DUAL BLOCKADE OF P-SELECTIN AND BETA(2)-INTEGRIN IN THE LIVER INFLAMMATORY RESPONSE AFTER UNCONTROLLED HEMORRHAGIC-SHOCK

Background: Neutrophil infiltration is a characteristic feature of the hepatic injury associated with prolonged hypotension. Previous work h as already stressed the important contribution of neutrophil-endotheli al cell interactions in the organ injury seen after hemorrhagic shock. Single-blockade strategies using monoclonal antibodies (MAbs) against either selectin or integrin receptors have been demonstrated to be ef fective in limiting the tissue inflammatory response observed in this Clinical disorder. One unexplored topic is the additive effect(s) and the potential antiinflammatory properties of the combined blocking of P-selectin plus beta(2)-integrin in the lives inflammatory response af ter uncontrolled hemorrhagic shock in rats. Study Design: Sprague-Dawl ey rats (n = 64) weighing 250-300 g were included in a three-phase mod el of uncontrolled hemorrhagic shock. A prehospital phase consisted of 90 minutes of fluid resuscitation with lactated Ringer's solution to Peach a mean arterial pressure (MAP) of 40 mmHg; a hospital phase cons isted of 60 minutes of hemostasis and fluid resuscitation with lactate d Ringer's solution to reach a MAP of 80 mmHg; and the third phase was 3 days of observation. All rats had 3 mL/100 g of blood volume shed d uring the initial 15 minutes. At 30 minutes, 75% tail amputation produ ced uncontrolled hemorrhagic shock. Four groups were randomized (n = 1 6 per group), and treatment at the beginning of resuscitation included normal saline (group 1); anti-P-selectin MAb, RMP-1 (group 2); aslti- beta(2),-integrin MAb, WT.3 (group 3); or anti-P-selectin plus anti-be ta(2)-integrin MAbs (groun 4). The folresuscitation, liver injury test s, liver tissue myeloperoxidase, and liver histology. Results: Dual bl ockade of P-selectin and beta(2)-integrin significantly reduced fluid requirements for resuscitation (p < 0.05). We also observed a statisti cally significant improvement (p < 0.05) in tests demonstrating hepati c injury, myeloperoxidase in hepatic tissue, and histology studies. Su rvival was increased from 40% in controls to 60% with the dual-blockad e treatment. Conclusions: These results indicate that dual-blockade st rategies aimed at P-selectin and beta(2)-integin provided st protectiv e effect in the liver inflammatory response after uncontrolled hemorrh agic shock in rats. Although dual blockade was more effective than eit her individual blockade alone, questions remain about the possible red undancy in the inflammatory adhesion pathways after this clinical cond ition. (J Am Coll Surg 1998;187: 22-31. (C) 1998 by the American Colle ge of Surgeons).