Nathens A B, Marshall J C, Watson R W, Dackiw A P, Rotstein O D
Department of Surgery, Toronto Hospital Ontario, Canada.
Surgery. 1996 Aug;120(2):360-6. doi: 10.1016/s0039-6060(96)80310-2.
Alterations in the cellular redox state play a critical role in cell signaling and cell activation, suggesting that administration of sulfhydryl-reactive agents may have important modulatory effects on the inflammatory response. We postulated that intracellular thiol depletion may attenuate the pulmonary inflammatory response after intratracheal administration of endotoxin (LPS) and that this attenuation would supersede the reduction in antioxidant defenses associated with depletion of the endogenous antioxidant, glutathione.
Sprague Dawley rats were administered diethylmaleate (6 mmol/kg intraperitoneally), a rapidly acting glutathione-depleting agent, followed by intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary flux of 125-I albumin and expressed as a permeability index.
Administration of diethylmaleate reduced lung glutathione levels from 1310 +/- 114 to 185 +/- 48 nmol/gm. This was associated with a reduction in the permeability index after LPS treatment (LPS, 0.22 +/- 0.03 versus LPS + diethylmaleate, 0.03 +/- 0.01). Bronchoalveolar lavage fluid polymorphonuclear neutrophil counts were markedly reduced in animals pretreated with diethylmaleate (LPS, 90.5 +/- 24 x 10(6) versus LPS + diethylmaleate, 1.9 +/- 0.4 x 10(6)). Peripheral blood polymorphonuclear neutrophils isolated from animals treated with diethylmaleate had equivalent chemotactic responses to n-formyl-methionyl-leucyl-phenylalanine and normal up-regulation of CD11b as determined by flow cytometry. Levels of bronchoalveolar lavage fluid tumor necrosis factor-alpha were unaffected.
Diethylmaleate attenuates LPS-induced lung injury through a reduction in lung polymorphonuclear neutrophil sequestration. Normal peripheral blood neutrophil chemotactic responses and CD11b expression suggest that thiol depletion might mediate this effect through inhibition of endothelial cell adhesion molecule activity.
细胞氧化还原状态的改变在细胞信号传导和细胞激活中起关键作用，这表明给予巯基反应性药物可能对炎症反应具有重要的调节作用。我们推测，细胞内巯基耗竭可能减轻气管内给予内毒素（LPS）后的肺部炎症反应，并且这种减轻作用将超过与内源性抗氧化剂谷胱甘肽耗竭相关的抗氧化防御能力的降低。
给Sprague Dawley大鼠腹腔注射马来酸二乙酯（6 mmol/kg），一种快速作用的谷胱甘肽耗竭剂，随后气管内给予LPS。通过测量125-I白蛋白的跨肺通量评估肺损伤，并表示为通透性指数。
给予马来酸二乙酯使肺谷胱甘肽水平从1310±114降至185±48 nmol/gm。这与LPS治疗后通透性指数的降低相关（LPS，0.22±0.03对LPS +马来酸二乙酯，0.03±0.01）。在预先用马来酸二乙酯处理的动物中，支气管肺泡灌洗液多形核中性粒细胞计数明显减少（LPS，90.5±24×10(6)对LPS +马来酸二乙酯，1.9±0.4×10(6)）。通过流式细胞术测定，从用马来酸二乙酯处理的动物中分离的外周血多形核中性粒细胞对n-甲酰甲硫氨酰-亮氨酰-苯丙氨酸具有同等的趋化反应和正常的CD11b上调。支气管肺泡灌洗液肿瘤坏死因子-α水平未受影响。
马来酸二乙酯通过减少肺多形核中性粒细胞的滞留减轻LPS诱导的肺损伤。正常的外周血中性粒细胞趋化反应和CD11b表达表明，巯基耗竭可能通过抑制内皮细胞粘附分子活性介导这种作用。
