Sivelestat protects against acute lung injury by up-regulating angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptors

Background: Acute lung injury (ALI) and its most severe manifestation of acute respiratory distress syndrome (ARDS) is a disease with a clinical mortality rate of up to 40% and is one of the most dangerous and common complications of severe coronavirus disease 2019 (COVID-19). Sivelestat (SIV) is the only licensed therapeutic medicine in the world for ALI/ARDS treatment. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis is critical in the prevention of ALI/ARDS. This study aims to investigate whether SIV alleviates lipopolysaccharides (LPS)-induced ALI by inhibiting the downregulation of ACE2/Ang-(1-7)/Mas receptor axis expression. Methods: In vivo, 90 male Sprague-Dawley rats were randomized into 5 groups. Then, we pretreated different groups of rats with dexamethasone (DEX) or SIV. Rats were sacrificed at three different time points (3, 6, and 12 hours) following LPS instillation. In vitro, RAW264.7 cells were divided into 11 groups. Different groups of cells were pretreated with DEX or SIV. And then added with LPS for 3, 6, and 12 hours. Next, we introduced A779, a potent Ang-(1-7) receptor antagonist, and DX600 as the ACE2 antagonist in different groups. Then the protein and messenger RNA (mRNA) expression levels of ACE2 in rat lung tissue and the expression levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and Ang-(1-7) in the rat serum and the cell culture supernatant were measured. And the data were statistically analyzed. Results: In vivo, the rats pretreated with SIV or DEX had significantly lower lung wet/dry (W/D) ratios and lung pathological alterations than those exposed to LPS only. Both in vivo and in vitro, we observed that SIV or DEX significantly attenuated the LPS-induced up-regulation of IL-6 and TNF-alpha levels, and the down-regulation of ACE2 and Ang-(1-7) levels. In vitro, the pretreatment of the RAW264.7 cells with DX600 and A779 significantly reduced and even abolished the protective effects of SIV. Conclusions: Therefore, it was concluded that SIV protected against LPS-induced ALI and decreased inflammatory cytokine release by up-regulating the ACE2/Ang-(1-7)/Mas receptor axis. Our results enrich the theoretical foundation for the clinical application of SIV and provide fresh ideas for the treatment of ALI/ARDS.