The Red Sea marine fungus Penicillium chrysogenum (Family: Ascomycota) comprises a panel of chemically diverse natural metabolites. A
meleagrin alkaloid was isolated from deep-sediment-derived P. chrysogenum Strain S003 and has been reported to exert antibacterial and cytotoxic activities. The present study aimed to explore the therapeutic potential of
meleagrin on
pulmonary fibrosis. Lung
fibrosis was induced in mice by a single intratracheal instillation of 2.5 mg/kg
bleomycin. Mice were given 5 mg/kg
meleagrin daily either for 3 weeks after
bleomycin administration in the treatment group or 2 weeks before and 3 weeks after
bleomycin administration in the protection group.
Bleomycin triggered excessive ROS production, inflammatory infiltration,
collagen overproduction and
fibrosis.
Bleomycin-induced
pulmonary fibrosis was attenuated by
meleagrin.
Meleagrin was noted to restore the
oxidant-
antioxidant balance, as evidenced by lower MDA contents and higher levels of SOD and
catalase activities and GSH content compared to the
bleomycin group.
Meleagrin also activated the Nrf2/HO-1
antioxidant signaling pathway and inhibited TLR4 and NF-κB gene expression, with a subsequent decreased release of pro-inflammatory
cytokines (TNF-α, IL-6 and IFN-γ). Additionally,
meleagrin inhibited
bleomycin-induced apoptosis by abating the activities of
pro-apoptotic proteins Bax and
caspase-3 while elevating Bcl2. Furthermore, it suppressed the gene expression of α-SMA, TGF-β1, Smad-2,
type I collagen and MMP-9, with a concomitant decrease in the
protein levels of TGF-β1, α-SMA, phosphorylated Smad-2, MMP-9,
elastin and
fibronectin. This study revealed that
meleagrin's protective effects against
bleomycin-induced
pulmonary fibrosis are attributed to its
antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic properties. Notably, the use of
meleagrin as a
protective agent against
bleomycin-induced lung
fibrosis was more efficient than its use as a treatment agent.