Pharmacological targeting of phosphodiesterase‐5 halts pulmonary fibrosis by suppressing epithelial‐mesenchymal transition via cGMP/PKG/Smad/HDAC2 pathway

BACKGROUND AND PURPOSE: Pulmonary fibrosis (PF) is a progressive and incurable disease with activation of epithelial-mesenchymal transition (EMT) as a crucial pathological step. Despite advances in elucidating its pathogenesis, therapeutic options for PF remain very limited. Although raising intracellular levels of cGMP mitigated fibrosis in animal models, the mechanism(s) underlying this action, particularly concerning EMT, remain unclear. PDE5, a key cGMP-hydrolyzing enzyme, is a promising therapeutic target, as some PDE5 inhibitors are in clinical use. EXPERIMENTAL APPROACH: Two well-established rat models of PF, induced by bleomycin or paraquat were used to elucidate the therapeutic potential and mechanisms underpinning effects of the PDE5 inhibitor tadalafil on pulmonary fibrogenesis. KEY RESULTS: Daily administration of tadalafil attenuated PF development and lung injury. even when administered at an advanced stage of PF, tadalafil significantly attenuated fibrotic progression and improved lung histopathology. Mechanistically, tadalafil exerted its therapeutic effect by suppressing the canonical TGF-β/Smad signaling pathway and EMT through a cGMP/PKG pathway. Immunohistochemical and immunofluorescence analyses corroborated the in‑vivo antifibrotic activity of tadalafil. Preliminary results indicated PKG‑dependent down-regulation of histone deacetylase 2 (HDAC2) expression and elevated acetylated histones. Knockdown and pharmacological inhibition of HDAC2 mimicked effects of tadalafil, whereas over-expression of HDAC2 negated tadalafil's effects on EMT, implying a key mechanistic role for HDAC2. CONCLUSIONS AND IMPLICATIONS: Tadalafil halted progression of PF by inhibiting EMT, most likely through a PKG-mediated pathway counteracting TGF-β-induced HDAC2 expression. Our findings, together with the well-tolerated safety profile. warrant immediate clinical assessment of repurposing tadalafil for the treatment of pulmonary fibrosis.