Abstracts
1997 Digestive Disease Week

Platelet activating factor antagonism reduces the systemic inflammatory response in a murine model of acute pancreatitis.

JS Lane, KE Todd, B Gloor, CF Chandler, AD Kau, SW Ashley*, HA Reber, DW McFadden. Departments of Surgery, UCLA School of Medicine and Sepulveda VA Medical Center, Los Angeles, CA and *Brigham and Women's Hospital, Boston, MA.

We have shown that the PAF antagonist, lexipafant, reduces the severity of local pancreatic inflammation in rodents. Previous studies have determined that PAF promotes neutrophil accumulation and macrophage activation. The purpose of this study was to determine whether lexipafant reduces the systemic component of the inflammatory response in a murine model of acute edematous pancreatitis. Methods: 48 female Swiss-Webster mice, weighing 20-30g, were divided into four equal groups. Group 1 received 50 ul of saline i.p. every hour for six hours (Sham). Group 2 received saline i.p. as in Group 1, plus lexipafant i.p. (25mg/kg-dose) starting one hour after induction of pancreatitis and every three hours thereafter (Sham/lexipafant). Group 3 received cerulein i.p. (50µg/kg-dose) every hour for 6 hours (AP). Group 4 received cerulein as in Group 3, plus lexipafant i.p. as in Group 2 (AP/Lexipafant). All animals were sacrificed 3 hrs after the last cerulein injection. Serum cytokine levels (IL-1ß, TNF-alpha) were determined by ELISA technique. Standard assays were performed for serum amylase activity and lung myeloperoxidase activity (MPO).

Results: Mean ± SEM; *p<0.05; **p<0.001 vs. group 3.

                    Group 1      Group 2       Group 3       Group 4
IL-1ß (pg/ml)     115.0±8.9     97.5±9.4     182.6±23.0    122.5±10.8*
TNF-alpha (pg/ml)  30.9±4.0     32.6±4.6      80.6±6.5      38.0±6.6**
MPO(U/g)            1.6±0.4      1.8±0.2       3.4±0.4       2.6±0.2*
Amylase (U/L)       697±106      639±52       1943±102      1649±110*

Conclusions: The PAF antagonist, lexipafant, reduces the severity of the systemic inflammatory response in a murine model of acute edematous pancreatitis. These results suggest that lexipafant may exert a systemic effect by blocking cytokine production and distant organ neutrophil activation.