Welsh C H, Lien D, Worthen G S, Weil J V
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Am Rev Respir Dis. 1988 Nov;138(5):1106-14. doi: 10.1164/ajrccm/138.5.1106.
Since neutrophils may be important in endotoxin-induced acute lung injury, we sought to determine whether injury produced by endotoxin in vivo would be modified by pentoxifylline, which decreases neutrophil adherence and lessens neutrophil activation in vitro. Anesthetized dogs received 4 micrograms/kg Salmonella enteriditis endotoxin intravenously after pretreatment with either saline or pentoxifylline 20 mg/kg intravenously administered followed by a continuous 0.1 mg/kg/min infusion. Two hours after endotoxin, pulmonary vascular permeability to protein was assessed as the lung extravascular accumulation of intravenously administered 113mIn-transferrin. Results expressed as the ratio of extra- to intravascular protein activities showed a clear increase over control values in dogs treated with endotoxin [0.064 +/- 0.003 (mean +/- SEM) and 0.31 +/- 0.14 respectively, p less than 0.05]. This increase with endotoxin was reversed by pentoxifylline to levels similar to control values (0.063 +/- 0.044, p less than 0.05). To determine whether pentoxifylline influenced neutrophil sequestration, thin sections of lung tissue were analyzed for neutrophil density using an intercept counting technique. Neutrophil density was doubled in dogs treated with endotoxin over that seen in controls (0.078 +/- 0.008 versus 0.042 +/- 0.006 neutrophils per alveolar septa, respectively, p less than 0.05) and this increase was significantly reduced by pentoxifylline treatment (0.048 +/- 0.009, p less than 0.05). Endotoxin increased lung retention of radiolabeled neutrophils and this was also prevented by pretreatment of the neutrophils with pentoxifylline. In summary, pentoxifylline decreases neutrophil accumulation and prevents the increase in pulmonary vascular permeability to protein induced by endotoxin. These data support the premise that pentoxifylline is protective against endotoxin-induced lung injury in vivo.
由于中性粒细胞可能在内毒素诱导的急性肺损伤中起重要作用，我们试图确定己酮可可碱是否会改变内毒素在体内引起的损伤，己酮可可碱在体外可降低中性粒细胞的黏附并减轻中性粒细胞的活化。麻醉的犬在静脉注射生理盐水或20mg/kg己酮可可碱预处理后，静脉注射4μg/kg肠炎沙门氏菌内毒素，随后以0.1mg/kg/min的速度持续输注。内毒素注射两小时后，通过静脉注射113mIn-转铁蛋白后肺血管外的蓄积来评估肺血管对蛋白质的通透性。以内血管与外血管蛋白质活性之比表示的结果显示，内毒素处理的犬与对照值相比有明显升高[分别为0.064±0.003（平均值±标准误）和0.31±0.14，p<0.05]。己酮可可碱可将内毒素引起的这种升高逆转至与对照值相似的水平（0.063±0.044，p<0.05）。为了确定己酮可可碱是否影响中性粒细胞的隔离，使用截距计数技术分析肺组织薄片中的中性粒细胞密度。内毒素处理的犬中性粒细胞密度比对照组增加了一倍（分别为每肺泡间隔0.078±0.008个中性粒细胞和0.042±0.006个中性粒细胞，p<0.05），己酮可可碱处理可显著降低这种增加（0.048±0.009，p<0.05）。内毒素增加了放射性标记中性粒细胞在肺内的滞留，而己酮可可碱预处理中性粒细胞也可防止这种情况。总之，己酮可可碱减少中性粒细胞的积聚，并防止内毒素诱导的肺血管对蛋白质通透性的增加。这些数据支持己酮可可碱在体内对内毒素诱导的肺损伤具有保护作用这一前提。
