MACROPHAGE PACIFICATION REDUCES RODENT PANCREATITIS-INDUCED HEPATOCELLULAR INJURY THROUGH DOWN-REGULATION OF HEPATIC TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA

Overproduction of tumor necrosis factor (alpha (TNF-alpha), interleuki n-1 beta (IL-1 beta), and nitric oxide (NO) is believed to be detrimen tal during the progression of acute pancreatitis, yet little is known about the hepatic production of these mediators and their role in medi ating pancreatitis-induced hepatic dysfunction. Rats were randomized t o receive a single intraperitoneal injection of the macrophage-pacifyi ng compound, CNI-1493 (1.0 mg/kg), or vehicle 1 hour before the induct ion of retrograde bile salt pancreatitis. Sham-operated animals served as controls. Animals were killed 18 hours later, with serum and liver s harvested to determine the degree of hepatocellular injury and the i nduction of TNF-alpha, IL-1 beta, and inducible nitric oxide synthase (iNOS). In addition, serum TNF-alpha and nitrites (end-product of NO b reakdown) were determined in each group to assess the mechanism of act ion of CNI-1493, TNF-alpha, IL-1 beta, and iNOS gene expression (by re verse-transcription polymerase chain reaction) as well as aspartate tr ansaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH) (but not alkaline phosphatase [ALP]) increased following the de velopment of pancreatitis (all P < .05). Macrophage pacification signi ficantly prevented the induction of TNF-alpha and IL-1 beta mRNA (but not iNOS), resulting in lessened serum AST, ALT, and LDH tall P < .05) . Serum TNF-alpha protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and T NF-alpha protein production was significantly attenuated in animals re ceiving CNI-1493. Hepatocellular, but not bile duct, injury occurs dur ing: experimental pancreatitis that is associated with hepatic TNF-alp ha, IL-1 beta, and iNOS mRNA gene induction, as well as TNF-alpha prot ein and nitrite production. Preventing the production of TNF-alpha and IL-1 beta by macrophage pacification attenuates the hepatocellular da mage, suggesting that these mediators play a role in pancreatitis-indu ced hepatic injury.