Beyond its mucolytic mechanism, carbocisteine protects against cyclophosphamide-induced lung injury by modulating TLR-4/NF-κB signaling, oxidative stress, and PPARγ.

Cyclophosphamide (CP) is prescribed in oncology practice for the management of multiple malignancies. Despite its therapeutic efficacy, its use is frequently accompanied by toxicities, including pulmonary complications. The present investigation explored whether the mucoregulatory compound carbocisteine (S-carboxymethylcysteine; SCMC) could confer protection against CP-provoked acute lung injury. Adult male rats were administered 250 mg/kg/day SCMC orally for seven consecutive days, and a single dose of CP (100 mg/kg) on the fifth day. CP exposure resulted in marked pulmonary injury, as evidenced by histopathological alterations along with increased deposition of collagen, elastic fibers and hemosiderin. CP elevated lung MDA, MPO, TNF-α and IL-1β, and upregulated TLR-4, NF-κB p65, Bax, and cleaved caspase-3. Additionally, administration of CP decreased GSH, SOD, catalase, and Bcl-2. SCMC remarkably mitigated tissue alterations and the deposition of collagen, elastic fibers and hemosiderin. SCMC restored antioxidants and Bcl-2, reduced MDA, MPO, Bax, caspase-3 and inflammatory cytokines, and downregulated TLR-4/NF-κB pathway. SCMC upregulated lung PPARγ in CP-administered rats. In conclusion, SCMC markedly alleviates CP-induced lung injury by attenuating oxidative stress, inflammation, and apoptosis, and modulation of TLR-4/NF-κB pathway and PPARγ. These data support the potential application of SCMC as an adjuvant strategy to limit CP-associated pulmonary toxicity.