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

Wolfson, Marla R.; Wu, Jichuan; Hubert, Terrence L.; Gregory, Timothy J.; Mazela, Jan; Shaffer, Thomas H.

doi:10.1038/pr.2012.96

Cited by 20 publications

(18 citation statements)

References 51 publications

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“…However, at 300 minutes, Synsurf-treated lambs had a significantly higher PaO 2 /FiO 2 ratio accompanied by a lower calculated shunt (Synsurf versus saline at 180 minutes and Synsurf versus saline- and Curosurf®-treated lambs at 300 minutes; Figures 2A and 3). Notably, the Synsurf-treated lambs not only had a more sustained improvement in oxygenation, they also had lower tidal volumes and associated lower PaCO 2 levels (Figures 4A and 2B), similar to what was described by Wolfson et al for lambs treated with lucinactant in their study 34…”

Section: Discussionsupporting

confidence: 86%

“…They also found that the circulating PMN cell numbers returned to prenatal values by 6–8 hours after birth 44. The peptide-containing synthetic surfactant lucinactant, has recently been shown to be associated with less systemic (plasma IL [interleukin]-6 and IL-8) and lung inflammation (proinflammatory markers), better lung expansion, and lower ventilator requirements than no surfactant treatment or treatment with porcine-and bovine-derived surfactants 34. We found that a systemic inflammatory response as reflected by changes in PMNs was only detectable in the Curosurf® group, but although the total white blood cell count and neutrophil count in this group increased significantly between birth and 5 hours of life, it was no different from the values found in the other two groups at 5 hours.…”

Section: Discussionmentioning

confidence: 99%

“…A novel peptide-containing synthetic surfactant, Surfaxin®, a SP-B mimetic, was recently approved by the US Food and Drug Administration. This surfactant was evaluated against porcine- and bovine-derived surfactants in the 125–128-day preterm lamb model in regard to its potential to modulate lung inflammation following initiation of mechanical ventilation 34. Surfactant treatment after commencing ventilation improved lung compliance to a similar extent compared to no surfactant treatment.…”

Section: Discussionmentioning

confidence: 99%

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Surfactant treatment before first breath for respiratory distress syndrome in preterm lambs: comparison of a peptide-containing synthetic lung surfactant with porcine-derived surfactant

Zyl¹,

Smith²

2013

DDDT

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BackgroundIn a recent study utilizing a saline-lavaged adult rabbit model, we described a significant improvement in systemic oxygenation and pulmonary shunt after the instillation of a novel synthetic peptide-containing surfactant, Synsurf. Respiratory distress syndrome in the preterm lamb more closely resembles that of the human infant, as their blood gas, pH values, and lung mechanics deteriorate dramatically from birth despite ventilator support. Moreover, premature lambs have lungs which are mechanically unstable, with the advantage of being able to measure multiple variables over extended periods. Our objective in this study was to investigate if Synsurf leads to improved systemic oxygenation, lung mechanics, and histology in comparison to the commercially available porcine-derived lung surfactant Curosurf® when administered before first breath in a preterm lamb model.Materials and methodsA Cesarean section was performed under general anesthesia on 18 time-dated pregnant Dohne Merino ewes at 129–130 days gestation. The premature lambs were delivered and ventilated with an expiratory tidal volume of 6–8 mL/kg for the first 30 minutes and thereafter at 8–10 mL/kg. In a randomized controlled trial, the two surfactants tested were Synsurf and Curosurf®, both at a dose of 100 mg/kg phospholipids (1,2-dipalmitoyl-L-α-phosphatidylcholine; 90% in Synsurf, 40% in Curosurf®). A control group of animals was treated with normal saline. Measurements of physiological variables, blood gases, and lung mechanics were made before and after surfactant and saline replacement and at 15, 30, 45, 60, 90, 120, 180, 240 and 300 minutes after treatment. The study continued for 5 hours.ResultsSurfactant treatment led to a significant improvement in oxygenation within 30 minutes, with the Synsurf group and the Curosurf® group having significantly higher ratios between arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2; P = 0.021) compared to that of the control (saline-treated) animals. Dynamic compliance improved in the three groups over time, with no intergroup differences. All of the surfactant-treated animals survived, and one in the saline group died before the study ended. Histology between groups was not different, showing mild–moderate injury patterns.Discussion: Treatment with surfactants before first breath clearly resulted in improved systemic oxygenation within 30 minutes of instillation. Both Synsurf- and Curosurf®-treated animals experienced similar and more sustained improvement in oxygenation and decreased calculated shunt compared to saline-treated animals.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Surfactant treatment before first breath for respiratory distress syndrome in preterm lambs: comparison of a peptide-containing synthetic lung surfactant with porcine-derived surfactant

Zyl¹,

Smith²

2013

DDDT

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“…For example, neonatal asphyxia induced by transient occlusion of the umbilical cord before birth has been shown to lead to reperfusion injury and to mimic the intrauterine hypoxia that complicates a proportion of human births . Further, hypoxic injury following preterm birth and associated newborn respiratory disease is also studied in sheep models . More recently, sheep models have been developed to investigate intrauterine inflammation induced by injection or infusion of lipopolysaccharides or bacterial infection .…”

Section: Discussionmentioning

confidence: 99%

“…However, complement activity during gestational development animal models of human pregnancy is under‐investigated. The sheep model has gained popularity in examining gestational inflammation and preterm birth pathology including gestational reperfusion injury, in utero Ureaplasma parvum infection and Escherichia coli lipopolysaccharide (LPS)‐mediated inflammation . Moreover, complement has been shown to be activated or play a role in the underlying pathogenesis in non‐sheep models and humans for these conditions .…”

Section: Introductionmentioning

confidence: 99%

Comparison of Complement Activity in Adult and Preterm Sheep Serum

Ahmed

Kemp

Payne

et al. 2014

American J Rep Immunol

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Guinea pig erythrocytes were identified as the optimal target, although sensitizing them with rabbit antiguinea pig erythrocyte antibody did not enhance the lysis by maternal sheep serum. In contrast, preterm neonatal sheep serum was unable to efficiently lyse guinea pig erythrocytes unless pre-sensitized with antibody. Further investigation revealed that maternal serum contained high levels of antibodies that cross-reacted with guinea pig and rabbit erythrocytes, while no cross-reacting antierythrocyte antibodies were found in preterm neonatal serum. Therefore, unlike primates, rabbits, and guinea pigs, no transplacental transfer of maternal IgG to foetal sheep occurs. Use of exogenous complement regulators is often used to dissect the contribution of complement to disease pathogenesis; however, we found that while full-length soluble human complement receptor 1 (sCR1, CDX-1135) was able to inhibit lysis of guinea pig erythrocytes by human and rat serum, no inhibition of sheep serum could be observed. Investigation of complement contribution to disease pathogenesis in the future will require the identification of an inhibitor that is effective against sheep complement.

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Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury

Wolfson

Enkhbaatar

Fukuda

et al. 2020

Clinical & Translational Med

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Background Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI. Methods Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid. Results Dose‐response and PA‐type comparisons of outcomes demonstrated sustained superiority with low‐volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding. Conclusions We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.

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

Cited by 20 publications

References 51 publications

Surfactant treatment before first breath for respiratory distress syndrome in preterm lambs: comparison of a peptide-containing synthetic lung surfactant with porcine-derived surfactant

Surfactant treatment before first breath for respiratory distress syndrome in preterm lambs: comparison of a peptide-containing synthetic lung surfactant with porcine-derived surfactant

Comparison of Complement Activity in Adult and Preterm Sheep Serum

Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury

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