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Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

ABSTRACT: Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.

SUBMITTER: Leppkes M

PROVIDER: S-EPMC4793047 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

Leppkes Moritz M Maueröder Christian C Hirth Sebastian S Nowecki Stefanie S Günther Claudia C Billmeier Ulrike U Paulus Susanne S Biermann Mona M Munoz Luis E LE Hoffmann Markus M Wildner Dane D Croxford Andrew L AL Waisman Ari A Mowen Kerri K Jenne Dieter E DE Krenn Veit V Mayerle Julia J Lerch Markus M MM Schett Georg G Wirtz Stefan S Neurath Markus F MF Herrmann Martin M Becker Christoph C

Nature communications 20160311

Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and m ...[more]

PMID: 26964500

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Project description:ImportanceThe operative scenarios with the highest postoperative pancreatic fistula (POPF) risk represent situations in which fistula prevention and mitigation strategies have the strongest potential to affect surgical outcomes after pancreaticoduodenectomy. Evidence from studies providing risk stratification is lacking.ObjectiveTo investigate whether pancreaticojejunostomy (PJ) or pancreaticogastrostomy (PG), both with externalized transanastomotic stent, is the best reconstruction method for patients at high risk of POPF after pancreaticoduodenectomy.Design, setting, and participantsA single-center, phase 3, randomized clinical trial was conducted at the Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy, from July 12, 2017, through March 15, 2019, among adults undergoing elective pancreaticoduodenectomy and considered at high risk for pancreatic fistula after intraoperative assessment of the fistula risk score, some of whom were randomized to undergo PG or PJ. All analyses were performed on an intention-to-treat basis.InterventionsIntervention consisted of PJ or PG, both with externalized transanastomotic stent and octreotide omission.Main outcomes and measuresThe primary end point was POPF. The secondary end points were Clavien-Dindo grade 3 or higher morbidity, postpancreatectomy hemorrhage, delayed gastric emptying, and average complication burden.ResultsA total of 604 patients were screened for eligibility; 82 were at high risk for POPF (fistula risk score, 7-10), and 72 were randomized undergo PG (n?=?36; 20 men and 16 women; median age, 65 years [interquartile range, 23-82]) or PJ (n?=?36; 26 men and 10 women; median age, 63 years [interquartile range, 35-79]). There was no significant difference in the incidence of POPF between patients who underwent PG and patients who underwent PJ (18 [50.0%] vs 14 [38.9%]; P?=?.48), but for patients who developed a POPF, the mean (SD) average complication burden was lower for those who underwent PJ than for those who underwent PG (0.25 [0.13] vs 0.39 [0.17]; P?=?.04). The rates of postpancreatectomy hemorrhage (14 [38.9%] in the PG group vs 9 [25.0%] in the PJ group; P?=?.31) and delayed gastric emptying (16 [44.4%] in the PG group vs 18 [50.0%] in the PJ group; P?=?.81) were similar, but patients who underwent PG presented with a significantly higher incidence of Clavien-Dindo grade 3 or higher morbidity than those who underwent PJ (17 [47.2%] vs 8 [22.2%]; P?=?.047).Conclusions and relevanceAmong patients at the highest risk for POPF, those who underwent PG or PJ experienced similar rates of POPF. However, PG was associated with an increased incidence of Clavien-Dindo grade 3 or higher morbidity and with an increased average complication burden for the patients who developed a POPF. For patients at high risk for pancreatic fistula, PJ with the use of externalized stent and octreotide omission should be considered the most appropriate technical strategy.Trial registrationClinicalTrials.gov Identifier: NCT03212196.

Dataset Information

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

Publications

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

Similar Datasets

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