Sivelestat sodium: a novel therapeutic agent in a mouse model of acute exacerbation pulmonary fibrosis through multiple mechanisms.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe condition with high morbidity and mortality, characterized by increased inflammation, oxidative stress, apoptosis and epithelial barrier damage. However, there are a few drugs available for the treatment of AE-IPF. Although sivelestat sodium (SIV) has been shown to be an effective agent for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) through various mechanisms, including reduction of inflammation and oxidative stress, the therapeutic potential of SIV in managing AE-IPF remains limited. This study aims to investigate the protective potential of SIV in AE-IPF mouse model through multiple mechanisms. Methods: Male C57BL/6J mice were used to establish the acute exacerbation of pulmonary fibrosis (AE-PF) mouse model through intratracheal instillation of bleomycin (BLM) followed by lipopolysaccharide (LPS). SIV was administered intraperitoneally at a dose of 100 mg/kg daily for 3 or 7 days post-LPS challenge. The therapeutic efficacy was assessed through micro-computed tomographic (Micro-CT), histopathological analysis, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and Western blotting. Results: SIV significantly alleviated AE-PF symptoms in mice, as demonstrated by reductions in inflammation, structural damage, and collagen formation. Additionally, SIV reduced neutrophil elastase (NE) activity, highlighting its pharmacological effectiveness. Importantly, SIV reduced oxidative stress in AE-PF mice by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway, leading to increased superoxide dismutase (SOD) activity and decreased reactive oxygen species (ROS) levels. Furthermore, SIV significantly reduced lung inflammation, as evidenced by decreased interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) levels in bronchoalveolar lavage fluid (BALF), possibly mediated by the inhibition of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. Moreover, SIV exhibited anti-apoptotic properties by modulating the B-cell lymphoma 2 (Bcl-2)/BCL2-associated X protein (Bax)/cleaved caspase-3 pathway. Meanwhile, SIV improved epithelial barrier integrity, as shown by enhanced expression of tight junction proteins and adherens junction protein. Conclusions: SIV demonstrates significant protective effects in AE-PF mice by mitigating inflammation, oxidative stress, apoptosis, and preserving epithelial barrier integrity. These findings suggest that SIV is a promising therapeutic candidate for the treatment of AE-IPF.