Evaluation of regional lung mass and growth in neonates with bronchopulmonary dysplasia using ultrashort echo time magnetic resonance imaging.

RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common long term pulmonary morbidity in premature infants and is characterized by impaired lung growth and development. We hypothesized that lung mass growth is a critical factor in determining outcomes in infants with BPD. OBJECTIVES: To measure regional lung density and mass in infants with BPD and compare to clinical variables. METHODS: We conducted a retrospective cohort study of neonates (n = 5 controls, n = 46 with BPD). Lung mass and lung density were calculated using ultrashort echo time (UTE) magnetic resonance imaging (MRI). MEASUREMENTS AND MAIN RESULTS: Lung mass increased with increasing corrected gestational age at the time of MRI in all patients. Total, right, and left lung mass in infants with BPD trended higher than control infants (65.7 vs. 49.9 g, 36.2 vs. 26.8 g, 29.5 vs. 23.1 g, respectively). Babies with BPD who survived to discharge had higher relative lung mass than control infants and infants with BPD that did not survive to discharge (21.6 vs. 15.7 g/kg, p = .01). There was a significant association between the rate of lung mass growth and linear growth at the time of MRI (p = .034). CONCLUSIONS: Infants with BPD are capable of building lung mass over time. While this lung mass growth in infants with BPD may not represent fully functional lung tissue, higher lung mass growth is associated with increased linear growth.

Early life surfactant protein-D levels in bronchoalveolar lavage fluids of extremely preterm neonates.

Surfactant protein-D (SP-D) is a hydrophilic protein with multiple crucial anti-inflammatory and immunological functions. It might play a role in the development and course of pulmonary infections, acute respiratory distress syndrome, and other respiratory disorders. Only few small neonatal studies have investigated SP-D: we aimed to investigate the links between this protein, measured in the first hours of life in extremely preterm neonates, and clinical outcomes, as well its relationship with pulmonary secretory phospholipase A2 (sPLA2). Bronchoalveolar lavage fluids were obtained within the first 3 h of life. SP-D and sPLA2 were measured with ELISA and radioactive method, respectively; epithelial lining fluid concentrations were estimated with urea ratio. Clinical data were prospectively collected. One hundred extremely preterm neonates were nonconsecutively studied. SP-D was significantly raised with increasing gestational age (24-26 wk: 68 [0-1,694], 27 or 28 wk: 286 [0-1,328], 29 or 30 wk: 1,401 [405-2,429] ng/mL, overall P = 0.03). SP-D was significantly higher in cases with clinical chorioamnionitis with fetal involvement (1,138 [68-3,336]) than in those without clinical chorioamnionitis with fetal involvement (0 [0-900] ng/mL, P < 0.001). SP-D was lower in infants with bronchopulmonary dysplasia (BPD) (251 [0-1,550 ng/mL]) compared with those without bronchopulmonary dysplasia (BPD) or who died before its diagnosis (977 [124-5,534 ng/mL], P = 0.05) and this was also significant upon multivariate analysis [odds ration (OR): 0.997 (0.994-0.999), P = 0.024], particularly in neonates between 27- and 28-wk gestation. SP-D significantly correlated with the duration of hospital stay (ρ = -0.283, P = 0.002), invasive ventilation (ρ = -0.544, P = 0.001), and total sPLA2 activity (ρ = 0.528, P = 0.008). These findings help understanding the role of SP-D early in life and support further investigation about the role of SP-D in developing BPD.NEW & NOTEWORTHY Surfactant protein-D increases with gestational age and is inversely associated with BPD development. These results have been obtained in the first hours of life of extremely preterm neonates with optimal perinatal care.

Magnetic Resonance Imaging-Based Evaluation of Anatomy and Outcome Prediction in Infants with Esophageal Atresia.

INTRODUCTION: There is currently no validated diagnostic modality to characterize the anatomy and predict outcomes of tracheal esophageal defects, such as esophageal atresia (EA) and tracheal esophageal fistulas (TEFs). We hypothesized that ultra-short echo-time MRI would provide enhanced anatomic information allowing for evaluation of specific EA/TEF anatomy and identification of risk factors that predict outcome in infants with EA/TEF. METHODS: In this observational study, 11 infants had pre-repair ultra-short echo-time MRI of the chest completed. Esophageal size was measured at the widest point distal to the epiglottis and proximal to the carina. Angle of tracheal deviation was measured by identifying the initial point of deviation and the farthest lateral point proximal to the carina. RESULTS: Infants without a proximal TEF had a larger proximal esophageal diameter (13.5 ± 5.1 mm vs. 6.8 ± 2.1 mm, p = 0.07) when compared to infants with a proximal TEF. The angle of tracheal deviation in infants without a proximal TEF was larger than infants with a proximal TEF (16.1 ± 6.1° vs. 8.2 ± 5.4°, p = 0.09) and controls (16.1 ± 6.1° vs. 8.0 ± 3.1°, p = 0.005). An increase in the angle of tracheal deviation was positively correlated with duration of post-operative mechanical ventilation (Pearson r = 0.83, p < 0.002) and total duration of post-operative respiratory support (Pearson r = 0.80, p = 0.004). DISCUSSION: These results demonstrate that infants without a proximal TEF have a larger proximal esophagus and a greater angle of tracheal deviation which is directly correlated with the need for longer post-operative respiratory support. Additionally, these results demonstrate that MRI is a useful tool to assess the anatomy of EA/TEF.

Intravenous surfactant protein D inhibits lipopolysaccharide-induced systemic inflammation.

BACKGROUND: Surfactant protein D (SP-D) is an innate host defense protein that clears infectious pathogens from the lung and regulates pulmonary host defense cells. SP-D is also detected in lower concentrations in plasma and many other non-pulmonary tissues. Plasma levels of SP-D increase during infection and other proinflammatory states; however, the source and functions of SP-D in the systemic circulation are largely unknown. We hypothesized that systemic SP-D may clear infectious pathogens and regulate host defense cells in extrapulmonary systems. METHODS: To determine if SP-D inhibited inflammation induced by systemic lipopolysaccharide (LPS), E.coli LPS was administered to mice via tail vein injection with and without SP-D and the inflammatory response was measured. RESULTS: Systemic SP-D has a circulating half-life of 6 h. Systemic IL-6 levels in mice lacking the SP-D gene were similar to wild type mice at baseline but were significantly higher than wild type mice following LPS treatment (38,000 vs 29,900 ng/ml for 20 mg/kg LPS and 100,700 vs 73,700 ng/ml for 40 mg/kg LPS). In addition, treating wild type mice with purified intravenous SP-D inhibited LPS induced secretion of IL-6 and TNFα in a concentration dependent manner. Inhibition of LPS induced inflammation by SP-D correlated with SP-D LPS binding suggesting SP-D mediated inhibition of systemic LPS requires direct SP-D LPS interactions. CONCLUSIONS: Taken together, the above results suggest that circulating SP-D decreases systemic inflammation and raise the possibility that a physiological purpose of increasing systemic SP-D levels during infection is to scavenge systemic infectious pathogens and limit inflammation-induced tissue injury.

Comparison of Airway Pressure Release Ventilation to High-Frequency Oscillatory Ventilation in Neonates with Refractory Respiratory Failure.

Background: Airway pressure release ventilation (APRV) is a relatively new mode of ventilation in neonates. We hypothesize that APRV is an effective rescue mode in infants failing conventional ventilation and it is comparable in survival rates to rescue with high-frequency oscillatory ventilation (HFOV). Methods: This is a 6-year retrospective cohort study of infants that failed synchronized intermittent mandatory ventilation (SIMV) and were rescued with either APRV or HFOV. For comparison, we divided infants into two groups (28-37 and >37 weeks) based on their corrected gestational age (CGA) at failure of SIMV. Results: Ninety infants were included in the study. Infants rescued with APRV (n = 46) had similar survival rates to those rescued with HFOV (n = 44)-28-37 weeks CGA (APRV 78% vs. HFOV 84%, p = 0.68) and >37 weeks CGA (APRV 76% vs. HFOV 72%, p = 0.74). Use of APRV was not associated with an increase in pneumothorax (APRV 0% and HFOV 10%, p = 0.31, in 28-37 weeks CGA, and APRV 0% and HFOV 4%, p = 0.22, in >37 weeks CGA). Conclusion: APRV can be effectively used to rescue infants with refractory respiratory failure on SIMV. When compared to HFOV, rescue with APRV is not associated with an increase in mortality or pneumothorax.

Quantitative cardiopulmonary magnetic resonance imaging in neonatal congenital diaphragmatic hernia.

BACKGROUND: Pulmonary arterial hypertension, impaired cardiac function and lung hypoplasia are common in infants with congenital diaphragmatic hernia (CDH) and are associated with increased morbidity and mortality. Robust noninvasive methods to quantify these abnormalities in early infancy are lacking. OBJECTIVE: To determine the feasibility of MRI to quantify cardiopulmonary hemodynamics and function in infants with CDH and to investigate left-right blood flow and lung volume discrepancies. MATERIALS AND METHODS: We conducted a prospective MRI study of 23 neonates (isolated left CDH: 4 pre-repair, 7 post-repair, 3 pre- and post-repair; and 9 controls) performed on a small-footprint 1.5-tesla (T) scanner. We calculated MRI-based pulmonary arterial blood flow, left ventricular eccentricity index, cardiac function and lung volume. Using the Wilcoxon rank sum test for continuous data and Fisher exact test for categorical data, we made pairwise group comparisons. RESULTS: The right-to-left ratios for pulmonary artery blood flow and lung volume were elevated in pre-repair and post-repair CDH versus controls (flow: P<0.005; volume: P<0.05 pre-/post-repair). Eccentricity index at end-systole significantly differed between pre-repair and post-repair CDH (P<0.01) and between pre-repair CDH and controls (P<0.001). CONCLUSION: Cardiopulmonary MRI is a viable method to serially evaluate cardiopulmonary hemodynamics and function in critically ill infants and is useful for capturing left-right asymmetries in pulmonary blood flow and lung volume.

Tracheostomy prediction model in neonatal bronchopulmonary dysplasia via lung and airway MRI.

RATIONALE: Clinical management of neonatal bronchopulmonary dysplasia (BPD) is often imprecise and can vary widely between different institutions and providers, due to limited objective measurements of disease pathology severity. There is critical need to improve guidance on the application and timing of interventional treatments, such as tracheostomy. OBJECTIVES: To generate an imaging-based clinical tool for early identification of those patients with BPD who are likely to require later tracheostomy and long-term mechanical ventilation. METHODS: We conducted a prospective cohort study of n = 61 infants (55 BPD, 6 preterm non-BPD). Magnetic resonance imaging (MRI) scores of lung parenchymal disease were used to create a binomial logistic regression model for predicting tracheostomy requirement. This model was further investigated using clinical variables and MRI-quantified tracheomalacia (TM). MEASUREMENTS AND MAIN RESULTS: A model for predicting tracheostomy requirement was created using MRI parenchymal score. This model had 89% accuracy, 100% positive predictive value (PPV), and 85% negative predictive value (NPV), compared with 84%, 60%, and 83%, respectively, when using only relevant clinical variables. In a subset of patients with airway MRI (n = 36), a model including lung and TM measurements had 83% accuracy, 92% PPV, and 78% NPV. CONCLUSIONS: MRI-based measurements of parenchymal disease and TM can be used to predict need for tracheostomy in infants with BPD, more accurately than clinical factors alone. This prediction model has strong potential as a clinical tool for physicians and families for early determination of tracheostomy requirement.

Full-Length Recombinant hSP-D Binds and Inhibits SARS-CoV-2.

SARS-CoV-2 infection of host cells is driven by binding of the SARS-CoV-2 spike-(S)-protein to lung type II pneumocytes, followed by virus replication. Surfactant protein SP-D, member of the front-line immune defense of the lungs, binds glycosylated structures on invading pathogens such as viruses to induce their clearance from the lungs. The objective of this study is to measure the pulmonary SP-D levels in COVID-19 patients and demonstrate the activity of SP-D against SARS-CoV-2, opening the possibility of using SP-D as potential therapy for COVID-19 patients. Pulmonary SP-D concentrations were measured in bronchoalveolar lavage samples from patients with corona virus disease 2019 (COVID-19) by anti-SP-D ELISA. Binding assays were performed by ELISAs. Protein bridge and aggregation assays were performed by gel electrophoresis followed by silver staining and band densitometry. Viral replication was evaluated in vitro using epithelial Caco-2 cells. Results indicate that COVID-19 patients (n = 12) show decreased pulmonary levels of SP-D (median = 68.9 ng/mL) when compared to levels reported for healthy controls in literature. Binding assays demonstrate that SP-D binds the SARS-CoV-2 glycosylated spike-(S)-protein of different emerging clinical variants. Binding induces the formation of protein bridges, the critical step of viral aggregation to facilitate its clearance. SP-D inhibits SARS-CoV-2 replication in Caco-2 cells (EC90 = 3.7 µg/mL). Therefore, SP-D recognizes and binds to the spike-(S)-protein of SARS-CoV-2 in vitro, initiates the aggregation, and inhibits viral replication in cells. Combined with the low levels of SP-D observed in COVID-19 patients, these results suggest that SP-D is important in the immune response to SARS-CoV-2 and that rhSP-D supplementation has the potential to be a novel class of anti-viral that will target SARS-CoV-2 infection.

Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Infants with Congenital Diaphragmatic Hernia: A Novel Tool for Direct Assessment of Severity of Pulmonary Hypertension and Hypoplasia.

OBJECTIVES: To assess the feasibility of magnetic resonance imaging (MRI) for postnatal assessment of pulmonary vascularity in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Infants with prenatally diagnosed CDH (n = 24) received postnatal pulmonary MRI. Infants with nonpulmonary birth defects served as controls (n = 5). Semiautomatic segmentation was performed to obtain total vascular volume using time of flight images to assess vascularity. RESULTS: Average vascular density (vascular volume/lung volume) in control infants was 0.23 ± 0.06 mm3/mm3 compared with 0.18 ± 0.06 mm3/mm3 in infants with CDH is (P = .09). When stratified further based on CDH severity, the difference between control infants and moderate CDH group was statistically significant. (0.23 mm3/mm3 vs 0.15 mm3/mm3, P = .01). Ipsilateral vascular density on MRI in infants with CDH significantly correlated with the prenatal pulmonary hypertensive index (P = .0004, Spearman R = +0.87) and with number of days on mechanical ventilation (P = .04, Spearman R = -0.44), total days on inhaled nitric oxide (P = .02, Spearman R = -0.47), use of epoprostenol for acute pulmonary hypertension (PH) (0.14 mm3/mm3 vs 0.20 mm3/mm3, P = .005), and use of sildenafil for chronic PH (0.15 mm3/mm3 vs 0.19 mm3/mm3, P = .03). CONCLUSIONS: Our results suggest that postnatal pulmonary vascularity assessed by MRI strongly correlates with prenatal and postnatal markers of PH severity and that pulmonary vascularity may serve as a direct measure of pulmonary vascular hypoplasia in infants with CDH.

Case Report: Esophageal Bronchus in a Neonate, With Image, Histological, and Molecular Analysis.

In this case report, we describe the clinical course of a neonate who presented initially with respiratory distress and later with choking during feeding. He was subsequently found to have an esophageal bronchus to the right upper lung lobe, a rare communicating bronchopulmonary foregut malformation. Histological and molecular analysis of the fistula and distal tissues revealed that the proximal epithelium from the esophageal bronchus has characteristics of both esophageal and respiratory epithelia. Using whole exome sequencing of the patient's and parent's DNA, we identified gene variants that are predicted to impact protein function and thus could potentially contribute to the phenotype. These will be the subject of future functional analysis.

Surfactant protein D and bronchopulmonary dysplasia: a new way to approach an old problem.

Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.

Developmental basis of trachea-esophageal birth defects.

Trachea-esophageal defects (TEDs), including esophageal atresia (EA), tracheoesophageal fistula (TEF), and laryngeal-tracheoesophageal clefts (LTEC), are a spectrum of life-threatening congenital anomalies in which the trachea and esophagus do not form properly. Up until recently, the developmental basis of these conditions and how the trachea and esophagus arise from a common fetal foregut was poorly understood. However, with significant advances in human genetics, organoids, and animal models, and integrating single cell genomics with high resolution imaging, we are revealing the molecular and cellular mechanisms that orchestrate tracheoesophageal morphogenesis and how disruption in these processes leads to birth defects. Here we review the current understanding of the genetic and developmental basis of TEDs. We suggest future opportunities for integrating developmental mechanisms elucidated from animals and organoids with human genetics and clinical data to gain insight into the genotype-phenotype basis of these heterogeneous birth defects. Finally, we envision how this will enhance diagnosis, improve treatment, and perhaps one day, lead to new tissue replacement therapy.

Evaluation of recombinant human SP-D in the rat premature lung model.

BACKGROUND: The lungs of premature and term babies are structurally different from the adult lungs. Preterm lungs are underdeveloped, non-compliant in terms of breathing, often need mechanical ventilation and these patients commonly develop syndromes as a consequence of their prematurity, such as bronchopulmonary dysplasia (BPD). Surfactant protein SP-D could be a therapy for BPD. However, there is a need for an animal model that resembles the structural characteristics of premature lungs to test SP-D and future molecules that will target the newborn population. The aim of this study was to develop and validate a pre-clinical model of early alveolarization and structurally premature lungs in 10-day-old rats, and establish the dose safety and distribution of rhSP-D administered intratracheally to premature lungs. METHODS: Ten-day-old Sprague Dawley rats were selected to develop the lung model. SP-D was administered intratracheally. Bronchoalveolar lavage fluid and lungs were collected to evaluate inflammation and SP-D distribution. RESULTS: The 10-day-old rat pup demonstrates early alveolarization features of premature lung development and it tolerates daily intratracheal injections for up to 14 days. The intratracheal administration of rhSP-D, at a dose of 8 mg/kg, does not induce an inflammatory response or histological signs of toxicity in the premature lung, even with a daily administration for 14 days. The pharmacokinetic distribution of rhSP-D in premature lungs has a half-life of ∼9 h, and the incorporation into blood is minimal. CONCLUSIONS: 10-day-old rats are a good pre-clinical animal model of premature lungs, and rhSP-D can be intratracheally administered at doses up to 8 mg/kg without expecting adverse reactions.

Cardiovascular magnetic resonance imaging derived septal curvature in neonates with bronchopulmonary dysplasia associated pulmonary hypertension.

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.

Structure and activity of human surfactant protein D from different natural sources.

Surfactant protein D (SP-D) is a C-type lectin that participates in the innate immune defense of lungs. It binds pathogens through its carbohydrate recognition domain in a calcium-dependent manner. Human surfactant protein D (hSP-D) has been routinely obtained from bronchoalveolar lavage of patients suffering from pulmonary alveolar proteinosis (PAP) and from amniotic fluid (AF). As a consequence of the disease, hSP-D obtained from PAP is found in higher amounts and is mainly composed of higher order oligomeric forms. However, PAP-hSP-D has never been directly compared with nonpathological human protein in terms of structure and biological activity. Moreover, the quantitative distribution of the different hSP-D oligomeric forms in human protein obtained from a natural source has never been evaluated. In this work, we have determined the quantitative distribution of AF-hSP-D oligomers, characterized the sugars attached through the N-glycosylation site of the protein, and compared the activity of hSP-D from AF and PAP with respect to their ability to bind and agglutinate bacteria. We have found that fuzzy balls (40%) are the most abundant oligomeric form in AF-hSP-D, very closely followed by dodecamers (33%), with both together constituting 73% of the protein mass. The glycan attached to the N-glycosylation site was found to be composed of fucose, galactose, sialic acid, and N-acetylglucosamine. Finally, in the functional assays performed, hSP-D obtained from PAP showed higher potency, probably as a consequence of its higher proportion of large oligomers compared with hSP-D from AF.

SP-D loaded PLGA nanoparticles as drug delivery system for prevention and treatment of premature infant's lung diseases.

Preterm infants, particularly those who born between 23 and 28 weeks' gestation, suffer from a very high incidence of respiratory distress syndrome (RDS) related to pulmonary immaturity and inability to make Pulmonary Surfactant (PS). These infants are supported by the use of oxygen, ventilators, and routine administration of surfactant replacement. The currently commercial surfactant replacement therapies do not contain hydrophilic surfactant proteins such as Surfactant Protein D (SP-D). These proteins have a key role in the innate lung host defense, thus the development of a sustained release vehicle that provides SP-D for long periods in preterm infants' lungs would exploit the therapeutic potential of SP-D and other pulmonary medications. The proposed SP-D delivery system is based on nanoparticles (NPs) composed of poly (lactic acid-co-glycolic acid) (PLGA), a biodegradable, FDA approved biopolymer. The resulted NPs were spherical with high Zeta potential value, were not toxic to A-549 lungs cells, and did not induce any inflammatory response in mouse's lungs for short and long-term periods. Moreover, SP-D released from NPs showed biological activity for several days and in vivo release experiment of SP-D loaded NPs revealed that SP-D was released from NPs in mouse lungs with different NPs delivery doses.

Magentic Resonance Imaging Evaluation of Regional Lung Vts in Severe Neonatal Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia is a heterogeneous lung disease characterized by regions of cysts and fibrosis, but methods for evaluating lung function are limited to whole lung rather than specific regions of interest.Objectives: Respiratory-gated, ultrashort echo time magnetic resonance imaging was used to test the hypothesis that cystic regions of the lung will exhibit a quantifiable Vt that will correlate with ventilator settings and clinical outcomes.Methods: Magnetic resonance images of 17 nonsedated, quiet-breathing infants with severe bronchopulmonary dysplasia were reconstructed into end-inspiration and end-expiration images. Cysts were identified and measured by using density threshold combined with manual identification and segmentation. Regional Vts were calculated by subtracting end-expiration from end-inspiration volumes in total lung, noncystic lung, total-cystic lung, and individual large cysts.Measurements and Main Results: Cystic lung areas averaged larger Vts than noncystic lung when normalized by volume (0.8 ml Vt/ml lung vs. 0.1 ml Vt/ml lung, P < 0.002). Cyst Vt correlates with cyst size (P = 0.012 for total lung cyst and P < 0.002 for large cysts), although there was variability between individual cyst Vt, with 22% of cysts demonstrating negative Vt. Peak inspiratory pressure positively correlated with total lung Vt (P = 0.027) and noncystic Vt (P = 0.015) but not total lung cyst Vt (P = 0.8). Inspiratory time and respiratory rate did not improve Vt of any analyzed lung region.Conclusions: Cystic lung has greater normalized Vt when compared with noncystic lung. Ventilator pressure increases noncystic lung Vt, but inspiratory time does not correlate with Vt of normal or cystic lung.

Functional characterization of the different oligomeric forms of human surfactant protein SP-D.

Surfactant Protein D (SP-D) is a collectin protein that participates in the innate immune defense of the lungs. SP-D mediates the clearance of invading microorganisms by opsonization, aggregation or direct killing, which are lately removed by macrophages. SP-D is found as a mixture of trimers, hexamers, dodecamers and higher order oligomers, "fuzzy balls". However, it is unknown whether there are differences between these oligomeric forms in functions, activity or potency. In the present work, we have obtained fractions enriched in trimers, hexamers and fuzzy balls of full-length recombinant human (rh) SP-D by size exclusion chromatography, in a sufficient amount to perform functional assays. We have evaluated the differences in protein lectin-dependent activity relative to aggregation and binding to E. coli, one of the ligands of SP-D in vivo. Fuzzy balls are the most active oligomeric form in terms of binding and aggregation of bacteria, achieving 2-fold binding higher than hexamers and 50% bacteria aggregation at very short times. Hexamers, recently described as a defined oligomeric form of the protein, have never been isolated or tested in terms of protein activity. rhSP-D hexamers efficiently bind and aggregate bacteria, achieving 50-60% aggregation at final time point and high protein concentrations. Nevertheless, trimers are not able to aggregate bacteria, although they bind to them. Therefore, SP-D potency, in functions that relay on the C-lectin activity of the protein, is proportional to the oligomeric state of the protein.

Cardiac Magnetic Resonance Imaging Evaluation of Neonatal Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.Objectives: We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.Methods: A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.Measurements and Main Results: PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.Conclusions: MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.