3,4-Dimethoxycinnamic acid from coffee silverskin biowaste ameliorates bleomycin-induced pulmonary fibrosis via modulating caveolin-1-dependent activation of NF-κB, TGF-β1/Smad3, and ERK1/2 signaling pathways

The aim of the current study was to explore the potential beneficial effect of 3,4-dimethoxycinnamic acid (DMCA), obtained from coffee silverskin (CS) biowaste, on bleomycin-induced lung fibrosis in rats and elucidate its possible underlying mechanisms. Lung fibrosis was induced in rats by a single intratracheal administration of bleomycin. DMCA (25 and 50 mg/kg) and pirfenidone (50 mg/kg) were orally administered. Our results showed that DMCA markedly reduced lactate dehydrogenase activity, total protein content, and total and differential inflammatory cell counts in the bronchoalveolar lavage fluid. DMCA also inhibited oxidative stress and nuclear factor kappa B (NF-κB)-mediated tumor necrosis factor and interleukin-1β production. Furthermore, DMCA markedly downregulated the pulmonary levels of transforming growth factor beta 1 (TGF-β1), SMAD family member 3 (Smad3), and extracellular signal-regulated kinase 1/2 (ERK1/2), concurrently with a marked reduction in collagen-1 expression in the lung. Contrarily, DMCA upregulated lung caveolin-1 expression. These findings were concomitantly accompanied by remarkable improvement in the lung histopathology. In conclusion, DMCA effectively mitigates bleomycin-induced lung fibrosis in rats, which is comparable to pirfenidone, through antioxidant, anti-inflammatory, and anti-fibrotic effects. These beneficial effects are mainly mediated through boosting caveolin-1 expression that halts NF-κB, TGF-β1/smad3, and ERK1/2 signaling pathways.