THE PHYSIOLOGICAL CONSEQUENCES OF MACROPHAGE PACIFICATION DURING SEVERE ACUTE-PANCREATITIS

Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflamma tory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the me chanism by which blockade produces these benefits. Prior to the induct ion of lethal acute pancreatitis, rats were randomized to receive a si ngle dose (.01,.1, 1.0, or 10 mg/kg) of a macrophage-pacifying compoun d (CNI-1493) or vehicle. Escalating doses provided incremental increas es in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 m g/kg). To evaluate the physiologic mechanism responsible for the impro ved survival, continuous arterial blood pressure, serial hematocrit, a scites volume, pancreatic edema, bronchoalveolar leukocytes and protei n, and pancreatic histology were determined in additional rats receivi ng CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-a and nitrites we re also determined to assess the mechanism of action of CNI-1493. Macr ophage pacification decreased pancreatitis severity as determined by e nzyme release and pancreatic histology score. Ascites volume and bronc hoalveolar protein levels were also decreased, indicating that CNI-149 3 prevents the loss of circulating blood volume and maintains hematocr it and mean arterial pressure, thus improving survival. CNI-1493 preve nted the increase of serum tumor necrosis factor-a but not serum nitri tes, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death ir this model of pancreatitis.