RESUMEN
PURPOSE: Recent studies have indicated that cytokines and inflammatory responses are related to hemorrhagic shock-(HS) induced acute lung injury. Novel, synthetic, broad-acting serine protease inhibitors that protect a wide range of animals from lethal shock have been evaluated as potential immunoresuscitation modulators. The aim of this study was to test the hypothesis that a test modulator could decrease serum and tissue pro-inflammatory mediator levels, prevent HS-induced acute lung injury, and suppress activation of the inflammatory cascade. METHODS: This HS model consisted of four phases: Phase I, initiation of HS (from 15~30 min) with a volume-controlled hemorrhage of 2.7 mL/100 g over 15 min; Phase II, maintenance of HS (HS Phase, from 30~90 min), with maintenance of shock without resuscitation; Phase III, resuscitation (RT phase, from 90~150 min), with reinfusion of 1.5 mL/100 g of blood and Ringer's lactate fluid; and Phase IV, observation and post-resuscitation (OB phase, from 150~270 min). The test rats were randomized into two groups of 15: group 1 with fluid resuscitation (control group) and group 2 with fluid and 0.5mg/kg nafamostat mesilateinfusion (treated group). RESULTS: The mean arterial pressure (MAP) of the treated group increased significantly during the observation and post-resuscitation period (Phase IV, OB 90 min). The heart rate of the control group increased significantly during the maintenance of shock (Phase II, HS 60 min), resuscitation (Phase III, RT 30 and 60 min), and observation periods (Phase IV, OB 120 min). The serum concentrations for IL-6 and IL-10 did not differ significantly between the treated and control groups. The TNF-alpha levels for the treated group were significantly lower than those of the control group (p<0.05). At the end of the observation period (OB 120 min), the treated group had significantly lower concentrations of IL-8 in the bronchoalveolar lavage fluid (BALF) than the control group (676.7+/-791.9 vs. 1062.5+/-609.9, p=0.013). CONCLUSION: We conclude that the tested serine protease inhibitor improves hemodynamic parameters, prevents acute lung injury after HS, and attenuates a robust proinflammatory cytokine response in rats.