Sivelestat Sodium Hydrate

Acute lung injury (ALI) is characterized by significant neutrophil infiltration in the lungs, representing a life‐threatening condition with diverse etiologies. However, the mechanisms regulating neutrophil–alveolar epithelial interactions and the pathophysiological roles of neutrophil infiltration in ALI remain incompletely understood.

A dose of 20 mg/kg lipopolysaccharide (LPS) was intratracheally instilled to induce ALI models in 10‐week‐old male microRNA‐223 knockout mice (miR‐223 −/− ) and wild‐type (WT) mice, with control group mice receiving an equal volume of phosphate‐buffered saline (PBS). After 24 h of instillation, lung tissues and peripheral blood were collected from the mice. In vivo, quantitative PCR (qPCR) measured miR‐223 and neutrophil elastase (NE) mRNA levels, while Western blot (WB), enzyme‐linked immunosorbent assay (ELISA), and hematoxylin–eosin (H&E) staining assessed neutrophil extracellular traps (NETs) markers (H3Cit, myeloperoxidase [MPO]), inflammatory cytokines (TNF‐α, IL‐1β, and IL‐6), and lung injury severity. In vitro, HL‐60‐derived neutrophil‐like cells were cocultured with alveolar epithelial cells under LPS stimulation. The roles of the miR‐223/NE/NETs axis were further investigated using the NETs inhibitor GSK484 and the NE inhibitor Sivelestat.

WB experiments showed an increase in NETs‐related proteins MPO and H3Cit in the lungs of WT ALI mice, with significantly enhanced expression in miR‐223 −/− mice. The lung injury scores and mortality rates in miR‐223 −/− mice were significantly exacerbated, accompanied by increased neutrophil infiltration in the lungs. Levels of inflammatory factors (TNF‐α, IL‐1β, and IL‐6) in the serum of miR‐223 −/− mice were significantly elevated. In vitro coculture experiments demonstrated that miR‐223 deficiency in neutrophil‐like cells augmented NETs formation and inflammatory responses, leading to increased damage to alveolar epithelial cells. However, in vivo inhibition of NETs with GSK484 or NE with Sivelestat in miR‐223 −/− mice significantly attenuated neutrophil infiltration, inflammation, and lung injury, and improved survival. Similarly, Sivelestat pretreatment reduced NET formation and conferred protection against ALI. Consistent with the in vivo findings, inhibition of NETs with GSK484 or NE with Sivelestat in the coculture system similarly attenuated epithelial damage and inflammatory response.

This study reveals that the miR‐223/NE axis critically regulates NETs formation, modulating neutrophil inflammatory infiltration and neutrophil–epithelial interactions to exacerbate ALI. These findings provide potential therapeutic targets for ALI.

To observe the therapeutic effect of sivelestat sodium on acute lung injury and explore its mechanism.

Eighty-six patients with acute lung injury admitted from April 2022 to December 2023 were selected as the research objects. According to the principle of randomized control and single-blindness, they were randomly divided into the observation group (43 cases) and the control group (43 cases). The control group was given conventional symptomatic treatment, while the observation group was treated with sivelestat sodium on this basis. The mechanical ventilation, ICU stay, hospital stay, and 28-day mortality were compared between the 2 groups. The differences in pulmonary function, inflammatory factors, oxygenation index (PaO 2 /FiO 2 ), and respiratory rate (RR) between the 2 groups were detected and compared.

The duration of mechanical ventilation, ICU stay, and hospitalization in the observation group were significantly shorter than those in the control group, while there was no difference in 28-day mortality between the 2 groups ( P  > .05). Before treatment, pulmonary function indexes were compared between the 2 groups ( P  > .05). On the 5th and 7th days of treatment, the vital capacity and maximum ventilation volume of the 2 groups were significantly increased compared with those before treatment, and the values of pulmonary function indexes in the observation group at the same time point were better than those in the control group ( P  < .05). Before treatment, the inflammatory factors, PaO 2 /FiO 2 , and RR in the 2 groups were compared ( P  > .05). On the 5th and 7th day after treatment, the tumor necrosis factor-α, interleukin-1β, RR, and intercellular adhesion molecule-1 (ICAM-1) in the 2 groups were significantly decreased compared with those before treatment, while the NOD-like receptors (NLR) family pyrin domain containing 6 (NLRP6) and PaO 2 /FiO 2 were significantly increased. At the same time, the values of tumor necrosis factor-α, interleukin-1β, ICAM-1, and RR after decreased and NLRP6 and PaO 2 /FiO 2 after increased in the observation group were better than those in the control group ( P  < .05).

Sivelestat sodium can improve lung function, correct PaO 2 /FiO 2 , and promote rehabilitation in patients with acute lung injury, which may be related to the regulation of NLRP6, ICAM-1, and other inflammatory factors.