Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS

Abstract

Background: Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants.

Methods: Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination.

Results: SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant.

Conclusion: These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant.

Figure 1

Lung physiological profile (mean ± SD) in ventilated preterm lambs without surfactant treatment (negative controls, open circles), or SRT with beractant (filled circles), poractant alfa (open squares), or lucinactant (filled squares). (a) PaO₂ increased as compared to baseline values and negative controls, independent of SRT group (**P < 0.001; ^†P < 0.05). Over time, the oxygenation response in lambs treated with lucinactant was sustained and greater than in lambs treated with beractant (*P < 0.001) or poractant alfa (^‡P < 0.05). (b) PaCO₂ decreased (P < 0.001) over time in all groups. Following SRT, PaCO₂ was lower than in negative controls for all SRT groups out to 2 h (**P < 0.001), beractant to 3 h (**P < 0.01), and poractant alfa to 4 h (^†P < 0.05) (^‡P < 0.05 beractant vs. poractant alfa). (c) pH increased (**P < 0.001) over time in all SRT groups and was greater than in negative controls, independent of SRT group. (d) Respiratory compliance increased (**P < 0.001) as compared with baseline values and over time, independent of group. Improvement in compliance was greater (**P < 0.001) in all SRT groups as compared with negative controls; no significant differences were noted between SRT groups. (e) PIP was significantly (P < 0.001) different over time as a function of group, lower in lucinactant-treated animals as compared with negative controls and animals treated with beractant at all time points (**P < 0.001; ^†P < 0.05) and poractant alfa (^‡P < 0.05) at 3 to 4 h. (f) PEEP increased (P < 0.001) over time, independent of group and was lower in lucinactant-treated animals at 3 to 4 h than in all other groups (^‡P < 0.05; **P <0.001). (g) FRC increased (P < 0.001) over time, independent of group and was greater in lucinactant-(**P < 0.001; ^†P < 0.05) or poractant alfa–treated (^‡P < 0.05) animals at 3 to 4 h than in those treated with beractant or negative controls. (h) Oxygenation index in all SRT animals was lower (**P < 0.001) than baseline and negative controls; no significant differences between SRT groups were noted. (i) Ventilation efficiency index increased (P < 0.01) over time in all SRT animals and was greater (**P < 0.001) in animals treated with lucinactant than in those treated with beractant at 3 h and all other groups at 4 h. FRC, functional residual capacity; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; SRT, surfactant replacement therapy.

Figure 2

Representative micrographs of regional lung sections of matched area obtained from one preterm lamb of each group. Top panels: nondependent lung; bottom panels: dependent lung. (a,b) Negative controls. (c,d) Beractant-treated. (e,f) Poractant alfa–treated. (g,h) Lucinactant-treated. Original magnification: 100×.

Figure 3

Histomorphological profile. (a) Expansion index, total lung. (b) Expansion index, regional lung. (c) Number of opened gas exchange units per fixed field, total lung. (d) Number of opened gas exchange units per fixed field, regional lung. For (b) and (d), open bars are nondependent, solid bars are dependent lung. Independent of lung region, the expansion index of lungs from lambs treated with SRT was greater (*P < 0.01) than those not treated with surfactant. Regional differences in expansion were noted for beractant-treated lungs, with less (**P < 0.001) expansion in the dependent than the nondependent region and as compared with the dependent region of lungs treated with lucinactant. The number of expanded gas exchange units was greater (*P < 0.01) in lucinactant- or poractant alfa–treated lungs than those not treated with surfactant, independent of region. Relative to beractant-treated lungs, the number of expanded gas exchange units was greater (**P < 0.001) in those treated with lucinactant. SRT, surfactant replacement therapy.

Figure 4

Lung inflammatory profile. Total and regional lung tissue levels of (a,b) IL-8; (c,d) IL-6; (e,f) MPO. For (b), (d), and (f), open bars are nondependent, solid bars are dependent lung. Independent of lung region, all were lower (*P < 0.01) following lucinactant treatment as compared with no surfactant treatment. Lung IL-8 following lucinactant treatment was also lower (**P < 0.01) than following treatment with beractant, and those treated with poractant alfa also had lower lung IL-8 (*P < 0.05) than did negative controls, independent of region. Lung IL-6 following lucinactant treatment was lower (*P < 0.01) than in all other groups, independent of region. Lung MPO was lower (*P < 0.01) following lucinactant or beractant treatment as compared with negative controls, independent of region. IL, interleukin; MPO, myeloperoxidase.

Figure 5

Plasma cytokine concentrations. Open bars are baseline and solid bars are 4 h values. (a). Plasma IL-8 following lucinactant or poractant alfa treatment was lower (*P < 0.01) than in negative controls and those treated with lucinactant had lower plasma IL-8 levels than those treated with beractant (**P < 0.01). (b) Plasma IL-6 was lower (*P < 0.01) in all SRT groups as compared with in negative controls. In addition, plasma IL-6 (b) in those treated with either lucinactant or poractant alfa was lower (**P < 0.05) than in those treated with beractant. IL, interleukin; SRT, surfactant replacement therapy.