Surfactant "fortification" by topical inhibition of nuclear factor-κB activity in a newborn piglet lavage model
OBJECTIVE: In acute respiratory distress syndrome of term newborn infants, surfactant replacement may be effective because endogenous surfactant is decreased and structurally changed. Inflammation is central to acute respiratory distress syndrome, and hence, attenuation of proinflammatory transcription factor nuclear factor (NF)-κB activation in the lung might prevent secondary loss of surfactant function. In this study, we tested the hypothesis that the topical use of a NF-κB inhibitor (IκB kinase-NF-κB essential modulator binding domain [IKK-NBD] peptide), together with surfactant as a carrier substance, improves surfactant function by attenuation of pulmonary inflammation during 24 hrs of mechanical ventilation in a neonatal piglet model of acute respiratory distress syndrome by repeated airway lavage. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory of a university children's hospital. SUBJECTS: A total of 24 anesthetized, mechanically ventilated newborn piglets. INTERVENTIONS: After 20 ± 6 (mean ± sd) lavages to induce lung failure and inflammation, a porcine surfactant (100 mg/kg) with (S+IKK) or without (S) 1.25 mg of IKK-NBD peptide, or an air bolus (control) was administered into the airways. Lung function was monitored throughout 24 hrs of mechanical ventilation and completed by ex vivo analyses. MEASUREMENTS AND MAIN RESULTS: Pao2 (S+IKK, 125 ± 16 mm Hg; S, 105 ± 33; control, 61 ± 20), ventilation efficiency index, functional residual capacity, compliance of the respiratory system, and extravascular lung water (S+IKK, 24 ± 2 mL/kg; S, 30 ± 7; control, 34 ± 8) were all significantly improved in S+IKK piglets after 24 hrs. Decreased leukocyte concentrations in bronchoalveolar lavage (S+IKK, 152 ± 94 cells/μL; S, 202 ± 100; control, 276 ± 57) were observed together with reduced acid sphingomyelinase activity, lowered ceramide concentrations, improved surfactant function (minimum surface tension: S+IKK, 10.8 ± 6.1 mN/m; S, 13.2 ± 3.9; control, 20.9 ± 8.5), and decreased NF-κB activation in lung tissue. CONCLUSION: Supplementation of exogenous surfactant with a NF-κB inhibitor to create a "fortified" surfactant improves gas exchange, lung function, and pulmonary edema during 24 hrs of mechanical ventilation, without a secondary functional relapse. Inhibition of NF-κB suppressed acid sphingomyelinase activity and ceramide generation, indicating a novel proinflammatory link of NF-κB.
- Acid sphingomyelinase
- Fortified surfactant
- Lung edema
- Neonatal acute respiratory distress syndrome
- Surface tension