Selective NF-kappaB inhibition, but not dexamethasone, decreases acute lung injury in a newborn piglet airway inflammation model.

Abstract

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.

• Authors: Philipp von Bismarck, Karsten Klemm, Carlos-Francisco García Wistädt, Supandi Winoto-Morbach, Stefan Schütze, Martin F Krause
• Journal: Pulmonary pharmacology & therapeutics (Pulm Pharmacol Ther) Vol. 22 Issue 4 Pg. 297-304 (Aug 2009) ISSN: 1522-9629 [Electronic] England
• PMID: 19254776 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Interleukin-8
• NF-kappa B
• Pulmonary Surfactants
• Leukotriene B4
• Dexamethasone

Topics

• Acute Disease
• Animals
• Animals, Newborn (physiology)
• Anti-Inflammatory Agents (pharmacology)
• Blood Cell Count
• Bronchoalveolar Lavage Fluid (cytology)
• Dexamethasone (pharmacology)
• Inflammation (complications, pathology)
• Interleukin-8 (metabolism)
• Leukotriene B4 (metabolism)
• Lung Diseases (pathology, prevention & control)
• NF-kappa B (antagonists & inhibitors)
• Neutrophils (physiology)
• Organ Size
• Pulmonary Gas Exchange
• Pulmonary Surfactants (therapeutic use)
• Respiration, Artificial (adverse effects)
• Respiratory Tract Diseases (complications, pathology)
• Swine