Renoprotective activity of sivelestat in severe acute pancreatitis in rats

Abstract

Acute pancreatitis, affecting 382,014 individuals annually in China, is life-threatening in its severe form. Since acute pancreatitis-associated morbidity or mortality is attributable mainly to functional failure of the vital organs, significant research efforts have focused on the identification of novel agents with potential organ-protective properties in the hope of developing approaches to improve the outcome of acute pancreatitis. In a previous study, we demonstrated that sivelestat, a specific inhibitor of neutrophil elastase (NE), is effective in protecting against lung failure in rats with taurocholate-induced acute pancreatitis. As part of the analyses extended from that study, the present study aimed to evaluate the role of sivelestat in the protection against acute pancreatitis-associated renal injury. Renal histopathology and major renal function parameters were analyzed in renal tissue and blood specimens collected from rats with acute pancreatitis induced by the surgical administration of sodium taurocholate in the presence or absence of sivelestat treatment and in sham-operated control rats at various time-points. The extended analyses demonstrated that: i) sodium taurocholate induced apparent renal injury and dysfunction manifested by histological anomalies, including vacuolization and apoptosis of the cells of the tubular epithelial lining in the kidney, as well as biochemical aberrations in the blood (increases in levels of blood urea nitrogen, creatinine and tumor necrosis factor-α) and renal tissue (robust increases in NE activity and induced neutrophil chemoattractant-1 levels); and ii) sivelestat treatment effectively attenuated all taurocholate-induced histological anomalies and biochemical aberrations. These observations strongly suggest that the NE inhibitor, sivelestat, is effective in protecting against acute pancreatitis-associated renal injury.

Role of neutrophil extracellular traps in inflammatory evolution in severe acute pancreatitis

“…Furthermore, it has recently been considered a promising modality for the treatment of COVID-19, [134] and has also been proven to be effective in protecting against pancreatic, pulmonary, and renal injuries in rats with SAP. [135][136][137] PAD4 plays a crucial role in the formation of NETs. [27] Inhibiting the expression of PAD4 could markedly reduce NET formation, decrease the severity of pancreatitis and improve survival in mouse models of SAP.…”

“…Sivelestat, an NE inhibitor, can mitigate vascular permeability of the lung, ameliorate injuries in the alveolar epithelium and vascular endothelium, and improve pulmonary function and coagulopathy in patients with ALI/ARDS. Furthermore, it has recently been considered a promising modality for the treatment of COVID-19, [134] and has also been proven to be effective in protecting against pancreatic, pulmonary, and renal injuries in rats with SAP [135–137] …”

“…Furthermore, it has recently been considered a promising modality for the treatment of COVID-19, [ 134 ] and has also been proven to be effective in protecting against pancreatic, pulmonary, and renal injuries in rats with SAP. [ 135 – 137 ]…”