Seeger W, Hansen T, Rössig R, Schmehl T, Schütte H, Krämer H J, Walmrath D, Weissmann N, Grimminger F, Suttorp N
Department of Internal Medicine, Justus Liebig-University Giessen, FRG.
Microvasc Res. 1995 Jul;50(1):1-17. doi: 10.1006/mvre.1995.1033.
Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in inflammatory lung injury. We investigated the influence of pharmacological agents that increase intracellular c-AMP levels on endothelial and epithelial leakage in response to intravascular H2O2 challenge in buffer-perfused rabbit lungs. Endothelial permeability was assessed by determination of the capillary filtration coefficient (Kfc) and lung weight gain. Measurement of the clearance rate of inhaled aerosolized technetium-99m-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) from the lungs into the perfusion fluid was used as an index of alveolar epithelial permeability. Experiments were performed in the presence of acetylsalicylic acid to suppress H2O2-induced lung prostanoid generation and concomitant vasoconstriction. Under these conditions, H2O2 admixture to the perfusate (250 microM) caused a greater than eight-fold increase in Kfc values, resulting in > 30 g lung weight gain within 30 min in the absence of any significant vasopressor response. Pretreatment with the adenylate cyclase activators prostaglandin E1 (0.1 microM) and forskolin (0.1 microM), the dual phosphodiesterase type III/IV inhibitor zardaverine (10 microM) as well as combinations of these drugs all caused a nearly complete suppression of this early Kfc increase; and severe edema formation (> 30 g) was retarded to approximately 50-55 min. In addition to the microvascular leakage response, H2O2 caused a four- to five-fold increase in the [99mTc]DTPA clearance rate, starting within 15 min and culminating after approximately 35 min. Adenylate cyclase activation reduced this epithelial leakage response by approximately 30%, whereas zardaverine exerted no significant effect. We conclude that both microvascular endothelial and alveolar epithelial barrier function are severely compromised by intravascular H2O2 challenge in intact lungs. Pharmacological approaches to increase c-AMP levels, including both adenylate cyclase activation and phosphodiesterase inhibition, partially block the endothelial response and, to a lesser extent, the epithelial response.
中性粒细胞衍生的过氧化氢（H2O2）被认为在炎症性肺损伤中起重要作用。我们研究了能提高细胞内c-AMP水平的药物制剂对缓冲液灌注的兔肺血管内H2O2刺激所致内皮和上皮渗漏的影响。通过测定毛细血管滤过系数（Kfc）和肺重量增加来评估内皮通透性。测量从肺吸入到灌注液中的雾化99m锝标记二乙三胺五乙酸（[99mTc]DTPA）清除率，作为肺泡上皮通透性的指标。实验在乙酰水杨酸存在下进行，以抑制H2O2诱导的肺类前列腺素生成和伴随的血管收缩。在这些条件下，向灌注液中加入H2O2（250 microM）导致Kfc值增加超过八倍，在无任何明显血管加压反应的情况下，30分钟内肺重量增加>30克。用腺苷酸环化酶激活剂前列腺素E1（0.1 microM）和福斯高林（0.1 microM）、双磷酸二酯酶III/IV抑制剂扎达维林（10 microM）以及这些药物的组合进行预处理，均几乎完全抑制了这种早期Kfc增加；严重水肿形成（>30克）延迟至约50 - 55分钟。除微血管渗漏反应外，H2O2使[99mTc]DTPA清除率增加四至五倍，在15分钟内开始，约35分钟后达到峰值。腺苷酸环化酶激活使这种上皮渗漏反应降低约30%，而扎达维林无显著作用。我们得出结论，完整肺中血管内H2O2刺激会严重损害微血管内皮和肺泡上皮屏障功能。提高c-AMP水平的药理学方法，包括腺苷酸环化酶激活和磷酸二酯酶抑制，部分阻断内皮反应，并在较小程度上阻断上皮反应。
