Surfactant liposomes, encapsulating CuZn-superoxide dismutase (SOD) and catalase, increase alveolar type II cell antioxidant activity and protect cells against oxidant stress. We examined whether intratracheal instillation of antioxidant-surfactant liposomes increases lung antioxidant activity in premature rabbits. Pregnant New Zealand White rabbits were delivered by cesarean section on day 28 or 29 of gestation or allowed to deliver spontaneously. After premature birth or at 2 days of age in the term rabbits, the pups from each litter were divided into four groups. One group received 0.1 ml/15 g birth wt of antioxidant-surfactant liposomes by intratracheal injection and was then exposed to hyperoxia (> 95% oxygen) for 24 h and killed. The second group received an equal amount of surfactant liposomes without antioxidant enzymes and was exposed to hyperoxia for 24 h. The third group received air placebo and was exposed to hyperoxia for 24 h, and the fourth group was killed after birth if premature or at 2 days of age if term. After the pups were killed, lung homogenates were investigated for total SOD and catalase activity and DNA content. Each treatment group consisted of 12-15 rabbit pups. Lung antioxidant enzyme activity increased with advancing maturity. Among the premature rabbits, total lung SOD and catalase activity were lowest in the pups killed before hyperoxia and the air placebo controls exposed to hyperoxia, intermediate in the pups treated with liposomes without antioxidant enzymes and hyperoxia, and highest in the pups that received antioxidant-surfactant liposomes and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Although administration of exogenous corticosteroids accelerates the late gestational rise in fetal rat and lamb lung antioxidant enzyme activity, the effect of dosing intervals on these responses remains uncertain. We studied the persistence and efficacy of the antioxidant response in fetal lamb lung to a single fetal dose of corticosteroids injected between 121 and 127 days gestational age. Fetal lambs received 0.5 mg/kg of betamethasone (n = 35) or saline (n = 26) by fetal intramuscular injection 24 h, 48 h, 4 days, or 7 days before preterm delivery at 128 days gestation (term = 150 days). After delivery, the lambs were ventilated for 40 min and killed. Total superoxide dismutase, catalase, glutathione peroxidase activities, and lipid hydroperoxide levels were measured, using homogenized lung. The saline-injected controls were similar at all time points. Lung antioxidant enzyme activity was consistently higher and lipid hydroperoxide presence was lower in the betamethasone-treated groups. We conclude that the positive effect of a single fetal dose of betamethasone on lung antioxidant enzyme activity occurs within 24 h after exposure, persists over a period of 7 days without a major change in the magnitude of the response, and leads to a reduction in lipid hydroperoxide formation during immediate postdelivery oxygen exposure.

Surfactant protein A (SP-A) is a 248-residue, water-soluble, lipid-associating protein found in lung surfactant. Analysis of the amino acid sequence using the Eisenberg hydrophobic moment algorithm predicts that the SP-A segment spanning residues 114-144 has high hydrophobic moments, typical of lipid-associating amphipathic domains. The secondary structure, in vitro surface activity and in vivo lung activity of this SP-A sequence were studied with a 31-residue synthetic peptide analog (A114-144). Analysis of the secondary structure using circular dichroism and Fourier transform infrared spectroscopy indicated association with lipid dispersions and a dominant helical content. Surface activity measurements of A114-144 with surfactant lipid dispersions and the hydrophobic surfactant proteins B and C (SP-B/C) showed that A114-144 enhances surface activity under conditions of dynamic compression and respreading on a Langmuir/Wilhelmy surface balance. Synthetic surfactant dispersions containing A114-144 improved lung compliance in spontaneously breathing, 28-d premature rabbits to a greater degree than surfactant dispersions with synthetic SP-B/C and synthetic surfactant lipids alone. These observations indicate that inclusion of A114-144 may improve synthetic preparations currently used for surfactant replacement therapy.

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Although surfactant replacement therapy has dramatically improved the outcome of premature infants with respiratory distress syndrome, approximately 30% of treated infants show a transient or no response. Nonresponse to surfactant replacement therapy may be due to extreme lung immaturity and possibly surfactant inactivation. Surfactant inactivation involves aspecific biophysical events, such as interference with the formation or activity of an alveolar monolayer, and specific interactions with serum proteins, including antibodies, leaking into the alveolar space. As formulations containing surfactant proteins appear to better tolerate serum inactivation, we used an excised rat lung model to compare the susceptibility to serum inactivation of a mixture of synthetic phospholipids selected from surfactant lipid constituents, Exosurf (a protein-free synthetic surfactant), Survanta [containing surfactant proteins B and C (SP-B and -C)], and a porcine surfactant (containing SP-A, -B, and -C). For each of these preparations, we used pressure/volume determinations as an in situ measure of surfactant activity and retested the same preparations after mixing with human serum, a nonspecific surfactant inactivator. Human serum inactivated porcine surfactant to a lesser extent than Survanta, Exosurf, or synthetic phospholipids. Temperature exerted a significant effect on deflation stability, as shown by a greater lung compliance in untreated, normal lungs and a larger improvement in compliance after treating lavaged lungs with synthetic phospholipids at 37 degrees C than at 22 degrees C. We conclude that surfactant containing SP-A, -B, and -C is only moderately susceptible to inactivation with whole serum and may therefore exert a greater clinical response than protein-free surfactants or those containing only SP-B and -C.