Boost Kim A, Hoegl Sandra, Hofstetter Christian, Flondor Michael, Stegewerth Klaus, Platacis Ilka, Pfeilschifter Josef, Muhl Heiko, Zwissler Bernhard
Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
Pharmazentrum Frankfurt/ZAFES, University Hospital of Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
Intensive Care Med. 2007 May;33(5):863-871. doi: 10.1007/s00134-007-0588-0. Epub 2007 Mar 24.
We set out to investigate whether the nebulized and inhaled specific caspase-1 inhibitor Ac-YVAD-CHO has the potential to attenuate the pulmonary and systemic release of the caspase-1-dependent cytokines interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18) as well as their downstream enzymes iNOS and COX-2 in rat experimental endotoxaemia.
Controlled, randomized animal study in a university research facility.
Male Sprague-Dawley rats (n=32) were randomly treated as follows: Inhaled Ac-YVAD-CHO was administered in eight rats at a inhaled total dosage of 5 mg and in eight rats at a inhaled total dose of 0.5 mg before infusion of lipopolysaccharide (LPS; 5 mg/kg, i.v.). Eight animals received LPS only. Eight animals served as controls without endotoxaemia.
After 4h of endotoxaemia, levels of IL-1 beta, IL-18 and TNF-alpha in plasma and bronchoalveolar fluid (BALF) were analyzed. Nitric oxide (NO) release from alveolar macrophages was measured by Griess assay. Amounts of iNOS protein in alveolar macrophages and COX-2 protein in lung homogenates were determined by Western blotting. Significant reductions in release of IL-1 beta (-58%, p<0.05) and IL-18 (-51%, p<0.05) in plasma and IL-1 beta (-59%, p<0.05) in BALF were found in animals pretreated with inhaled caspase-1 inhibitor compared with animals without therapy. Expression of iNOS in alveolar macrophages and COX-2 in lung tissue was concurrently decreased in the treatment groups compared with control animals.
Our data demonstrate that administration of the caspase-1 inhibitor Ac-YVAD-CHO by inhalation is able to reduce the pulmonary and systemic release of proinflammatory mediators in rat endotoxaemia. These results further underscore that inhalation may constitute an effective route of anti-inflammatory drug administration, beneficial in the clinical setting of ARDS.
我们旨在研究雾化吸入特异性半胱天冬酶 -1抑制剂Ac-YVAD-CHO是否有可能减轻大鼠实验性内毒素血症中半胱天冬酶 -1依赖性细胞因子白细胞介素 -1β（IL-1β）和白细胞介素 -18（IL-18）以及它们的下游酶诱导型一氧化氮合酶（iNOS）和环氧化酶 -2（COX-2）的肺和全身释放。
在大学研究机构进行的对照、随机动物研究。
雄性Sprague-Dawley大鼠（n = 32），随机分为以下几组：8只大鼠在静脉注射脂多糖（LPS；5 mg/kg）前吸入总剂量为5 mg的Ac-YVAD-CHO，8只大鼠吸入总剂量为0.5 mg的Ac-YVAD-CHO。8只动物仅接受LPS注射。8只动物作为无内毒素血症的对照。
内毒素血症4小时后，分析血浆和支气管肺泡灌洗液（BALF）中IL-1β、IL-18和肿瘤坏死因子 -α（TNF-α）的水平。通过格里斯（Griess）测定法测量肺泡巨噬细胞释放的一氧化氮（NO）。通过蛋白质印迹法测定肺泡巨噬细胞中iNOS蛋白的含量和肺匀浆中COX-2蛋白的含量。与未治疗的动物相比，吸入半胱天冬酶 -1抑制剂预处理的动物血浆中IL-1β（-58%，p<0.05）和IL-18（-51%，p<0.05）的释放以及BALF中IL-1β（-59%，p<0.05）的释放均显著降低。与对照动物相比，治疗组肺泡巨噬细胞中iNOS的表达和肺组织中COX-2的表达同时降低。
我们的数据表明，吸入半胱天冬酶 -1抑制剂Ac-YVAD-CHO能够减少大鼠内毒素血症中促炎介质的肺和全身释放。这些结果进一步强调吸入可能是一种有效的抗炎药物给药途径，对急性呼吸窘迫综合征（ARDS）的临床治疗有益。
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