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.