Potential of sivelestat in protection against severe acute pancreatitis-associated lung injury in rats

Abstract

The incidence of acute pancreatitis has been rising worldwide in the past few decades. Despite extensive research efforts, the population-based mortality from acute pancreatitis remains high. Since dysfunction of multiple vital organs, most importantly the lungs, is the major cause of early death in acute pancreatitis patients, developing effective strategies to manage lung injury has become one of the focuses of recent research efforts aiming at improving the outcome of patients with acute pancreatitis. In this study, we attempted to create a rat model of acute pancreatitis through intraductal infusion of taurocholate and to evaluate the potential of sivelestat, a synthetic neutrophil elastase inhibitor, in protection against acute pancreatitis-associated lung injury using this rat model. The results demonstrated that: (1) 5% sodium taurocholate successfully induced histopathologic and biochemical abnormalities in the circulation, lung and pancreas characteristic of human acute pancreatitis, including an increase in amylase concentration and a decrease in partial arterial oxygen pressure (PaO2) in the blood, increases in activities of myeloperoxidase (MPO) (a lung injury marker) and neutrophil elastase (a quantitative indicator of neutrophil infiltration), and levels of malondialdehyde (an indicator of lipid peroxidation) and tumor necrosis factor-alpha (a major inflammatory mediator) in the lung; (2) intravenous administration of sivelestat effectively attenuated the taurocholate-induced abnormalities in all parameters analyzed except for serum amylase concentration. Our findings have validated the taurocholate model of acute pancreatitis and demonstrated great therapeutic potential for sivelestat in managing acute pancreatitis-associated lung injury.

Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice With Severe Acute Pancreatitis

“…A recent study showed that neutrophil-derived MMP-9 might play an important role in AP. 13 We found that challenge with taurocholate increased plasma levels of MMP-9 by nearly 8-fold ( Figure 4). Inhibition of NET formation reduced circulating levels of MMP-9 by 93% in animals exposed to taurocholate ( Figure 4).…”

“…It has been reported that neutrophil-derived reactive oxygen species (ROS) and enzymes, such as elastase and matrix metalloproteinase-9 (MMP-9) might contribute to neutrophil-mediated tissue damage in AP. 13,14 On top of those proposed mechanisms thus far, new aspects of neutrophil biology might help to explain how neutrophils cause tissue injury in the inflamed pancreas. Recent findings have demonstrated that activated neutrophils, beside secretion of antimicrobial compounds and phagocytic killing, can eliminate invading microorganisms by expelling nuclear DNA forming extracellular web-like structures decorated with nuclear histones as well as granular and cytoplasmic proteins.…”

Renoprotective activity of sivelestat in severe acute pancreatitis in rats

“…Since this study was an extension of a previous study from our group, the animals and their allocation, as well as the methods of pancreatitis induction and sivelestat treatment, were the same as described in our previous study (9). In summary, adult male Sprague-Dawley rats were randomized into the following groups: i) the experimental acute pancreatitis (EAP) group in which rats were induced to develop acute pancreatitis by the administration of sodium taurocholate through laparotomy under anesthesia; ii) the EAP plus sivelestat treatment group in which rats were injected with 2 mg/kg sivelestat through the superficial dorsal vein of the penis immediately following EAP induction; and iii) the control group in which a sham laparotomy was performed.…”

“…Tissue homogenate was prepared from frozen renal specimens using the method described for the homogenate preparation of lung tissue in our previous study (9). NE activity was determined spectrophotometrically using a chromogenic substrate.…”

“…In a previous study, we assessed the potential of sivelestat, a competitive inhibitor of human neutrophil elastase (NE) (8), in the protection against acute pancreatitis-associated lung injury in a rat model (9). As an extension of the analyses in our previous study, the present study aimed to evaluate the ability of sivelestat to protect against renal injury in acute pancreatitis in rats.…”