Effect of ulinastatin, a human urinary protease inhibitor, on heatstroke-induced apoptosis and inflammatory responses in rats

Abstract

Abstract. Ulinastatin has been demonstrated to protect against heatstroke by reducing cerebral ischemia and damage in rats. In order to extend these observations, apoptosis and systemic inflammatory responses were assessed in rats treated with ulinastatin prior to the initiation of heatstroke. Following the onset of heatstroke, histological analysis revealed that the hippocampal tissues displayed edema and damage. In addition, upregulation of malondialdehyde, inducible nitric oxide synthase (iNOS) and reactive oxygen species and downregulation of superoxide dismutase were observed compared with the respective levels in the control group. Furthermore, TUNEL staining and western blotting assays indicated that heatstroke induced cell apoptosis by increasing the Bax/Bcl-2 ratio and caspase-3 levels, and upregulating the protein expression levels of nuclear factor-κB, cyclooxygenase-2 and iNOS. However, the injury induced by heatstroke was significantly inhibited by ulinastatin pretreatment at doses of 5,000 and 10,000 IU/kg. Survival analysis of the rats subjected to heatstroke demonstrated that rats treated with ulinastatin at a dose of 10,000 IU/kg lived longer than those that did not receive ulinastatin treatment. These observations indicate that ulinastatin may protect against heatstroke by reducing apoptosis and systemic inflammatory responses.

Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials

“…However, it remains uncertain whether ulinastatin can be recommended as a standard medication for and ARDS. In animal models, ulinastatin attenuates the pathophysiological process of acute lung injury induced by lipopolysaccharide, scald injury, phosgene and seawater, among other injuries [23, 24, 71–73]. These benefits are mainly associated with inhibiting the activation of neutrophils, blocking nuclear factor-κB pathway, which plays a critical role in the regulation of pro-inflammatory (e.g.…”

“…TNF-α, IL-1β, IL-6), down-regulate chemokines (e.g. IL-8, macrophage inflammatory protein-2), and increases neutrophils apoptosis [5, 23, 24, 67, 68, 71–73]. In theory, ulinastatin could be a new option in ARDS treatment.…”

“…Moreover, ulinastatin possesses anti-inflammatory properties by reducing the elevation of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8), which are produced by neutrophil elastase [17–19]. Currently, several animal studies [23, 24], clinical trials [19, 25] and systematic reviews [11, 12] have confirmed its beneficial effect in lung protection. However, whether ulinastatin can be recommended as a standard medication for ARDS remains uncertain, since its clinical benefit has not been fully understood [26].…”

Ulinastatin inhibits renal tubular epithelial apoptosis and interstitial fibrosis in rats with unilateral ureteral obstruction

“…In addition, recent studies indicated that apoptosis in the hippocampus of gerbils increased after cerebral ischemia, while UTI treatment inhibited Bax molecule expression and increased Bcl-2 expression in ischemia-induced apoptosis in hippocampus and decreased the TUNEL+ and caspase-3+ cells in the hippocampal CA1 region induced by cerebral ischemia, thus improving ischemia-induced short-term memory impairment ( 9 ). UTI reduced the heatstroke-induced Bax/Bcl-2 ratio and caspase-3 levels in brain cells and inhibited cell apoptosis during cerebral injury ( 10 ). In this study, the TUNEL results showed that obvious renal tubular epithelial cell apoptosis occurred after 7 days of UUO surgery.…”

“…It is applied clinically for the treatment of acute pancreatitis and extracorporeal circulation injury and the prevention of shock and surgical invasion. Recent studies indicate that UTI inhibited cell apoptosis during brain injury ( 9 , 10 ) and had a protective function in various acute renal injuries ( 11 , 12 ). In addition, it has been reported that UTI inhibited lung ( 13 ) and renal ( 14 ) fibrosis; however, the specific mechanism is still not clear.…”