Sivelestat Sodium Hydrate

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a life-threatening syndrome induced by various diseases, including COVID-19. In the progression of ALI/ARDS, activated neutrophils play a central role by releasing various inflammatory mediators, including elastase. Sivelestat is a selective and competitive inhibitor of neutrophil elastase. Although its protective effects on attenuating ALI/ARDS have been confirmed in several models of lung injury, clinical trials have presented inconsistent results on its therapeutic efficacy. Therefore, in this report, we used a network pharmacology approach coupled with animal experimental validation to unravel the concrete therapeutic targets and biological mechanisms of sivelestat in treating ALI/ARDS. In bioinformatic analyses, we found 118 targets of sivelestat against ALI/ARDS, and identified six hub genes essential for sivelestat treatment of ALI/ARDS, namely ERBB2, GRB2, PTK2, PTPN11, ESR1, and CCND1. We also found that sivelestat targeted several genes expressed in human lung microvascular endothelial cells after lipopolysaccharide (LPS) treatment at 4 h (ICAM-1, PTGS2, RND1, BCL2A1, TNF, CA2, and ADORA2A), 8 h (ICAM-1, PTGS2, RND1, BCL2A1, MMP1, BDKRB1 and SLC40A1), and 24 h (ICAM-1). Further animal experiments showed that sivelestat was able to attenuate LPS-induced ALI by inhibiting the overexpression of ICAM-1, VCAM-1, and PTGS2 and increasing the phosphorylation of PTK2. Taken together, the bioinformatic findings and experimentative data indicate that the therapeutic effects of sivelestat against ALI/ARDS mainly focus on the early stage of ALI/ARDS by pharmacological modulation of inflammatory reaction, vascular endothelial injury, and cell apoptosis-related molecules.

Rheumatoid arthritis (RA) is chronic inflammatory disorder mainly affects the lining of articular cartilage of synovial joints characterized by severe inflammation and joint damage. The expression of proteolytic enzymes like MMP-2 and Neutrophil Elastase (NE) worsens the RA condition. To address this concern, we have synthesized dual enzyme targeted chlorotoxin conjugated nanomicelles loaded with sivelestat as broad spectrum treatment for RA.

Conjugation of the chlorotoxin over nanomicelle and incorporation of sivelestat in nanomicelle provide it dual targeting potential. The sivelestat loaded nanomicelle (SLM) evaluated for the drug release and in-vitro cytocompatibility. Further, investigated its in-vivo anti-arthritic potential on collagen-induced arthritis in wistar rats.

The microscopic observation of SLM showed spherical ball like appearance with size ranging from 190 to 230 nm. SLM showed good drug loading and encapsulation efficiency along with no cytotoxicity against healthy cell lines. In-vivo therapeutic assessment on collagen induced arthritis rat model showed potential chondroprotection. The microscopic visualization of articular cartilage by staining showed that it restores the cartilage integrity and lowers the expression of pro-inflammatory enzymes showed by Immunohistochemistry and Immunofluorescence. We observed that, it restrain the mediators of synovial inflammation by simultaneous inhibition of the proteolytic enzymes involved in swelling, cartilage destruction and joint damage which provides strong chondroprotection.

We report that significant alleviation of inflammation and inhibition of proteolytic enzymes together might provide enhanced potential for the treatment and management of RA.