It is not clear how the inflammatory necrotizing process in the retroperitoneal space is induced. Proposed pathophysiological mechanisms are largely based on animal models. Three key factors, acting sequentially, may account for regional necrosis:
1. intraglandular activation of pancreatic enzymes, which is probably responsible for pancreatic autodigestion;
2. overstimulation of inflammatory effector cells (e.g. macrophages, polymorphonuclear leukocytes);
3. vascular mechanisms (ischemia/reperfusion, hemorrhage).
The earliest morphologically detectable lesions in animal models involve acinar cells (necrosis), followed later by interstitial hemorrhage and inflammation ( Steer. 1992). Intra-acinar activation of proteolytic/lipolytic pancreatic enzymes, in particular trypsin, may be the initial mechanism triggering glandular autodigestion and terminating in regional necrosis (S.t.e.e.L.,1992). As with ischemia, trypsin catalyzes proteolytic conversion of xanthine dehydrogenase to xanthine oxidase ( Fig, 1).
Depending upon the amount of active trypsin, secondary exhaustion of the antiprotease systems, and the extent of acinar cell injury, these cascade activations extend to the gland and the peripancreatic region. Transient impaction of biliary stones in the terminal common bile duct or spasm/edema of the sphincter of Oddi persisting after stone passage may conceivably lead to premature zymogen activation (SteerJ992). Alcohol may decrease activity of trypsin inhibitors, increase production of lysosomal hydrolases, and impair separation between the latter and zymogens in the Golgi apparatus.
Fig. 1 Excess intra-acinar generation of trypsin results in protease-antiprotease imbalance, secondary glandular and periglandular activation of pancreatic proenzymes and factors of the cascade systems of proteases, and induction of an oxidant stress via the hypoxanthine-xanthine oxidase pathway: a 1 -AT, arantitrypsin; a2-M, a2-macroglobulin; PSTI, pancreatic secretory trypsin inhibitor. (Modified with permission from OMs§on..il.9§.§).)
Other factors which determine the severity of pancreatitis include local microcirculatory disturbances and massive glandular invasion by macrophages and polymorphonuclear neutrophils (Gios.s..eta( 1993). The close interplay between the direct toxic effect of prematurely activated digestive enzymes, local microcirculatory impairment, and toxic substances released by overactivated neutrophils and macrophages is responsible for the severity of the inflammatory reaction and the ensuing necrosis (Fig 2). Although premature intra-acinar activation of zymogens seems to be the initial step in this chain of events, the respective roles of these three mechanisms in the development of pancreatic necrosis remain controversial (Gross. §.L§L 1993).
Fig. 2 Pathophysiology of pancreatic necrosis and subsequent multiple organ dysfunction syndrome: interrelation between premature activation of trypsin, microcirculatory impairment, and overstimulation of macrophages and polymorphonuclear neutrophils (PMNs).
Was this article helpful?