von Bismarck Philipp, Klemm Karsten, García Wistädt Carlos-Francisco, Winoto-Morbach Supandi, Schütze Stefan, Krause Martin F
Department of Paediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 20, Kiel, Germany.
Pulm Pharmacol Ther. 2009 Aug;22(4):297-304. doi: 10.1016/j.pupt.2009.02.002. Epub 2009 Feb 28.
Acute respiratory failure in neonates (e.g. ARDS, meconium aspiration pneumonitis, pneumonia) is characterized by an excessive inflammatory response, governing the migration of polymorpho-nuclear leukocytes (PMNLs) into lung tissue and causing consecutive impairment of gas exchange and lung function. Critical to this inflammatory response is the activation of nuclear factor-kappaB (NF-kappaB) that is required for transcription of the genes for many pro-inflammatory mediators. We asked whether the inhibition of NF-kappaB activity using either a selective inhibitor (IKK-NBD peptide) or dexamethasone would be more effective in decreasing NF-kappaB activity and chemokine expression in pulmonary cells. Changes in lung function were repeatedly assessed for 24h following induction of acute respiratory failure and therapeutic intervention. We conducted a randomized, controlled, prospective animal study with mechanically ventilated newborn piglets which underwent repeated airway lavage (20+/-2 [SEM]) to remove surfactant and to induce lung inflammation. Admixed to 100 mg kg(-1) surfactant, piglets then received either IKK-NBD peptide (S+IKK), a selective inhibitor of NF-kappaB activation, its control peptide without intrinsic activity, dexamethasone (S+Dexa), its solvent aqua, or an air bolus only (all groups n=8). After 24h of mechanical ventilation, the following differences were measured: PaO(2)/FiO(2) (S+IKK 230+/-9 mm Hg vs. S+Dexa 188+/-14, p<0.05); ventilation efficiency index (0.18+/-0.01 [3800/(PIP-PEEP)()f()PaCO(2)] vs. 0.14+/-0.01, p<0.05); extravascular lung water (24+/-1 ml kg(-1) vs. 29+/-2, p<0.05); PMNL in BAL fluid (112+/-21 cells microl(-1) vs. 208+/-34, p<0.05), IL-8 (351+/-117 pg ml(-1) vs. 491+/-144, p=ns) and leukotriene B(4) (23+/-7 pg ml(-1) vs. 71+/-11, p<0.01) in BAL fluid. NF-kappaB activity in the nucleus of pulmonary cells differed by 32+/-5% vs. 55+/-3, p<0.001. Differences between these two intervention groups were more pronounced in the second half of the observation period (hours 12-24). At 24h of mechanical ventilation, inhibition of NF-kappaB activity by IKK-NBD peptide admixed to surfactant as a carrier caused improved gas exchange, lung function and reduced pulmonary inflammation, as evidenced by reduction in PMNL migration into lung tissue due to reduced nuclear NF-kappaB activity. We conclude that IKK-NBD admixture to surfactant in acute neonatal respiratory failure is superior to dexamethasone administration within the first 24h.
新生儿急性呼吸衰竭（如急性呼吸窘迫综合征、胎粪吸入性肺炎、肺炎）的特征是炎症反应过度，导致多形核白细胞（PMNLs）迁移至肺组织，并连续损害气体交换和肺功能。这种炎症反应的关键是核因子-κB（NF-κB）的激活，它是许多促炎介质基因转录所必需的。我们研究了使用选择性抑制剂（IKK-NBD肽）或地塞米松抑制NF-κB活性是否能更有效地降低肺细胞中NF-κB活性和趋化因子表达。在诱导急性呼吸衰竭和进行治疗干预后的24小时内，反复评估肺功能变化。我们对机械通气的新生仔猪进行了一项随机、对照、前瞻性动物研究，这些仔猪接受了反复气道灌洗（20±2 [标准误]）以清除表面活性剂并诱导肺部炎症。然后，将仔猪与100 mg kg⁻¹表面活性剂混合，分别给予NF-κB激活的选择性抑制剂IKK-NBD肽（S+IKK）、无内在活性的对照肽、地塞米松（S+Dexa）、其溶剂水或仅给予空气团注（所有组n = 8）。机械通气24小时后，测量以下差异：动脉血氧分压/吸入氧分数值（S+IKK为230±9 mmHg，S+Dexa为188±14，p<0.05）；通气效率指数（0.18±0.01 [3800/(气道峰压-呼气末正压)呼吸频率动脉血二氧化碳分压]，S+IKK组对比S+Dexa组为0.14±0.01，p<0.05）；血管外肺水（24±1 ml kg⁻¹对比29±2，p<0.05）；支气管肺泡灌洗液中的PMNL（112±21个细胞/μl对比208±34，p<0.05）、支气管肺泡灌洗液中的白细胞介素-8（351±117 pg/ml对比491±144，p=无显著性差异）和白三烯B4（23±7 pg/ml对比71±11，p<0.01）。肺细胞核中的NF-κB活性差异为32±5%对比55±3，p<0.001。这两个干预组之间的差异在观察期后半段（12至24小时）更为明显。在机械通气24小时时，作为载体与表面活性剂混合的IKK-NBD肽抑制NF-κB活性可改善气体交换、肺功能并减轻肺部炎症，这表现为由于核NF-κB活性降低，PMNL向肺组织的迁移减少。我们得出结论，在急性新生儿呼吸衰竭中，将IKK-NBD与表面活性剂混合在最初24小时内优于给予地塞米松。
