Gillespie M N, Olson J W, Hennig B, Cohen D A, McClain C J, Goldblum S E
University of Kentucky College of Pharmacy, Division of Pharmacology and Toxicology, College of Medicine, Lexington.
Toxicol Appl Pharmacol. 1989 Mar 15;98(1):134-43. doi: 10.1016/0041-008x(89)90141-5.
Previous studies have shown that abnormal alveolar macrophages and biological activity resembling the macrophage-derived mediator interleukin-1 (IL-1) can be detected in bronchoalveolar lavage fluid from rats with monocrotaline-induced lung injury and pulmonary hypertension. To determine if monokines might play a pathogenic role in this model, the present study evaluated the effects of a murine monokine preparation enriched in IL-1 bioactivity on selected events characterizing the early pneumotoxic response to monocrotaline, including pulmonary edema and protein extravasation, pulmonary vascular hyperreactivity, and enhanced lung tissue activity of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). Intravenous injection of the monokine preparation containing 200 units/kg IL-1 (quantified by lymphocyte activating factor assay) into intact rats produced pulmonary edema within 3 hr manifested by increases in the lung wet-to-dry weight ratio and in the extent of pulmonary albumin extravasation. The edema had resolved within 24 hr of monokine administration as indicated by a return to control levels of the wet-to-dry weight ratio and albumin extravasation index. The monokine preparation also increased the transfer of albumin across monolayers of cultured porcine pulmonary vascular endothelial cells. While salt solution-perfused rat lungs isolated from animals treated 3 hr previously with the monokine preparation were hyporesponsive to angiotensin II, preparations derived from animals treated 24 hr previously were markedly hyperresponsive to the vasoconstrictor actions of the peptide. Pressor responses to potassium chloride and prostaglandin F2a were unaffected by exposure to the monokine preparation. Lung ODC activity in monokine-exposed animals did not differ from control at 3, 6, or 24 hr after treatment. In contrast, a 24-hr exposure of cultured pulmonary vascular endothelial cells to the monokine preparation increased ODC activity approximately 100-fold. These observations indicate that a monokine preparation containing IL-1 bioactivity causes transient pulmonary edema and pulmonary vascular hyperreactivity and increases ODC activity in pulmonary vascular endothelial cells. Because the monokine preparation mimics certain aspects of monocrotaline-induced pneumotoxicity in the rat, it is reasonable to postulate that monokines could play a pathogenic role in this and similar animal models of lung injury and pulmonary hypertension.
先前的研究表明，在患有野百合碱诱导的肺损伤和肺动脉高压的大鼠的支气管肺泡灌洗液中，可以检测到异常的肺泡巨噬细胞以及类似于巨噬细胞衍生介质白细胞介素-1（IL-1）的生物活性。为了确定单核因子是否可能在该模型中发挥致病作用，本研究评估了富含IL-1生物活性的鼠单核因子制剂对表征对野百合碱早期肺毒性反应的特定事件的影响，包括肺水肿和蛋白质渗出、肺血管高反应性以及多胺生物合成限速酶鸟氨酸脱羧酶（ODC）的肺组织活性增强。将含有200单位/千克IL-1（通过淋巴细胞激活因子测定法量化）的单核因子制剂静脉注射到完整大鼠体内，在3小时内产生肺水肿，表现为肺湿重与干重之比增加以及肺白蛋白渗出程度增加。如湿重与干重之比和白蛋白渗出指数恢复到对照水平所示，水肿在给予单核因子制剂后24小时内消退。单核因子制剂还增加了白蛋白跨培养的猪肺血管内皮细胞单层的转运。虽然从3小时前用单核因子制剂处理的动物分离的盐溶液灌注大鼠肺对血管紧张素II反应性降低，但从24小时前处理的动物获得的制剂对该肽的血管收缩作用明显高反应。对氯化钾和前列腺素F2α的升压反应不受单核因子制剂暴露的影响。在处理后3、6或24小时，暴露于单核因子的动物的肺ODC活性与对照无差异。相比之下，培养的肺血管内皮细胞暴露于单核因子制剂24小时可使ODC活性增加约100倍。这些观察结果表明，含有IL-1生物活性的单核因子制剂可导致短暂性肺水肿和肺血管高反应性，并增加肺血管内皮细胞中的ODC活性。由于单核因子制剂模拟了大鼠中野百合碱诱导的肺毒性的某些方面，因此合理推测单核因子可能在这种及类似的肺损伤和肺动脉高压动物模型中发挥致病作用。
