Moving on from clinical animal-derived surfactants to peptide-based synthetic pulmonary surfactant.

Research on lung surfactant has exerted a great impact on newborn respiratory care and significantly improved survival and outcome of preterm infants with respiratory distress syndrome (RDS) due to surfactant deficiency because of lung immaturity. Current clinical, animal-derived, surfactants are among the most widely tested compounds in neonatology However, limited availability, high production costs, and ethical concerns about using animal-derived products constitute important limitations in their universal application. Synthetic lung surfactant offers a promising alternative to animal-derived surfactant by providing improved consistency, quality and purity, availability and scalability, ease of production and lower costs, acceptance, and safety for the treatment of neonatal RDS and other lung conditions. Third-generation synthetic surfactants built around surfactant protein B (SP-B) and C (SP-C) peptide mimics stand at the forefront of innovation in neonatal pulmonary medicine, while nasal continuous positive airway pressure (nCPAP) has become the standard non-invasive respiratory support for preterm infants. nCPAP can prevent the risk of chronic lung disease (bronchopulmonary dysplasia) and reduce lung injury by avoiding intubation and mechanical ventilation, is a relatively simple technique and can be initiated safely and effectively in the delivery room. Combining nCPAP with noninvasive, preferably aerosol, delivery of synthetic lung surfactant promises to improve respiratory outcomes for preterm infants, especially in low-and-middle income countries.

Structure and Function of Canine SP-C Mimic Proteins in Synthetic Surfactant Lipid Dispersions.

Lung surfactant is a mixture of lipids and proteins and is essential for air breathing in mammals. The hydrophobic surfactant proteins B and C (SP-B and SP-C) assist in reducing surface tension in the lung alveoli by organizing the surfactant lipids. SP-B deficiency is life-threatening, and a lack of SP-C can lead to progressive interstitial lung disease. B-YL (41 amino acids) is a highly surface-active, sulfur-free peptide mimic of SP-B (79 amino acids) in which the four cysteine residues are replaced by tyrosine. Mammalian SP-C (35 amino acids) contains two cysteine-linked palmitoyl groups at positions 5 and 6 in the N-terminal region that override the ß-sheet propensities of the native sequence. Canine SP-C (34 amino acids) is exceptional because it has only one palmitoylated cysteine residue at position 4 and a phenylalanine at position 5. We developed canine SP-C constructs in which the palmitoylated cysteine residue at position 4 is replaced by phenylalanine (SP-Cff) or serine (SP-Csf) and a glutamic acid-lysine ion-lock was placed at sequence positions 20-24 of the hydrophobic helical domain to enhance its alpha helical propensity. AI modeling, molecular dynamics, circular dichroism spectroscopy, Fourier Transform InfraRed spectroscopy, and electron spin resonance studies showed that the secondary structure of canine SP-Cff ion-lock peptide was like that of native SP-C, suggesting that substitution of phenylalanine for cysteine has no apparent effect on the secondary structure of the peptide. Captive bubble surfactometry demonstrated higher surface activity for canine SP-Cff ion-lock peptide in combination with B-YL in surfactant lipids than with canine SP-Csf ion-lock peptide. These studies demonstrate the potential of canine SP-Cff ion-lock peptide to enhance the functionality of the SP-B peptide mimic B-YL in synthetic surfactant lipids.

Evaluation of a Novel Dry Powder Surfactant Aerosol Delivery System for Use in Premature Infants Supported with Bubble CPAP.

Aerosolized lung surfactant therapy during nasal continuous positive airway pressure (CPAP) support avoids intubation but is highly complex, with reported poor nebulizer efficiency and low pulmonary deposition. The study objective was to evaluate particle size, operational compatibility, and drug delivery efficiency with various nasal CPAP interfaces and gas humidity levels of a synthetic dry powder (DP) surfactant aerosol delivered by a low-flow aerosol chamber (LFAC) inhaler combined with bubble nasal CPAP (bCPAP). A particle impactor characterized DP surfactant aerosol particle size. Lung pressures and volumes were measured in a preterm infant nasal airway and lung model using LFAC flow injection into the bCPAP system with different nasal prongs. The LFAC was combined with bCPAP and a non-heated passover humidifier. DP surfactant mass deposition within the nasal airway and lung was quantified for different interfaces. Finally, surfactant aerosol therapy was investigated using select interfaces and bCPAP gas humidification by active heating. Surfactant aerosol particle size was 3.68 µm. Lung pressures and volumes were within an acceptable range for lung protection with LFAC actuation and bCPAP. Aerosol delivery of DP surfactant resulted in variable nasal airway (0-20%) and lung (0-40%) deposition. DP lung surfactant aerosols agglomerated in the prongs and nasal airways with significant reductions in lung delivery during active humidification of bCPAP gas. Our findings show high-efficiency delivery of small, synthetic DP surfactant particles without increasing the potential risk for lung injury during concurrent aerosol delivery and bCPAP with passive humidification. Specialized prongs adapted to minimize extrapulmonary aerosol losses and nasal deposition showed the greatest lung deposition. The use of heated, humidified bCPAP gases compromised drug delivery and safety. Safety and efficacy of DP aerosol delivery in preterm infants supported with bCPAP requires more research.

Lung Surfactant Protein B Peptide Mimics Interact with the Human ACE2 Receptor.

Lung surfactant is a complex mixture of phospholipids and surfactant proteins that is produced in alveolar type 2 cells. It prevents lung collapse by reducing surface tension and is involved in innate immunity. Exogenous animal-derived and, more recently, synthetic lung surfactant has shown clinical efficacy in surfactant-deficient premature infants and in critically ill patients with acute respiratory distress syndrome (ARDS), such as those with severe COVID-19 disease. COVID-19 pneumonia is initiated by the binding of the viral receptor-binding domain (RBD) of SARS-CoV-2 to the cellular receptor angiotensin-converting enzyme 2 (ACE2). Inflammation and tissue damage then lead to loss and dysfunction of surface activity that can be relieved by treatment with an exogenous lung surfactant. Surfactant protein B (SP-B) is pivotal for surfactant activity and has anti-inflammatory effects. Here, we study the binding of two synthetic SP-B peptide mimics, Super Mini-B (SMB) and B-YL, to a recombinant human ACE2 receptor protein construct using molecular docking and surface plasmon resonance (SPR) to evaluate their potential as antiviral drugs. The SPR measurements confirmed that both the SMB and B-YL peptides bind to the rhACE2 receptor with affinities like that of the viral RBD-ACE2 complex. These findings suggest that synthetic lung surfactant peptide mimics can act as competitive inhibitors of the binding of viral RBD to the ACE2 receptor.

Combination of pioglitazone, a PPARγ agonist, and synthetic surfactant B-YL prevents hyperoxia-induced lung injury in adult mice lung explants.

INTRODUCTION: Hyperoxia-induced lung injury is characterized by acute alveolar injury, disrupted epithelial-mesenchymal signaling, oxidative stress, and surfactant dysfunction, yet currently, there is no effective treatment. Although a combination of aerosolized pioglitazone (PGZ) and a synthetic lung surfactant (B-YL peptide, a surfactant protein B mimic) prevents hyperoxia-induced neonatal rat lung injury, whether it is also effective in preventing hyperoxia-induced adult lung injury is unknown. METHOD: Using adult mice lung explants, we characterize the effects of 24 and 72-h (h) exposure to hyperoxia on 1) perturbations in Wingless/Int (Wnt) and Transforming Growth Factor (TGF)-ß signaling pathways, which are critical mediators of lung injury, 2) aberrations of lung homeostasis and injury repair pathways, and 3) whether these hyperoxia-induced aberrations can be blocked by concomitant treatment with PGZ and B-YL combination. RESULTS: Our study reveals that hyperoxia exposure to adult mouse lung explants causes activation of Wnt (upregulation of key Wnt signaling intermediates ß-catenin and LEF-1) and TGF-ß (upregulation of key TGF-ß signaling intermediates TGF-ß type I receptor (ALK5) and SMAD 3) signaling pathways accompanied by an upregulation of myogenic proteins (calponin and fibronectin) and inflammatory cytokines (IL-6, IL-1ß, and TNFα), and alterations in key endothelial (VEGF-A and its receptor FLT-1, and PECAM-1) markers. All of these changes were largely mitigated by the PGZ + B-YL combination. CONCLUSION: The effectiveness of the PGZ + B-YL combination in blocking hyperoxia-induced adult mice lung injury ex-vivo is promising to be an effective therapeutic approach for adult lung injury in vivo.

Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Emulation of the structure of the Saposin protein fold by a lung surfactant peptide construct of surfactant Protein B.

The three-dimensional structure of the synthetic lung Surfactant Protein B Peptide Super Mini-B was determined using an integrative experimental approach, including mass spectrometry and isotope enhanced Fourier-transform infrared (FTIR) spectroscopy. Mass spectral analysis of the peptide, oxidized by solvent assisted region-specific disulfide formation, confirmed that the correct folding and disulfide pairing could be facilitated using two different oxidative structure-promoting solvent systems. Residue specific analysis by isotope enhanced FTIR indicated that the N-terminal and C-terminal domains have well defined α-helical amino acid sequences. Using these experimentally derived measures of distance constraints and disulfide connectivity, the ensemble was further refined with molecular dynamics to provide a medium resolution, residue-specific structure for the peptide construct in a simulated synthetic lung surfactant lipid multilayer environment. The disulfide connectivity combined with the α-helical elements stabilize the peptide conformationally to form a helical hairpin structure that resembles critical elements of the Saposin protein fold of the predicted full-length Surfactant Protein B structure.

Aerosol Delivery of Lung Surfactant and Nasal CPAP in the Treatment of Neonatal Respiratory Distress Syndrome.

After shifting away from invasive mechanical ventilation and intratracheal instillation of surfactant toward non-invasive ventilation with nasal CPAP and less invasive surfactant administration in order to prevent bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome, fully non-invasive surfactant nebulization is the next Holy Grail in neonatology. Here we review the characteristics of animal-derived (clinical) and new advanced synthetic lung surfactants and improvements in nebulization technology required to secure optimal lung deposition and effectivity of non-invasive lung surfactant administration. Studies in surfactant-deficient animals and preterm infants have demonstrated the safety and potential of non-invasive surfactant administration, but also provide new directions for the development of synthetic lung surfactant destined for aerosol delivery, implementation of breath-actuated nebulization and optimization of nasal CPAP, nebulizer circuit and nasal interface. Surfactant nebulization may offer a truly non-invasive option for surfactant delivery to preterm infants in the near future.

Efficacy, dose-response, and aerosol delivery of dry powder synthetic lung surfactant treatment in surfactant-deficient rabbits and premature lambs.

BACKGROUND: Dry powder (DP) synthetic lung surfactant may be an effective means of noninvasive delivery of surfactant therapy to premature infants supported with nasal continuous positive airway pressure (nCPAP) in low-resource settings. METHODS: Four experimental DP surfactant formulations consisting of 70% of phospholipids (DPPC:POPG 7:3), 3% Super Mini-B (SMB) or its sulfur-free derivate B-YL as SP-B peptide mimic, 25% of lactose or trehalose as excipient, and 2% of NaCl were formulated using spray drying. In vitro surface activity was confirmed with captive bubble surfactometry. Surfactant particle size was determined with a cascade impactor and inhaled dose was quantified using a spontaneously breathing premature lamb lung model supported with CPAP. In vivo surfactant efficacy was demonstrated in three studies. First, oxygenation and lung compliance were monitored after intratracheal instillation of resuspended DP surfactant in intubated, ventilated, lavaged, surfactant-deficient juvenile rabbits. In dose-response studies, ventilated, lavaged, surfactant-deficient rabbits received 30, 60, 120 or 240 mg/kg of DP B-YL:Lactose or B-YL:Trehalose surfactant by aerosol delivery with a low flow aerosol chamber via their endotracheal tube. Noninvasive aerosolization of DP B-YL:Trehalose surfactant via nasal prongs was tested in spontaneous breathing premature lambs supported with nCPAP. Intratracheal administration of 200 mg/kg of Curosurf®, a liquid porcine surfactant, was used as a positive control. RESULTS: Mass median aerosol diameter was 3.6 µm with a geometric standard deviation of 1.8. All four experimental surfactants demonstrated high surface efficacy of intratracheal instillation of a bolus of ~ 100 mg/kg of surfactant with improvement of oxygenation and lung compliance. In the dose-response studies, rabbits received incremental doses of DP B-YL:Lactose or B-YL:Trehalose surfactant intratracheally and showed an optimal response in oxygenation and lung function at a dose of 120-240 mg/kg. Aerosol delivery via nasal prongs of 1 or 2 doses of ~ 100 mg/kg of B-YL:Trehalose surfactant to premature lambs supported with nCPAP resulted in stabilization of spontaneous breathing and oxygenation and lung volumes comparable to the positive control. CONCLUSION: These studies confirm the clinical potential of DP synthetic lung surfactant with B-YL peptide as a SP-B mimic to alleviate surfactant deficiency when delivered as a liquid bolus or as an aerosol.

Structural and functional stability of the sulfur-free surfactant protein B peptide mimic B-YL in synthetic surfactant lipids.

BACKGROUND: Optimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture. B-YL peptide is a 41-residue sulfur-free SP-B mimic with its cysteine and methionine residues replaced by tyrosine and leucine, respectively, to enhance its oxidation resistance. AIM: Testing the structural and functional stability of the B-YL peptide in synthetic surfactant lipids after long-term storage. METHODS: The structural and functional properties of B-YL peptide in surfactant lipids were studied using three production runs of B-YL peptides in synthetic surfactant lipids. Each run was held at 5 °C ambient temperature for three years and analyzed with structural and computational techniques, i.e., MALDI-TOF mass spectrometry, ATR-Fourier Transform Infrared Spectroscopy (ATR-FTIR), secondary homology modeling of a preliminary B-YL structure, and tertiary Molecular Dynamic simulations of B-YL in surfactant lipids, and with functional methods, i.e., captive bubble surfactometry (CBS) and retesting in vivo surface activity in surfactant-deficient young adult rabbits. RESULTS: MALDI-TOF mass spectrometry showed no degradation of the B-YL peptide as a function of stored time. ATR-FTIR studies demonstrated that the B-YL peptide still assumed stable alpha-helical conformations in synthetic surfactant lipids. These structural findings correlated with excellent in vitro surface activity during both quasi-static and dynamic cycling on CBS after three years of cold storage and in vivo surface activity of the aged formulations with improvements in oxygenation and dynamic lung compliance approaching those of the positive control surfactant Curosurf®. CONCLUSIONS: The structure of the B-YL peptide and the in vitro and in vivo functions of the B-YL surfactant were each maintained after three years of refrigeration storage.

Aerosol, chemical and physical properties of dry powder synthetic lung surfactant for noninvasive treatment of neonatal respiratory distress syndrome.

Inhalation of dry powder synthetic lung surfactant may assist spontaneous breathing by providing noninvasive surfactant therapy for premature infants supported with nasal continuous positive airway pressure. Surfactant was formulated using spray-drying with different phospholipid compositions (70 or 80 total weight% and 7:3 or 4:1 DPPC:POPG ratios), a surfactant protein B peptide analog (KL4, Super Mini-B, or B-YL), and Lactose or Trehalose as excipient. KL4 surfactant underperformed on initial adsorption and surface activity at captive bubble surfactometry. Spray-drying had no effect on the chemical composition of Super Mini-B and B-YL peptides and surfactant with these peptides had excellent surface activity with particle sizes and fine particle fractions that were well within the margins for respiratory particles and similar solid-state properties. Prolonged exposure of the dry powder surfactants with lactose as excipient to 40 °C and 75% humidity negatively affected hysteresis during dynamic cycling in the captive bubble surfactometer. Dry powder synthetic lung surfactants with 70% phospholipids (DPPC and POPG at a 7:3 ratio), 25% trehalose and 3% of SMB or B-YL showed excellent surface activity and good short-term stability, thereby qualifying them for potential clinical use in premature infants.

Close Association Between Platelet Biogenesis and Alveolarization of the Developing Lung.

Bronchopulmonary dysplasia (BPD) is a neonatal chronic lung disease characterized by an arrest in alveolar and vascular development. BPD is secondary to lung immaturity, ventilator-induced lung injury, and exposure to hyperoxia in extremely premature infants, leading to a lifelong impairment of lung function. Recent studies indicate that the lung plays an important role in platelet biogenesis. However, the dynamic change of platelet production during lung development and BPD pathogenesis remains to be elucidated. We investigated the dynamic change of platelet parameters in extremely premature infants during BPD development, and in newborn rats during their normal development from birth to adulthood. We further studied the effect of hyperoxia exposure on platelet production and concomitant pulmonary maldevelopment in an experimental BPD rat model induced by prolonged exposure to hyperoxia. We detected a physiological increase in platelet count from birth to 36 weeks postmenstrual age in extremely premature infants, but platelet counts in extremely premature infants who developed BPD were persistently lower than gestational age-matched controls. In line with clinical findings, exposure to hyperoxia significantly decreased the platelet count in neonatal rats. Lung morphometry analysis demonstrated that platelet counts stabilized with the completion of lung alveolarization in rats. Our findings indicate a close association between platelet biogenesis and alveolarization in the developing lung. This phenomenon might explain the reduced platelet count in extremely premature infants with BPD.

Neonatal ibuprofen exposure and bronchopulmonary dysplasia in extremely premature infants.

OBJECTIVE: To evaluate the association of ibuprofen exposure with the risk of bronchopulmonary dysplasia (BPD) in extremely premature infants. STUDY DESIGN: This was a retrospective study of all extremely premature infants admitted to a tertiary unit from 2016 to 2018. RESULTS: A total of 203 extremely premature infants were included in this study. The rate of BPD was significantly higher in infants with early exposure to ibuprofen (42.5%) compared to infants with no exposure (21.6%, P = 0.001). After adjusting for covariates, the risk of BPD was associated independently with ibuprofen exposure (odds ratios (OR) 2.296, 95% confidence interval (CI): 1.166-4.522, p = 0.016). Further analysis showed a trend towards higher risk of BPD in infants with successful patent ductus arteriosus (PDA) closure after ibuprofen treatment (32.3%) compared to non-treated infants (20.2%, p = 0.162). CONCLUSION: Our findings suggest that ibuprofen exposure may contribute to the occurrence of BPD in extremely preterm infants.

Aerosol delivery of dry powder synthetic lung surfactant to surfactant-deficient rabbits and preterm lambs on non-invasive respiratory support.

Background: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. Methods: A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, in vitro surface activity with captive bubble surfactometry, and in vivo activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. Results: FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated in vitro surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Conclusions: Aerosol delivery of DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.

Neonatal hematological parameters and the risk of moderate-severe bronchopulmonary dysplasia in extremely premature infants.

OBJECTIVE: To evaluate the association between hematological parameters at birth and the risk of moderate-severe bronchopulmonary dysplasia (BPD) in a cohort of extremely preterm infants. METHODS: This is a retrospective study of all extremely premature infants admitted to the neonatal intensive care unit, Shenzhen Maternity and Child Healthcare Hospital from January 2016 to May 2018. Extremely prematurity was defined as a delivery at a gestational age ≤ 28 weeks or a birth weight ≤ 1000 g. BPD was diagnosed if oxygen exposure exceeded 28 days and the severity was decided at 36 weeks PMA or discharge. Multivariable analysis was performed to assess the independence of the association between hematological parameters at birth and risk of moderate or severe BPD. RESULTS: A total of 115 extremely premature infants were analyzed in this study. The median platelet count, neutrophil and monocyte count at birth were significantly higher in infants with moderate-severe BPD compared to infants without BPD (228 vs 194*109/l, P = 0.004; 5.0 vs 2.95*109/l, P = 0.023; 0.88 vs 0.63*109/l, P = 0.026, respectively) whereas the mean platelet volume was significantly lower in infants with moderate-severe BPD than those without BPD (9.1 vs 9.4 fl, P = 0.002). After adjusting for covariates, the risk of moderate-severe BPD was independently associated with platelet count≥207*109/l (odds ratio 3.794, 95% confidence interval: 1.742-8.266, P = 0.001). CONCLUSION: Our findings suggest that hematologic parameters at birth are different in extremely preterm infants who will develop moderate-severe BPD. A higher platelet count at birth may increase the risk of moderate-severe BPD after extremely premature birth.

A Combination of the Aerosolized PPAR-γ Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats.

BACKGROUND: Despite improvements in perinatal care, bronchopulmonary dysplasia (BPD) in extremely premature infants has not decreased. Postnatal surfactant therapy provides symptomatic relief from respiratory distress syndrome, but does not translate into a reduction in BPD. Therefore, the search for effective interventions to prevent BPD continues. OBJECTIVES: Since PPAR-γ agonists have been demonstrated to promote neonatal lung maturation and injury repair, we hypothesized that a formulation of a PPAR-γ agonist, pioglitazone (PGZ) and a synthetic lung surfactant (a surfactant protein B peptide mimic, B-YL) combined would stimulate lung maturation and block hyperoxia-induced neonatal lung injury more effectively than either modality alone. METHODS: One-day-old Sprague-Dawley rat pups were administered PGZ + B-YL via nebulization every 24 h for up to 72 h. The pups were exposed to either 21 or 95% O2, and then sacrificed. Their lungs were examined for markers of lung maturation (levels of PPAR-γ, SP-C and choline-phosphate cytidylyltransferase [CCT-α] and [3H]triolein uptake) and injury repair (bronchoalveolar lavage cell count and protein content, and levels of LEF-1, fibronectin, ALK5, and ß-catenin) by Western blot analysis. RESULTS: Markers of alveolar epithelial/mesenchymal maturation (PPAR-γ, SP-C, CCT-α, and triolein uptake) increased significantly in the PGZ + B-YL group, more than with either drug alone. Similarly, markers of hyperoxia-induced lung injury were blocked effectively with PGZ + B-YL treatment. CONCLUSIONS: Nebulized PPAR-γ agonist PGZ with a synthetic lung surfactant accelerates lung maturation and prevents neonatal hyperoxia-induced lung injury more than either modality alone, with the potential to provide more effective prevention of BPD.

A sulfur-free peptide mimic of surfactant protein B (B-YL) exhibits high in vitro and in vivo surface activities.

Background: Animal-derived surfactants containing surfactant proteins B (SP-B) and C (SP-C) are used to treat respiratory distress syndrome (RDS) in preterm infants. SP-B (79 residues) plays a pivotal role in lung function and the design of synthetic lung surfactant. Super Mini-B (SMB), a 41-residue peptide based on the N- and C-domains of SP-B covalently joined with a turn and two disulfides, folds as an α-helix hairpin mimicking the properties of these domains in SP-B. Here, we studied 'B-YL', a 41-residue SMB variant that has its four cysteine and two methionine residues replaced by tyrosine and leucine, respectively, to test whether these hydrophobic substitutions produce a surface-active, α-helix hairpin. Methods: Structure and function of B-YL and SMB in surfactant lipids were compared with CD and FTIR spectroscopy, and surface activity with captive bubble surfactometry and in lavaged, surfactant-deficient adult rabbits. Results: CD and FTIR spectroscopy of B-YL in surfactant lipids showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to SMB in lipids. B-YL in surfactant lipids demonstrated excellent in vitro surface activity and good oxygenation and dynamic compliance in lavaged, surfactant-deficient adult rabbits, suggesting that the four tyrosine substitutions are an effective replacement for the disulfide-reinforced helix-turn of SMB. Here, the B-YL fold may be stabilized by a core of clustered tyrosines linking the N- and C-helices through non-covalent interactions involving aromatic rings. Conclusions: 'Sulfur-free' B-YL forms an amphipathic helix-hairpin in surfactant liposomes with high surface activity and is functionally similar to SMB and native SP-B. The removal of the cysteines makes B-YL more feasible to scale up production for clinical application. B-YL's possible resistance against free oxygen radical damage to methionines by substitutions with leucine provides an extra edge over SMB in the treatment of respiratory failure in preterm infants with RDS.

Effect of a smaller target range on the compliance in targeting and distribution of oxygen saturation in preterm infants.

BACKGROUND: Following recent recommendations, the oxygen saturation (SpO2) target range for preterm infants in our nursery was narrowed towards the higher end from 85%-95% to 90%-95%. We determined the effect of narrowing the SpO2 target range on the compliance in target range and distribution of SpO2 in preterm infants. METHODS: Before and after changing the target range from 85%-95% to 90%-95%, infants <30 weeks of gestation receiving oxygen were compared during their admission on the neonatal intensive care unit. For each infant, distribution of SpO2 was noted by collecting SpO2 samples each minute, and the percentage of time spent with SpO2 within 90%-95% was calculated. Oxygen was manually adjusted. Hypoxaemic events (SpO2 <80%) where oxygen was titrated were analysed. RESULTS: Data were analysed for 104 infants (57 before and 47 after the range was narrowed). The narrower range was associated with an increase in the median (IQR) SpO2 (93% (91%-96%) vs 94% (92%-97%), p=0.01), but no increase in median time SpO2 within 90%-95% (49.2% (39.6%-59.7%) vs (46.9% (27.1%-57.9%), p=0.72). The distribution of SpO2 shifted to the right with a significant decrease in SpO2 <90%, but not <80%. The count of minute values for Sp02 <80% decreased, while the frequency and duration of hypoxaemic events and oxygen titration were not different. CONCLUSION: Narrowing the target range from 85%-95% to 90%-95% in preterm infants was associated with an increase in median SpO2 and a rightward shift in the distribution, but no change in time spent between 90% and 95%.

Epidemiology of Sepsis-like Illness in Young Infants: Major Role of Enterovirus and Human Parechovirus.

BACKGROUND: Sepsis-like illness is a main cause for hospital admission in young infants. Our aim was to investigate incidence, epidemiology and clinical characteristics of enterovirus (EV) and human parechovirus (HPeV) infections in young infants with sepsis-like illness. METHODS: This is a prospective observational cohort study in which infants younger than 90 days of age, presenting with sepsis-like symptoms in a secondary care children's hospital, underwent a full sepsis work-up. Clinical signs and infectious indices were recorded. EV or HPeV RNA was detected by polymerase chain reaction in plasma and/or cerebrospinal fluid (CSF). RESULTS: Infants were diagnosed with EV, HPeV, fever of unknown origin or severe infection. EV and HPeV were detected in 132 of 353 (37%) and 52 of 353 (15%) of cases, respectively. EV and HPeV have distinct seasonability. Some differences in clinical signs and symptoms occurred between children with EV and HPeV infection but were of limited clinical value. CSF pleocytosis occurred in 44% of EV positive infants, and only in 13% of those with HPeV infection. CONCLUSIONS: EV and HPeV infections are major causes of sepsis-like illness in infants < 90 days of age. Neither clinical characteristics nor laboratory indices were predictive for EV/HPeV infection. CSF pleocytosis occurs, but not in all patients. Testing for EV and HPeV in all young infants with sepsis-like illness is strongly advised.