INVESTIGATIONS INTO HYPERLIPIDEMIA AND ITS POSSIBLE ...

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this theory, zymogen granules that are accumulating in acinar cells co-localize with
lysosomes. Lysosomal enzymes, such as cathepsin B, are then thought to activate
trypsinogen into trypsin, which subsequently activates other zymogens. Evidence from
other studies indicate that the cytosolic concentration of free ionized calcium also plays
an important role in the intracellular activation of zymogens. 157-159 In addition to the
decreased secretion and intracellular activation of pancreatic enzymes, there is evidence
of disruption of the paracellular barrier in the pancreatic duct that allows its contents to
leak into the paracellular space, and also redirect the secretion of zymogen granules from
the apical pole to the basolateral region of the acinar cell and into the interstitial space. 156
Once intracellular activation of pancreatic enzymes has taken place, autodigestion of the
acinar cell follows and activated enzymes escape, initially into the pancreatic tissue
(leading to local effects) and subsequently into the peritoneal cavity and the systemic
circulation (potentially contributing to systemic effects). Local effects vary and can
range from mild interstitial edema to severe acinar cell necrosis, hemorrhage, and
peripancreatic fat necrosis. The extent and severity of local effects determine to a large
degree the systemic response. Acinar cell injury leads to recruitment and activation of
inflammatory cells (most importantly neutrophils and macrophages), which release
proinflammatory cytokines and other inflammatory mediators (such as interleukin [IL]-
1, IL-2, IL-6, IL-18, tumor necrosis factor-α, substance P, platelet-activating factor
[PAF]) that play a crucial role in modulating systemic complications of the disease. 155,160
Such systemic complications can include cardiovascular shock, acute renal failure,
neurologic abnormalities, disseminated intravascular coagulation (DIC), systemic