Proteases and Protease Inhibitors in Cerulein-Induced Acute Pancreatitis in Rats

Kruse, Peter; Lasson, Åke; Häge, Esther

doi:10.1006/jsre.1999.5609

Cited by 17 publications

(6 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed elevation of ␣ 2-AP in both mild and severe pancreatitis is intriguing and supports the findings of earlier studies, which reported certain antitrypsin activity of ␣ 2-AP [27,28] . As a serine protease inhibitor of plasmin it is supposed that changes in ␣ 2-AP levels may affect the process of fibrinolysis.…”

Section: Discussionsupporting

confidence: 79%

Dexamethasone Affects Inflammation but Not Trypsinogen Activation in Experimental Acute Pancreatitis

et al. 2008

View full text Add to dashboard Cite

Background/Aims: Trypsinogen activation and inflammation are early events in acute pancreatitis. This experimental study aimed to show the effects of dexamethasone on them. Methods: Cerulein and taurocholate pancreatitis were induced in 2 groups of 12 Wistar rats each. Six animals per group were injected with dexamethasone 1 h prior to the induction of acute pancreatitis. Amylase, phospholipase A2, TNF-α, IL-6, IL-10, α2-antiplasmin in plasma and trypsinogen activation peptide (TAP) in urine were measured in healthy rats, then 0.5 and 6 h after pancreatitis induction. A severity score based on edema, necrosis and ascites was calculated at 6 h. TNF-α, IL-6 and IL-10 were measured 0.5 h after laparotomy in a control sham-operated group of 6 rats. Results: Inflammatory markers increased early in the course of both mild and severe acute pancreatitis and were significantly lowered by dexamethasone. The severity score was higher in taurocholate than in cerulein pancreatitis. It was significantly decreased by dexamethasone only in rats with mild pancreatitis. TAP remained unchanged in mild pancreatitis compared to healthy animals but increased late in the course of taurocholate pancreatitis. Trypsinogen activation was not affected by dexamethasone at all. Conclusion: Inflammation occurred earlier than the increase in urinary TAP in severe pancreatitis in rats. Dexamethasone inhibited inflammation but had no influence on TAP levels in experimental mild and severe acute pancreatitis.

show abstract

Section: Discussionsupporting

confidence: 79%

Dexamethasone Affects Inflammation but Not Trypsinogen Activation in Experimental Acute Pancreatitis

et al. 2008

View full text Add to dashboard Cite

show abstract

“…In healthy rats, the parotid gland contributes more amylase to the circulation than the pancreas, and this end point has limited utility in monitoring pancreatic injury in this species (Nagy et al 2001). Exposure to cerulein or CCK has been reported by others to cause transient increases in serum amylase and especially serum lipase activity consistent with the stimulation of pancreatic secretions (Tsukamoto et al 1986; Kruse, Lasson, and Hage 1999). Decreases in amylase activity were noted in both 7-day and 26-week studies but not in the 4-week study (i.e., only high-dose males with significant decrease in amylase activity); this may reflect reduction in exocrine pancreatic secretory activity.…”

Section: Discussionsupporting

confidence: 55%

Species- and Dose-Specific Pancreatic Responses and Progression in Single- and Repeat-Dose Studies with GI181771X

2013

View full text Add to dashboard Cite

Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

show abstract

“…Management of this condition includes removal of any obstruction/s, nutritional regulation (including pancreatic enzyme supplementation and hydration), and pain management [ 47 ]. Pharmacologic interventions have targeted the inhibition of proteolytic enzymes using broad spectrum anti-protease inhibitors that showed variable outcomes in animals if delivered before disease onset [ 48 , 49 ]. Unfortunately, these inhibitors failed to show any effect in patients, possibly due to their administration after peak enzymatic activity, but which may be unavoidable given the short peak in enzymatic activity in patients [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice

2021

View full text Add to dashboard Cite

Background Symptoms associated with acute pancreatitis can be debilitating, and treatment remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis. Methods Acute pancreatitis was induced in adult male C57Bl/6J mice by administering cerulein (8 injections of 50 µg/kg I.P., spaced an hour apart), with XPro1595 (10 mg/kg, S.C.) or vehicle being administered approximately 18 h after the last injection. Serum was collected 6 or 18 h after the last cerulein injection, pancreatic tissue was collected 2 and 7 days post-induction, and brain hippocampal tissue was collected at 7 days post-induction. The animal’s pain level was assessed 3, 5 and 7 days post-induction. Results The induction of acute pancreatitis promoted a strong increase in serum amylase levels, which had receded back to baseline levels by the next morning. XPro1595 treatment began after amylase levels had subsided at 18 h, and prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model. Conclusion Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis.

show abstract

Proteases and Protease Inhibitors in Cerulein-Induced Acute Pancreatitis in Rats

Cited by 17 publications

References 40 publications

Dexamethasone Affects Inflammation but Not Trypsinogen Activation in Experimental Acute Pancreatitis

Dexamethasone Affects Inflammation but Not Trypsinogen Activation in Experimental Acute Pancreatitis

Species- and Dose-Specific Pancreatic Responses and Progression in Single- and Repeat-Dose Studies with GI181771X

Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice

Contact Info

Product

Resources

About