Beneficial effects of LEX032, a novel recombinant serine protease inhibitor, in murine traumatic shock

Abstract

The effects of LEX032, a novel recombinant serine protease inhibitor (i.e., serpin), were investigated in an experimental model of Noble-Collip drum shock. Pentobarbital-anesthetized rats subjected to drum trauma and receiving only the vehicle, developed severe traumatic shock with hypotension. These traumatized rats exhibited a survival time of 135 +/- 29 min, endothelial dysfunction, and a significant increase in intestinal myeloperoxidase activity. In contrast, LEX032 given intravenously (15 mg/kg bolus) resulted in a significant prolongation of survival time to 264 +/- 25 min (p < .01), a significant and sustained increase in mean arterial blood pressure, and a significant attenuation of intestinal myeloperoxidase activity (p < .05). Moreover, administration of LEX032 significantly preserved superior mesenteric artery (SMA) endothelial function as measured by the relaxation response of isolated (SMA) rings to acetylcholine, an endothelium-dependent vasodilator (64 +/- 10% vs. 25 +/- 6%, p < .01 compared with untreated trauma rats). Vasorelaxation responses to an endothelium-independent vasodilator, NaNO2, were unchanged in trauma. Our results indicate a significant protective role of LEX032 in traumatic shock, based on the preservation of endothelial function, reduced neutrophil accumulation in injured tissues, and increased survival time. These findings suggest that inhibition of serine proteases, some of which are from neutrophils, can be beneficial in traumatic shock in rats.