title: The physiologic consequences of macrophage pacification during severe acute pancreatitis.
abstract: Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-alpha and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-alpha but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.
authors.affiliation: Department of Surgery, University of South Florida, Tampa 33612, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: W
authors.initials: W
authors.lastname: Denham
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: A A
authors.initials: AA
authors.lastname: Kramer
authors.forename: K F
authors.initials: KF
authors.lastname: Salhab
authors.forename: J
authors.initials: J
authors.lastname: Norman
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001201:Ascites / Q000378:metabolism; D001647:Bile Acids and Salts / Q000494:pharmacology; D001794:Blood Pressure; D018893:Bronchoalveolar Lavage; D004305:Dose-Response Relationship, Drug; D006400:Hematocrit; D006835:Hydrazones / Q000494:pharmacology*; D008049:Lipase / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009573:Nitrites / Q000097:blood; D010195:Pancreatitis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000813:Anilides; D006146:Guanidines
chemical_list: D000681:Amylases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001647:Bile Acids and Salts; D006835:Hydrazones; D008049:Lipase; D009573:Nitrites; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines