Selective NF-κB 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-κB (NF-κB) that is required for transcription of the genes for many pro-inflammatory mediators. We asked whether the inhibition of NF-κB activity using either a selective inhibitor (IKK-NBD peptide) or dexamethasone would be more effective in decreasing NF-κB activity and chemokine expression in pulmonary cells. Changes in lung function were repeatedly assessed for 24 h 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-κB activation, its control peptide without intrinsic activity, dexamethasone (S+Dexa), its solvent aqua, or an air bolus only (all groups n = 8).After 24 h of mechanical ventilation, the following differences were measured: PaO2/FiO2 (S+IKK 230 ± 9 mmHg vs. S+Dexa 188 ± 14, p < 0.05); ventilation efficiency index (0.18 ± 0.01 [3800/(PIP-PEEP)*f*PaCO2] 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 μl−1 vs. 208 ± 34, p < 0.05), IL-8 (351 ± 117 pg ml−1 vs. 491 ± 144, p = ns) and leukotriene B4 (23 ± 7 pg ml−1 vs. 71 ± 11, p < 0.01) in BAL fluid. NF-κB 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 24 h of mechanical ventilation, inhibition of NF-κB 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-κB activity. We conclude that IKK-NBD admixture to surfactant in acute neonatal respiratory failure is superior to dexamethasone administration within the first 24 h.