Topical inhibition of nuclear factor-kappaB enhances reduction in lung edema by surfactant in a piglet model of airway lavage.
OBJECTIVE
Acute respiratory distress syndrome is occasionally seen in newborn infants due to a severe inflammatory process in the lungs that affects capillary-alveolar permeability, epithelial integrity, and type I and II pneumocyte function. The aim of this study was to investigate the effect of a topically applied nuclear factor-kappaB inhibitor (IkappaB kinase-NF-kappaB essential modulator binding domain [IKK-NBD] peptide) on gas exchange, lung function, lung fluids, and inflammation in a piglet model of repeated airway lavage that is characterized by surfactant deficiency, lung edema, and an inflammatory response.


METHODS
Prospective, randomized, controlled animal study.


METHODS
Research laboratory of a university children's hospital.


METHODS
A total of 24 anesthetized, mechanically ventilated newborn piglets.


METHODS
Repeated airway lavage was carried out until both the Pao2 decreased to approximately 40 mm Hg, while ventilating the piglets with an Fio2 of 0.6, and a peak inspiratory pressure of >/=18 cm H2O was needed to maintain tidal volume at 6 mL/kg. One group of piglets served as a control (n = 8), a second group (S, n = 8) received a porcine surfactant preparation (Curosurf), and a third group received IKK-NBD peptide admixed to surfactant (S+IN, n = 8).


RESULTS
After 6 hrs of mechanical ventilation after intervention, S+IN group piglets showed decreased extravascular lung water (S+IN vs. S, 20 +/- 3 vs. 28 +/- 10 mL/kg; p < .05) and a lesser protein content in the epithelial lining fluid (S+IN vs. S, 38 +/- 5 vs. 50 +/- 5 mg/L; p < .05). Functional residual capacity (S+IN vs. S, 16.7 +/- 6.3 vs. 12.2 +/- 4.3 mL/kg; p < .05), alveolar volume (S+IN vs. S, 5.4 +/- 1.8 vs. 4.6 +/- 1.5 mL/kg; p < .05), and lung mechanics were improved. Bronchoalveolar lavage showed a lesser percentage of polymorphonuclear leukocytes (S+IN vs. S, 70% +/- 6% vs. 82% +/- 3%; p < .01) and a reduction in the chemokine leukotriene B4 (S+IN vs. S, 2.0 +/- 0.6 vs. 3.5 +/- 1.4 pg/mL; p < .01).


CONCLUSIONS
A topically applied nuclear factor-kappaB inhibitor improves lung edema and lung volumes and reduces inflammation in this newborn piglet model of airway lavage.
Ankermann
Tobias
T
Department of Pediatrics, Christian-Albrechts-University, Kiel, Germany.
Reisner
Anja
A
Wiemann
Tina
T
Krams
Matthias
M
Köhler
Heike
H
Krause
Martin F
MF
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D057846:Cell-Penetrating Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D007231:Infant, Newborn; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology / Q000627:therapeutic use*; D011654:Pulmonary Edema / Q000188:drug therapy*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011663:Pulmonary Surfactants / Q000627:therapeutic use*; D011897:Random Allocation; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy* / Q000473:pathology; D015656:Respiratory Mechanics / Q000187:drug effects; D018709:Statistics, Nonparametric; D013552:Swine; D014109:Total Lung Capacity / Q000187:drug effects
D057846:Cell-Penetrating Peptides; D016207:Cytokines; C575063:IKK NBD peptide; D016328:NF-kappa B; D011663:Pulmonary Surfactants; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human