Attenuation of Multiple Organ Dysfunction in a Chronic Sheep Model by the 21-Aminosteroid U74389G

Abstract

Animal studies have shown that 21-aminosteroids have beneficial effects on cell and organ functions in several acute models of traumatic, hemorrhagic, and septic shock. However, it is not known if the 21-aminosteroid U74389G has any beneficial effect on organ functions in a recently developed chronic sheep model of multiple organ dysfunction after trauma. Furthermore, it is not known whether this drug has any effect onin vivoleukocyte function in this animal model. To study this, anesthetized animals were subjected to hemorrhagic shock (2 hr at a mean arterial blood pressure of 50 mmHg) and femoral reaming at Day 0. The following 5 days, endotoxin (ET; 0.75 μg/kg BW) and zymosan-activated plasma (ZAP; 20 ml/animal) were given every 12 hr. During the third phase (Days 6–10), the animals were merely observed. This kind of model resulted in progressive organ dysfunction indicated by increased cardiac output, decreased systemic vascular resistance, an increase of plasma-sorbitoldehydrogenase, impaired bilirubin metabolism, and impaired renal and lung function in nontreated animals. Animals receiving U74389G (3 mg/kg BW) during resuscitation from hemorrhagic shock and each time before ET/ZAP administration showed less severe organ dysfunction. Furthermore, U74389G showed beneficial effects on lung function, although it had no effect on accumulation of leukocytes in the lung or on the chemiluminescence response of isolated leukocytes from bronchoalveolar lavage fluid. These results suggest that U74389G may be a useful therapeutic agent in the prevention of multiple organ dysfunction after hemorrhagic and traumatic shock.