Anti-ICAM-1 antibody modulates late onset of acinar cell apoptosis and early necrosis in taurocholate-induced experimental acute pancreatitis

The hallmark of severe acute pancreatitis (SAP) is massive acinar cell deat h by necrosis. However, programmed, apoptotic acinar cell death has also be en observed. Little is known about the dynamics, localization, and inductiv e factors of acinar cell apoptosis in SAP. We therefore induced SAP in rats by retrograde infusion of 3% sodium taurocholatc. Starting as early as 5 m inutes after taurocholate administration, small scattered groups of acinar cells showed zymogen degranulation, loss of cell polarity, cytoplasmic micr ovacuolization, and nuclear shrinkage, but no DNA degradation, thus featuri ng necrosis. The areas of necrotic acini extended at later time points givi ng rise to larger areas of complete parenchymal breakdown after 6 hours. Pa renchymal degradation was paralleled by neutrophil infiltration and signifi cant tumor necrosis factor (TNF)-alpha mRNA up-regulation. Up to the 12-hou r interval, apoptotic acinar cells detected by TUNEL were as rare as in hea lthy pancreata. At 24 hours, however, the acinar apoptotic rare in nonnecro tic parenchyma had dramatically increased. Pretreatment of rats with anti-I CAM-1 antibody prior to pancreatitis induction led to a significant reducti on of neutrophil infiltration along with decreased TNF-alpha mRNA expressio n throughout the 24-hour observation period without affecting the presence and dynamics of necrosis. However. anti-ICAM-1 pretreatment decreased the e xtent of acinar cell damage by necrosis and extensively suppressed acinar c ell apoptosis. We conclude that taurocholate induces two sequential pattern s of acinar cell death in terms of very early necrosis followed by late apo ptosis during the postucute phase of SAP. The progression of necrosis and t he late apoptotic acinar cell death seem to be influenced by the local pres ence of neutrophils via a TNF-alpha -dependent mechanism. In addition to au gmenting necrosis. neutrophils might have an apoptosis-inducing potential i n SAP.