ABSTRACT
RATIONALE: In acute inflammatory lung disease in newborn infants, exogenous surfactant only transiently improves lung function. We hypothesized that the transient nature of this protection is in part explained by elevated acid sphingomyelinase (a-SMase) activity that may inactivate surfactant and promote proinflammatory responses. OBJECTIVES: We investigated the intermediate-term effects (>12 h) of a-SMase inhibition in a neonatal piglet model of repeated airway lavage by the intratracheal use of the a-SMase inhibitor imipramine, together with exogenous surfactant as a carrier substance. METHODS: After surfactant washout and induction of pulmonary inflammation, lung function was monitored over 24 hours of mechanical ventilation and followed by ex vivo analyses. In addition, we studied the effect of lipopolysaccharide inhalation in a-SMase-deficient mice at 48 hours. MEASUREMENTS AND MAIN RESULTS: Surfactant washout increased both pulmonary a-SMase activity and ceramide content; this was attenuated by surfactant and prevented in the surfactant plus imipramine group. Compared with surfactant alone, Pa(O(2)), dynamic compliance, and extravascular lung water were improved in the final 12 hours in the surfactant plus imipramine group. At 24 hours, lavage fluid leukocyte counts and IL-8 concentrations decreased, and physical surfactant film properties improved. In the mouse model at 48 hours, a-SMase-deficient mice showed reduced pulmonary ceramide levels and attenuated leukocyte influx into the alveolar space. CONCLUSIONS: We conclude that stabilization of exogenous surfactant by adding imipramine to create a "fortified surfactant preparation" improves lung function in a clinically relevant piglet model, and that this effect can be attributed to the inhibition of a-SMase as evidenced in the mouse model.
Subject(s)
Enzyme Inhibitors/therapeutic use , Imipramine/therapeutic use , Pulmonary Gas Exchange/physiology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/physiopathology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Animals , Animals, Newborn , Bronchoalveolar Lavage , Ceramides/metabolism , Disease Models, Animal , Lung Compliance/physiology , Male , Mice , Mice, Inbred C57BL , Pulmonary Edema/etiology , Pulmonary Edema/metabolism , Pulmonary Edema/prevention & control , Respiratory Distress Syndrome/etiology , Swine , Time FactorsABSTRACT
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)-[kappa]B 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-[kappa]B inhibitor (I[kappa]B kinase-NF-[kappa]B 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/microL; 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-[kappa]B activation in lung tissue. CONCLUSION: Supplementation of exogenous surfactant with a NF-[kappa]B 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-[kappa]B suppressed acid sphingomyelinase activity and ceramide generation, indicating a novel proinflammatory link of NF-[kappa]B.
