Platelet activating factor antagonism reduces the systemic inflammatory response in a murine model of acute pancreatitis.
BACKGROUND
The platelet activating factor (PAF) antagonist, Lexipafant, has been used in experimental models and clinical trials to treat severe acute pancreatitis (AP). The purpose of this study was to determine whether Lexipafant reduces the local and systemic components of AP in a murine model of mild, edematous AP.


METHODS
Forty-eight female Swiss-Webster mice were divided into four groups. Group 1 received 50 microl of saline ip every hour for 6 h (sham). Group 2 received saline treatment, plus Lexipafant (25 mg/kg dose ip, every 3 h starting 1 h after the first saline injection) (sham/Lex). Group 3 received cerulein (50 microg/kg dose ip, every hour for 6 h) (AP). Group 4 received AP, plus therapeutic treatment with Lexipafant (AP/Lex). Animals were sacrificed 3 h after the last injection. Serum cytokine levels were determined by ELISA. Standard assays were performed for serum amylase activity and lung myeloperoxidase activity (MPO). Histology was scored by two blinded investigators.


RESULTS
Serum cytokines (TNFalpha, IL-1beta), lung MPO, and serum amylase activity were reduced by PAF antagonism. Histology showed a trend toward improvement with Lexipafant, but did not reach statistical significance.


CONCLUSIONS
The PAF antagonism reduces the severity of systemic inflammation when given after the induction of mild AP in mice. These results suggest that Lexipafant may be useful in the treatment of mild pancreatitis after its clinical onset.
Lane
J S
JS
Department of Surgery, UCLA Medical Center, Los Angeles, CA 90095, USA.
Todd
K E
KE
Gloor
B
B
Chandler
C F
CF
Kau
A W
AW
Ashley
S W
SW
Reber
H A
HA
McFadden
D W
DW
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010195:Pancreatitis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009195:Peroxidase / Q000032:analysis; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007093:Imidazoles; D007375:Interleukin-1; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000681:Amylases; D007930:Leucine; C103289:lexipafant