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.