Selective NF-kappaB inhibition, but not dexamethasone, decreases acute lung injury in a newborn piglet airway inflammation model.
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.
von Bismarck
Philipp
P
Department of Paediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 20, Kiel, Germany.
Klemm
Karsten
K
García Wistädt
Carlos-Francisco
CF
Winoto-Morbach
Supandi
S
Schütze
Stefan
S
Krause
Martin F
MF
D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001772:Blood Cell Count; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology*; D007249:Inflammation / Q000150:complications* / Q000473:pathology*; D016209:Interleukin-8 / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008171:Lung Diseases / Q000473:pathology* / Q000517:prevention & control*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000502:physiology; D009929:Organ Size; D011659:Pulmonary Gas Exchange; D011663:Pulmonary Surfactants / Q000627:therapeutic use; D012121:Respiration, Artificial / Q000009:adverse effects; D012140:Respiratory Tract Diseases / Q000150:complications* / Q000473:pathology*; D013552:Swine
D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D016328:NF-kappa B; D011663:Pulmonary Surfactants; D007975:Leukotriene B4; D003907:Dexamethasone