Sato K, Stelzner T J, O'Brien R F, Weil J V, Welsh C H
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver.
Am J Respir Cell Mol Biol. 1991 Mar;4(3):219-27. doi: 10.1165/ajrcmb/4.3.219.
Pentoxifylline, a methylxanthine with phosphodiesterase inhibitor activity, attenuates endotoxin-induced pulmonary vascular protein leak and decreases lung neutrophil accumulation in vivo. In vitro, pentoxifylline decreases neutrophil activation as measured by superoxide release and phagocytosis of latex beads. To test the hypothesis that the beneficial effect of pentoxifylline may be via a direct effect on the endothelial cells as well as via prevention of neutrophil activation, we incubated bovine pulmonary artery endothelial cell monolayers with endotoxin and pentoxifylline in the presence or absence of human neutrophils. Albumin clearance across the monolayers was used as an index of endothelial permeability. Endotoxin (1.0 micrograms/ml) increased albumin clearance in a dose- and time-dependent fashion (207.5 +/- 25%, P less than 0.05). Co-incubation with neutrophils enhanced this effect. Pentoxifylline significantly attenuated the endotoxin-induced increase in albumin clearance both with and without neutrophils, and lessened endotoxin-induced cell lysis (chromium release) and morphologic changes. Because increased endothelial cyclic adenosine monophosphate (cAMP) levels may decrease protein permeability and pentoxifylline increases cAMP in neutrophils, we measured cAMP levels in endothelial cells. Incubation with pentoxifylline failed to raise cAMP levels in endothelial cells, in contrast to incubation with aminophylline. In conclusion, pentoxifylline attenuates endotoxin-induced increase in albumin clearance across endothelial monolayers both in the presence and absence of neutrophils. These results suggest that part of the protective effect of pentoxifylline may be mediated via effects on endothelium. Furthermore, this pentoxifylline-mediated endothelial barrier effect appears to be independent of an effect on cAMP.
己酮可可碱是一种具有磷酸二酯酶抑制活性的甲基黄嘌呤，可减轻内毒素诱导的肺血管蛋白渗漏，并减少体内肺中性粒细胞的积聚。在体外，通过超氧化物释放和乳胶珠吞噬作用测定，己酮可可碱可降低中性粒细胞的活化。为了检验己酮可可碱的有益作用可能是通过对内皮细胞的直接作用以及预防中性粒细胞活化这一假设，我们在有或无人类中性粒细胞存在的情况下，将牛肺动脉内皮细胞单层与内毒素和己酮可可碱一起孵育。白蛋白跨单层的清除率用作内皮通透性指标。内毒素（1.0微克/毫升）以剂量和时间依赖性方式增加白蛋白清除率（207.5±25%，P<0.05）。与中性粒细胞共同孵育可增强此效应。无论有无中性粒细胞，己酮可可碱均能显著减轻内毒素诱导的白蛋白清除率增加，并减轻内毒素诱导的细胞裂解（铬释放）和形态学变化。由于内皮细胞中环磷酸腺苷（cAMP）水平升高可能会降低蛋白质通透性，且己酮可可碱可增加中性粒细胞中的cAMP，因此我们测量了内皮细胞中的cAMP水平。与氨茶碱孵育不同，己酮可可碱孵育未能提高内皮细胞中的cAMP水平。总之，无论有无中性粒细胞，己酮可可碱均可减轻内毒素诱导的内皮单层白蛋白清除率增加。这些结果表明，己酮可可碱的部分保护作用可能是通过对内皮的作用介导的。此外，这种己酮可可碱介导的内皮屏障效应似乎与对cAMP的作用无关。
