PURPOSE OF REVIEW: In this article, we review important advances in our understanding of the mechanisms of pancreatitis. RECENT FINDINGS: The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. SUMMARY: Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.
PURPOSE OF REVIEW: In this article, we review important advances in our understanding of the mechanisms of pancreatitis. RECENT FINDINGS: The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. SUMMARY: Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.
Authors: A J Hietaranta; A K Saluja; L Bhagat; V P Singh; A M Song; M L Steer Journal: Biochem Biophys Res Commun Date: 2001-01-12 Impact factor: 3.575
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Authors: David C Whitcomb; Jessica LaRusch; Alyssa M Krasinskas; Lambertus Klei; Jill P Smith; Randall E Brand; John P Neoptolemos; Markus M Lerch; Matt Tector; Bimaljit S Sandhu; Nalini M Guda; Lidiya Orlichenko; Samer Alkaade; Stephen T Amann; Michelle A Anderson; John Baillie; Peter A Banks; Darwin Conwell; Gregory A Coté; Peter B Cotton; James DiSario; Lindsay A Farrer; Chris E Forsmark; Marianne Johnstone; Timothy B Gardner; Andres Gelrud; William Greenhalf; Jonathan L Haines; Douglas J Hartman; Robert A Hawes; Christopher Lawrence; Michele Lewis; Julia Mayerle; Richard Mayeux; Nadine M Melhem; Mary E Money; Thiruvengadam Muniraj; Georgios I Papachristou; Margaret A Pericak-Vance; Joseph Romagnuolo; Gerard D Schellenberg; Stuart Sherman; Peter Simon; Vijay P Singh; Adam Slivka; Donna Stolz; Robert Sutton; Frank Ulrich Weiss; C Mel Wilcox; Narcis Octavian Zarnescu; Stephen R Wisniewski; Michael R O'Connell; Michelle L Kienholz; Kathryn Roeder; M Michael Barmada; Dhiraj Yadav; Bernie Devlin Journal: Nat Genet Date: 2012-11-11 Impact factor: 38.330