Society for Surgery of the Alimentary Tract

1998 Abstract: ENDOTHELIN ANTAGONISM REDUCES THE SYSTEMIC INFLAMMA-TORY RESPONSE IN A MURINE MODEL OF INTESTINAL ISCHEMIA/REPERFUSION. J.S. Lane, K.E. Todd, D.A. Rigberg, B. Gloor MD, A.D. Kau, S.W. Ashley*, D.W. McFadden, H.A. Reber, C.F. Chandler, Departments of Surgery, UCLA School of Medicine, Los Angeles CA, *Brigham and Women's Hospital, Boston MA. 74

Abstracts
1998 Digestive Disease Week

#978

ENDOTHELIN ANTAGONISM REDUCES THE SYSTEMIC INFLAMMA-TORY RESPONSE IN A MURINE MODEL OF INTESTINAL ISCHEMIA/
REPERFUSION. J.S. Lane, K.E. Todd, D.A. Rigberg, B. Gloor MD, A.D. Kau, S.W. Ashley, D.W. McFadden, H.A. Reber, C.F. Chandler, Departments of Surgery, UCLA School of Medicine, Los Angeles CA, Brigham and Women's Hospital, Boston MA.

Endothelin peptides are known to be involved in the systemic inflammatory response by stimulating cytokine production and neutrophil chemotaxis. Intestinal ischemia/reperfusion(I/R) has been associated with increased systemic cytokine levels and neutrophil accumulation in distant organs. We now investigate the effect of endothelin antagonism on the inflammatory response in a murine model of intestinal I/R.

METHODS: Forty-eight female Swiss-Webster mice were divided into four groups. Group 1 underwent forty-five minutes of superior mesenteric artery occlusion followed by three hour reperfusion (I/R). Group 2 underwent laparotomy alone(Sham). Group 3 underwent I/R, plus treatment with the endothelin antagonist, PD145065, 20 mg/kg IP every two hours, starting one hour before reperfusion(Pre-tx). Group 4 was treated with an equal dose of PD145065, starting one hour after reperfusion(Post-tx). Animals were sacrificed three hours after sham/reperfusion. Serum cytokine levels were determined by ELISA. Lung was harvested for determination of myeloperoxidase(MPO) activity. Histologic scoring of jejunal sections was performed by two blinded investigators.

RESULTS: Mean ± SEM, *p < 0.05 vs. I/R, **p < 0.01 vs. I/R

	I/R	Sham	Pre-tx	Post-tx
TNF__(pg/ml)	78.5 ± 9.9	14.4 ± 2.9**	46.1 ± 3.4**	45.9 ± 11.1*
IL-6 (pg/ml)	932.8 ± 297.7	227.7 ± 56.0**	159.6 ± 44.6**	51.9 ± 9.8**
IL-10 (pg/ml)	703 ± 73	101 ± 21**	473 ± 45*	407 ± 29**
Lung MPO (U/g)	4.01 ± 0.1	1.6 ± 0.2**	2.6 ± 0.1*	3.7 ± 0.2
Histologic Score	9.18 ± 0.77	0.90 ± 0.27**	4.14 ± 0.56**	5.91 ± 0.99*

CONCLUSIONS: The endothelin antagonist, PD145065, reduced the markers of local and systemic inflammation in a murine model of intestinal I/R. This effect was present whether PD145065 was given before or after reperfusion. Endothelin antagonism may be effective by reducing cytokine production and pulmonary neutrophil accumulation. This mechanism appears to be independent of increases in IL-10 levels.

Abstracts1998 Digestive Disease Week

Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.

Abstracts
1998 Digestive Disease Week