Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis.
We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.
Van Acker
Gijs J D
GJ
Dept. of Surgery, Tufts-New England Medical Center, 860 Washington St., Boston, MA 02111, USA.
Weiss
Eric
E
Steer
Michael L
ML
Perides
George
G
D000199:Actins / Q000378:metabolism; D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002108:Ceruletide; D018932:Chemokine CCL2 / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D021381:Protein Transport; D022142:Secretory Vesicles / Q000201:enzymology; D012720:Severity of Illness Index; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism*; D014362:Trypsinogen / Q000378:metabolism*
D000199:Actins; C400541:CA 074 methyl ester; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004151:Dipeptides; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016328:NF-kappa B; D002108:Ceruletide; D014362:Trypsinogen; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001192:Arylsulfatases; D000681:Amylases; D014357:Trypsin; D002401:Cathepsin B