Carraway M S, Welty-Wolf K E, Kantrow S P, Huang Y C, Simonson S G, Que L G, Kishimoto T K, Piantadosi C A
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):938-49. doi: 10.1164/ajrccm.157.3.9707129.
Recruitment of polymorphonuclear leukocytes (PMN) through upregulation of cellular adhesion molecules is a proposed mechanism of injury in sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that pretreatment of baboons with a monoclonal antibody to human E- and L-selectin (EL-246) during sepsis would decrease PMN influx into tissues and result in less organ injury during gram-negative sepsis. We studied 14 anesthetized, ventilated adult baboons; six animals received 1 mg/kg of EL-246 before infusion of an LD100 of live Escherichia coli and six received the E. coli infusion without antibody therapy. Two other animals received 1 mg/kg of EL-246 intravenously without an infusion of bacteria. Intermittent measurements were made of circulatory pressures, cardiac output, urine output, arterial blood gases, ventilation:perfusion ratio (VA/Q), and hematologic status. The experiments were ended at 48 h or at the time of death. Tissues were harvested for pathology and biochemical measurements. The E. coli infusions were associated with a hyperdynamic state, pulmonary hypertension, systemic hypotension, decreased urine output (UOP), and metabolic acidosis. The antibody partly blocked PMN migration, but there were few significant physiologic or biochemical differences between the EL-246-treated and untreated animals. In the antibody-treated animals, UOP was decreased, metabolic acidosis was worsened, and median survival time was decreased significantly. We conclude that treatment with an antibody to E- and L-selectin in gram-negative sepsis does not improve gas exchange or protect against lung injury, and is associated with decreased survival time in primates.
通过上调细胞粘附分子来募集多形核白细胞（PMN）是脓毒症和急性呼吸窘迫综合征（ARDS）中一种假定的损伤机制。我们假设在脓毒症期间用抗人E-选择素和L-选择素的单克隆抗体（EL-246）预处理狒狒，会减少PMN向组织内的流入，并在革兰氏阴性脓毒症期间导致较轻的器官损伤。我们研究了14只麻醉、通气的成年狒狒；6只动物在输注致死剂量（LD100）的活大肠杆菌之前接受1mg/kg的EL-246，另外6只接受大肠杆菌输注但未进行抗体治疗。另外两只动物静脉注射1mg/kg的EL-246但未输注细菌。间歇性测量循环压力、心输出量、尿量、动脉血气、通气/灌注比（VA/Q）和血液学状态。实验在48小时或动物死亡时结束。采集组织进行病理学和生化测量。大肠杆菌输注与高动力状态、肺动脉高压、全身低血压、尿量减少（UOP）和代谢性酸中毒有关。该抗体部分阻断了PMN的迁移，但在接受EL-246治疗和未治疗的动物之间，几乎没有显著的生理或生化差异。在接受抗体治疗的动物中，UOP降低，代谢性酸中毒加重，中位生存时间显著缩短。我们得出结论，在革兰氏阴性脓毒症中用抗E-选择素和L-选择素抗体治疗并不能改善气体交换或预防肺损伤，并且与灵长类动物生存时间缩短有关。
