S-allylmercapto-N-acetylcysteine ameliorates pulmonary fibrosis in mice via Nrf2 pathway activation and NF-κB, TGF-β1/Smad2/3 pathway suppression

Pulmonary fibrosis (PF) is a chronic lung disease characterised by alveolar inflammatory injury, alveolar septal thickening, and eventually fibrosis. Patients with severe Coronavirus Disease 2019 (COVID-19) may have left a certain degree of pulmonary fibrosis. PF is commonly caused by oxidative imbalance and inflammatory damage. S-allylmercapto-N-acetylcysteine (ASSNAC) exhibits anti-oxidative and anti-inflammatory effects in other diseases. However, the pharmacodynamics of ASSNAC remain unclear for PF. This investigation aimed to evaluate the efficacy and mechanism of ASSNAC against PF. The PF model was established by TGF-β1 stimulating HFL-1 cells in vitro. ASSNAC exhibited the potential to inhibit fibroblast transformation into myofibroblasts. Also, in the PF mice model with bleomycin (BLM), the sodium salt of ASSNAC (ASSNAC-Na) inhalation was treated. ASSNAC remarkably improved mice's lung tissue structure and collagen deposition. The important indicator proteins of PF, collagen Ⅰ, collagen Ⅲ, and α-SMA significantly decreased in the ASSNAC treated groups. Besides, ASSNAC attenuated oxidative stress by reversing glutathione (GSH), superoxide dismutase (SOD) levels and interfering with Nrf2/NOX4 signaling pathways. ASSNAC showed an anti-inflammatory effect by reducing the number of inflammatory cells and inflammatory cytokines, such as TNF-α and IL-6, and blocking the NF-κB signaling pathway. ASSNAC inhibited fibroblast differentiation by blocking the TGF-β1/Smad2/3 signaling pathway. This study implicates that ASSNAC alleviates pulmonary fibrosis through fighting against oxidative stress, reducing inflammation and inhibiting fibroblast differentiation. [Display omitted] •ASSNAC is first time proposed to treat pulmonary fibrosis through multiple ways.•ASSNAC activates Nrf2/NOX4 signaling pathway in vivo and in vitro and provides GSH to play antioxidant role.•ASSNAC activates NF-κB signaling pathway in vivo and in vitro and reduces inflammatory response to play an anti-fibrosis role.•ASSNAC alleviates pulmonary fibrosis by inhibiting TGF-β1/Smad2/3 signaling pathway in vivo and in vitro.•Inhalable administration is better than oral for lung diseases.