The pancreas as a source of cardiovascular cell activating factors

Objective: Physiological shock leads to elevated levels of plasma factors t hat activate circulating leukocytes and endothelial cells, thereby compromi sing microvascular functions. The nature and source of these plasma-derived activators are unknown. To examine the possible origin of these factors, w e homogenized rat internal organs and measured their activity on cardiovasc ular cells in vivo and in vitro. Methods: Fresh tissue samples from small intestine, spleen, heart, liver, k idney, adrenals, and pancreas were homogenized. Their ability to induce leu kocyte pseudopod formation and nitroblue tetrazolium (NBT) reduction was te sted and their impact in vivo on blood pressure, survival, and microvascula r cell injury was examined. Results: A dramatic increase (p < 0.001) in leukocyte activation compared t o controls was observed with pancreas homogenate but not with homogenates f rom the other organs. Leukocyte activation was induced by homogenates of ot her tissues only after prior incubation with substimulatory concentrations of pancreatic homogenate. Pancreatic serine proteases, trypsin and chymotry psin: which did not stimulate leukocytes, also generated activity from othe r tissues. Leukocyte pseudopod formation could be significantly inhibited b y adding the serine protease inhibitor 6-amidino-2-naphthyl p-guanidinobenz oate dimethanesulfonate (ANGD) during tissue homogenization (p < 0.001). In jection of pancreatic homogenate into rats led to increased plasma hydrogen peroxide levels and an instantaneous drop in mean arterial pressure that w as often lethal. These responses were prevented by prior infusion of ANGD ( p < 0.001). Intravital microscopy of the rat mesentery confirmed that super fusion of filtered pancreatic homogenate leads to significant increases in cell death (p < 0.05); as detected by propidium iodide, and hydrogen peroxi de formation (p < 0.05), as determined by dichlorofluorescein diacetate (DC FH) fluorescence. Conclusion: These results suggest that pancreatic enzymes attack tissue and generate cellular activators that are associated with organ dysfunction in shock.