Within a few hours after one injection of fresh human serum by the intraperitoneal route only, mice developed pancreatic acinar cell
necrosis and
inflammation,
fat necrosis, elevated serum
amylase and a shocklike state. The extent of these lesions and mortalities were roughly dose dependent and were not noticeably modified by either different fasting cycles or
pilocarpine. Acinar cell changes and
necrosis usually developed first in subserosal acini. The earliest ultrastructural change detected was nonspecific swelling of cytoplasmic compartments which was reversible but also preceded the cytoplasmic degradation that developed in cells undergoing
necrosis. Notably, zymogen granule dissolution neither preceded nor accompanied this swelling, but developed pari passu with cell degradation. Occasionally, intact granules were found in necrotic cells. Serum was cytotoxic for isolated acinar cells in vitro, even in the presence of soybean
trypsin inhibitor. These results (1) indicate that the injury mechanism in vivo is directly initiated through contact of serum with acinar cell surfaces and is independent of
zymogen secretions and
trypsin activation, and (2) suggest that a rapid disturbance in cell membrane permeability results, the magnitude of which being the primary determinant of cell death. Pancreatic toxicity of human serum was abolished by aging, heating,
ethylenediaminetetraacetic acid,
heparin,
zymosan,
cobra venom factor, and absorptions with mouse red blood cells, against which fresh, unabsorbed serum was hemolytic. Pancreatic toxicity in vitro and, to a much lesser extent, in vivo was reconstituted by combining the red blood cell-absorbed serum with either heated serum, or with
IgM-enriched, but not
IgG serum fractions. Fresh cord serum was virtually nontoxic and could substitute for absorbed serum in such reconstitutions. These results indicate that the injury mechanism involves at least two serum components. By both circumstance and analogy, other results and a review of other examples of foreign sera toxicity suggest that they are components of a
complement-dependent, cytotoxic heterophile antibody system. The relevance of this odd phenomenon is that it offers a simple model of
acute pancreatitis, contributes to the debunking of traditional notions of the pivotal role of
zymogens in the initiation of
acute pancreatitis, and hints at a potential pathogenetic connection between
pancreatitis and products of immune or related reactions.