The effect of lexipafant on bacterial translocation in acute necrotizing pancreatitis in rats.
Bacterial translocation (BT) from the gastrointestinal tract to mesenteric lymph nodes (MLNs) and other extra intestinal organs is an important source of infection in acute pancreatitis (AP). Lexipafant (BB-882) is a potent platelet-activating factor receptor antagonist that has an anti-inflammatory effect. To examine whether BB-882 could affect BT in acute necrotizing pancreatitis, 48 male Sprague Dawley rats (250-350 g) were studied. AP was induced in Group I and Group II by pressure injection of 3% taurocholate and trypsin into the common biliopancreatic duct (1 mL/kg of body weight). Group I rats received BB-882 (10 mg/kg, i.p. qd) and Group II rats received a similar volume of normal saline as a placebo postoperatively for 2 days. Group III and Group IV received BB-882 and placebo, respectively, after an exploratory laparotomy. At 48 hours postoperatively, blood was drawn for culture, serum amylase, and tumor necrosis factor (TNF)-alpha determinations. Specimens from MLNs, spleen, liver, pancreas, and cecum were harvested for culture of gram-positive, gram-negative, and anaerobic bacteria. Quantitative cecal cultures of gram-positive, gram-negative, and anaerobic bacteria were obtained. A point scoring system for five histological features that include interstitial edema, inflammatory cellular infiltration, fat necrosis, parenchymal necrosis, and hemorrhage was used to evaluate the severity of pancreatitis. There was no difference in serum amylase levels (2415 +/- 127 IU/L versus 2476 +/- 170 IU/L), serum TNF-alpha levels (7820 +/- 1396 pg/mL versus 7318 +/- 681 pg/mL), and the mean pancreatic histology score (5.9 +/- 1.2 versus 6.5 +/- 1.1) between Group I and Group II, respectively (P > 0.05). Seven of 12 Group I rats had BT to MLNs, compared with 11 of 12 rats in Group II (P > 0.05). Five of 12 Group I rats had BT to distant sites such as pancreas, spleen, liver, and/or blood, compared with 11 of 12 rats in Group II (P < 0.05). BB-882 treatment decreases bacterial spread to distant sites, but does not reduce serum amylase levels and serum TNF-alpha levels or ameliorate pancreatic damage in rats with AP.
Department of General Surgery, Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Q
Q
Liu
G
G
Djuricin
H
H
Rossi
K
K
Bewsey
C
C
Nathan
P
P
Gattuso
R A
RA
Weinstein
R A
RA
Prinz
D000681:Amylases / Q000097:blood; D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008198:Lymph Nodes / Q000382:microbiology; D008297:Male; D019283:Pancreatitis, Acute Necrotizing / Q000097:blood / Q000382:microbiology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007093:Imidazoles; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D000681:Amylases; D007930:Leucine; C103289:lexipafant