ACUTE-PANCREATITIS INDUCES CYTOKINE PRODUCTION IN ENDOTOXIN-RESISTANTMICE

Objective The purpose of this study was to determine whether pathologi c progression and cytokine responses in acute pancreatitis (AP) are al tered in the absence of endotoxemia, Summary Background Data Previous studies have demonstrated that AP is characterized by rapid production and release of inflammatory cytokines, which play a major role in the local pancreatic and systemic complications of this disease, infectio n and endotoxemia have been implicated as a major source of morbidity and death in AP and as possible stimuli for the overwhelming cytokine response seen in this disease. Methods AP was induced by a choline-def icient and ethionine-supplemented diet for 4 days in normal C57BV/6J m ice (controls, n = 23) and in CD14 knockout mice (CD14KO, n = 23), whi ch cannot produce circulating cytokines in response to endotoxin. Cont rol and endotoxin-resistant mice were killed at time O, then at 24, 48 , 72, and 96 hours after the start of the diet. At each time point ser um was collected for amylase, glucose, and cytokine measurements (tumo r necrosis factor-alpha [TNF alpha] and interleukin-1 beta [IL1 beta]) , and the pancreas was removed far histologic examination. TNF alpha w as measured with a bioassay using WEHI-2F cells and IL1 beta with a bi oassay using D10.G4.1 cells. Results CD14KO mice developed biochemical manifestations of AP with alterations in amylase levels, hypoglycemia , weight loss, and histologic changes of pancreatitis similar to the p attern seen in control mice. TNF alpha and IL1 beta production had sim ilar kinetics in both groups, with significant peak TNF alpha serum le vels at 72 hours and a progressive rise of IL1 beta levels throughout the study period. Histologic changes appeared earlier and were more pr onounced in the control versus the CD14KO mice. However, the mortality rate was identical (20% at 96 hours) for both groups. Conclusions The se results demonstrate that the progression of AP, the cytokine respon se associated with the disease, and early death are independent of end otoxin action. These findings, which suggest that an uncharacterized s timulus is responsible for triggering the cytokine cascade in this dis ease, may have significant implications for the management of patients with AP.