Inflammation section

Pancreatitis is inflammation in the pancreas. The pancreas is a long, flat glandular organ that sits tucked behind the stomach in the upper abdomen. The pancreas is considered as exocrine and endocrine organ which produces enzymes that help digestion and hormones that help regulate the way your body processes sugar (glucose). Pancreatitis can occur as acute pancreatitis — meaning it appears suddenly and lasts for days. Or pancreatitis can occur as chronic pancreatitis, which is pancreatitis that occurs over many years. Mild cases of pancreatitis may go away without treatment, but severe cases can cause life-threatening complications.

In fact, this type of inflammation is sterile inflammation at the same time we have previously found that neutrophils recruitment play a critical roles in trypsin activation and tissue damage in acute pancreatitis. More details in the below article ... Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis. Abdulla A1, Awla D, Thorlacius H, Regnér S. Author information Abstract The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP. PMID: 21810937 DOI: 10.1189/jlb.0411195

Beside phagocytosis, antimicrobial proteins releasing and reactive oxygen species generation, activated neutrophils have been reported to use another mechanism called NETosis. it is process by which activated neutrophils expel web-like structures called neutrophil extracellular traps(NETs). NETs composed from chromatin fibers that are decorated with granule-derived antimicrobial peptides and enzymes such as neutrophil elastase , cathepsin G, and myeloperoxidase (MPO). Although their role in protect the host against the pathogens by traping and killing the invading pathogens, NETs also have been reported to have critical role in various inflammatory diseases such as sepsis, arthritis, and vasculitis. Moreover, in our previous study, we have found that NETs mediate trypsin activation and tissue damage in AP, see the below articles..... Gastroenterology. 2015 Dec;149(7):1920-1931.e8. doi: 10.1053/j.gastro.2015.08.026. Epub 2015 Aug 22. Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice With Severe Acute Pancreatitis. Merza M1, Hartman H1, Rahman M1, Hwaiz R1, Zhang E2, Renström E2, Luo L1, Mörgelin M3, Regner S1, Thorlacius H4. Author information Abstract BACKGROUND & AIMS: Neutrophils are involved in the development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported to contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to the development of AP in mice. METHODS: AP was induced in C57BL/6 mice by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine. Pancreata were collected and extracellular DNA was detected by Sytox green staining, levels of CXC chemokines, histones, and cytokines also were measured. Cell-free DNA was quantified in plasma samples. Signal transducer and activator of transcription 3 phosphorylation and trypsin activation were analyzed in isolated acinar cells. NETs were depleted by administration of DNase I to mice. Plasma was obtained from healthy individuals (controls) and patients with severe AP. RESULTS: Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice and increased levels of cell-free DNA in plasma. Neutrophil depletion prevented taurocholate-induced deposition of NETs in the pancreas. Administration of DNase I to mice reduced neutrophil infiltration and tissue damage in the inflamed pancreas and lung, and decreased levels of blood amylase, macrophage inflammatory protein-2, interleukin 6, and high-mobility groups protein 1. In mice given taurocholate, DNase I administration also reduced expression of integrin α M (macrophage-1 antigen) on circulating neutrophils. Similar results occurred in mice with L-arginine-induced AP. Addition of NETs and histones to acinar cells induced formation of trypsin and activation of signal transducer and activator of transcription 3; these processes were blocked by polysialic acid. Patients with severe AP had increased plasma levels of NET components compared with controls. CONCLUSIONS: NETs form in the pancreata of mice during the development of AP, and NET levels are increased in plasma from patients with AP, compared with controls. NETs regulate organ inflammation and injury in mice with AP, and might be targeted to reduce pancreatic tissue damage and inflammation in patients. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. KEYWORDS: Chemokines; Histones; Inflammation; Leukocytes Comment in Neutrophil Extracellular Traps Provide a Grip on the Enigmatic Pathogenesis of Acute Pancreatitis. [Gastroenterology. 2015] PMID: 26302488 DOI: 10.1053/j.gastro.2015.08.026 Received: 28 June 2018 | Accepted: 9 November 2018 DOI: 10.1002/jcp.27874 ORIGINAL RESEARCH ARTICLE Targeting peptidylarginine deiminase reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis Raed Madhi | Milladur Rahman | Dler Taha | Matthias Mörgelin* | Henrik Thorlacius Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Lund, Sweden Correspondence Henrik Thorlacius, Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden. Email: henrik.thorlacius@med.lu.se Present address *Matthias Mörgelin, Colzyx, Medicon Village, 223 81 Lund, Sweden. Funding information Swedish Research Council, Grant/Award Number: 2017‐01621; Einar and Inga Nilsson Foundation Abstract Recent evidence suggests that neutrophil extracellular traps (NETs) play an important role in the development of acute pancreatitis (AP). Herein, we examined the role of peptidylarginine deiminase (PAD), which has been shown to regulate NET formation, in severe AP. AP was induced by retrograde of taurocholate infusion into pancreatic duct in C57BL/6 mice. PAD was pharmacologically inhibited using Cl‐amidine, a pan‐ PAD inhibitor. Pancreata were collected, and histones, citrullinated histone 3, chemokines, myeloperoxidase, and NETs were quantified. Chemokines, matrix metalloproteinase‐9 (MMP‐9), interleukin‐6 (IL‐6), and DNA‐histone complexes were determined in plasma samples. Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice. Pretreatment with Cl‐amidine markedly reduced the NET formation in the inflamed pancreas. Moreover, inhibition of PAD decreased the levels of blood amylase as well as edema, acinar cell necrosis, hemorrhage, and neutrophil infiltration in the pancreas of animals with AP. Administration of Cl‐amidine attenuated the myeloperoxidase levels in the pancreas and lung of mice exposed to taurocholate. In addition, Cl‐amidine decreased pancreatic levels of CXC chemokines, plasma levels of IL‐6, and MMP‐9 in mice with severe AP. This study shows that Cl‐amidine is a potent inhibitor of NET formation in severe AP. Also, our results suggest that PAD regulates pathological inflammation and tissue damage in the inflamed pancreas. Thus, targeting PAD might be a useful strategy to treat patients with severe AP. KEYWORDS chemokines, histones, inflammation, leukocyte and pancreas