Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents

Kui, Balázs; Balla, Zsolt; Végh, Eszter T.; Pallagi, Petra; Venglovecz, Viktória; Iványi, Béla; Takács, Tamás; Hegyi, Péter; Rakonczay, Zoltán

doi:10.1038/labinvest.2013.143

Cited by 41 publications

(36 citation statements)

References 101 publications

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“…l ‐Arg metabolizes into NO by NOS and induces oxidative/nitrosative stress, which react with ROS to form ONOO − . Thus, oxidative/nitrosative stress induced CP through lipid peroxidation, injury to cell membrane/cytoskeleton, impairment of intracellular protein, DNA damage, and inflammation, which finally cause acinar cell destruction . Furthermore, increased oxidative and nitrosative stress can trigger inflammation and iNOS signaling in several pathological conditions .…”

Section: Discussionmentioning

confidence: 99%

Sodium Butyrate Ameliorates l‐Arginine‐Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress

Kanika

Khan

Jena

2015

J Biochem & Molecular Tox

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Several reports indicated that histone deacetylases (HDACs) play a crucial role in inflammation and fibrogenesis. Sodium butyrate (SB) is a short-chain fatty acid having HDAC inhibition potential. The present study aimed to evaluate the protective effect of SB against L-arginine (L-Arg)-induced pancreatic fibrosis in Wistar rats. Pancreatic fibrosis was induced by twice intraperitoneal (i.p.) injections of 20% L-Arg (250 mg/100 g) at 2-h interval on day 1, 4, 7, and 10, whereas SB (800 mg/kg/day) was administrated for 10 days. At the end of the study, biochemical estimations, histological alterations, DNA damage, and the expression of various proteins were evaluated. Posttreatment of SB decreased L-Arg-induced oxidative and nitrosative stress, DNA damage, histological alterations, and fibrosis. Interestingly, posttreatment of SB significantly decreased the expression of α-smooth muscle actin, interleukin-1β, inducible nitric oxide synthase, and 3-nitrotyrosine. The present study demonstrated that posttreatment of SB alleviates L-Arg-induced pancreatic damage and fibrosis in rat.

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Section: Discussionmentioning

confidence: 99%

Sodium Butyrate Ameliorates l‐Arginine‐Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress

Kanika

Khan

Jena

2015

J Biochem & Molecular Tox

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“…Although the mechanism remains unclear, administering excess basic amino acids or derivatives of naturally occurring amino acids can cause severe acute and sometimes lethal pancreatitis 60 . The mechanisms whereby these agents cause pancreatitis is unclear.…”

Section: Animal Models Of Clinical Acute Pancreatitismentioning

confidence: 99%

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

Gorelick

Lerch

2017

Cellular and Molecular Gastroenterology and Hepatology

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Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.

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“…L-arginine does not act through CCK receptors, yet Stat2 loss is also protective in this model of pancreatitis. The mechanism by which L-arginine causes pancreatitis is not fully understood but cellular metabolic disturbances liberate damage-associated molecular patterns which can trigger MAPK-containing signalling pathways [18, 19]. Thus Stat2 seems to play a wide role in MAPK-mediated signal transduction in response to injury that is agnostic of the initial triggering stimulus.…”

Section: Discussionmentioning

confidence: 99%

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Heath

Britton

Kudo

et al. 2019

Preprint

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Severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However its role in sterile inflammation is unknown. We hypothesised that Stat2 determines severity of non-infective inflammation in the pancreas.Wild type (WT) and Stat2−/− mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2−/− bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells.Stat2−/− mice were protected from cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2−/− mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2−/− mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/Stat2−/− bone-marrow chimera were protected from pancreatitis irrespective of host or recipient genotype.Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow derived cells.

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Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents

Cited by 41 publications

References 101 publications

Sodium Butyrate Ameliorates l‐Arginine‐Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress

Sodium Butyrate Ameliorates l‐Arginine‐Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

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