a copper chelator, against bleomycin (BLM)-induced PF in rats and explored the underlying mechanisms. PF was induced by intratracheal administration of BLM (5 mg/kg). Rats were randomly allocated into seven groups: normal control, TRI alone, BLM control, and four BLM plus TRI prophylactic or therapeutic groups receiving low (55 mg/kg) or high (110 mg/kg) TRI doses orally. Results demonstrated that TRI dramatically reversed BLM-elevated serum levels of lactate dehydrogenase and alkaline phosphatase, markers of tissue damage. The protective effects of TRI were multifaceted: it exhibited potent antifibrotic activity by reducing collagen buildup and inhibiting TGF-β, CTR1, LOX, and COL1 expression; it acted as an antioxidant by increasing antioxidant status and significantly upregulating Nrf2; and it served as an anti-inflammatory agent by decreasing inflammatory cytokines (TNF-α and IL-6) and modulating the NF-κB pathway by increasing NF-κB expression while limiting its activation and nuclear translocation, thereby reducing inflammatory signaling. Histopathological and immunohistochemical analyses confirmed substantial attenuation of collagen deposition and structural lung damage. Overall, TRI demonstrated potent antifibrotic, antioxidant, and anti-inflammatory properties, effectively protecting lung tissue against BLM-induced injury. These findings highlight copper chelation as a promising therapeutic strategy for pulmonary fibrosis and warrant further investigation into TRI’s clinical potential.