Questioning current concepts in acute pancreatitis: Endotoxin contamination of porcine pancreatic elastase is responsible for experimental pancreatitis-associated distant organ failure

Fabian Geisler, Hana Algül, Marc Riemann, Roland M. Schmid

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The systemic inflammatory response syndrome is responsible for pancreatitis-associated mortality. Recent in vitro and in vivo studies have suggested that pancreatic elastase is one missing link between the localized inflammatory process in the pancreas and distant organ dysfunction and failure. It has been shown that pancreatic elastase activates transcription factors, including NF-κB, and induces TNF-α secretion in myeloid cells via TLRs. In this study we demonstrate that a highly purified low endotoxin pancreatic elastase preparation (El-UP) failed both to activate NF-κB and to induce TNF-α release in RAW 264.7 cells and bone marrow-derived macrophages. In contrast, a less purified elastase preparation (El-IV) caused activation of NF-κB and was able to induce TNF-α release at very low concentrations. These effects were sensitive to pretreatment of the cells with polymyxin B and were resistant to heat inactivation. Endotoxin activity as determined by the Limulus amebocyte lysate assay was >3 orders of magnitude lower in the low endotoxin elastase preparation (El-UP) compared with less purified elastase preparations (El-IV). In contrast to contaminated elastase or LPS, elastase free of contamination (El-UP) failed to induce elevated serum TNF-α levels or pulmonary neutrophil infiltration after i.p. application in mice and did not induce lethality when coinjected with D-galactosamine. Failure of low endotoxin elastase (El-UP) to induce proinflammatory effects in vivo and in vitro was not due to functional inactivity of the elastase preparation, as determined by elastase activity assay. These results question current concepts of direct proinflammatory effects attributed to pancreatic elastase.

Original languageEnglish
Pages (from-to)6431-6439
Number of pages9
JournalJournal of Immunology
Volume174
Issue number10
DOIs
StatePublished - 15 May 2005
Externally publishedYes

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