Preterm Lung Injury Research Articles

Optimized lung expansion ventilation modulates ventilation-induced lung injury in preterm lambs.

Preterm infants close to viability commonly require mechanical ventilation (MV) for respiratory distress syndrome. Despite commonly used lung-sparing ventilation techniques, rapid lung expansion during MV induces lung injury, a risk factor for bronchopulmonary dysplasia. This study investigates whether ventilation with optimized lung expansion is feasible and whether it can further minimize lung injury. Therefore, optimized lung expansion ventilation (OLEV) was compared to conventional volume targeted ventilation. Twenty preterm lambs were surgically delivered after 132 days of gestation. Nine animals were randomized to receive OLEV for 24 h, and seven received standard MV. Four unventilated animals served as controls (NV). Lungs were sampled for histological analysis at the end of the experimental period. Ventilation with OLEV was feasible, resulting in a significantly higher mean ventilation pressure (0.7-1.3 mbar). Temporary differences in oxygenation between OLEV and MV did not reach clinically relevant levels. Ventilation in general tended to result in higher lung injury scores compared to NV, without differences between OLEV and MV. While pro-inflammatory tumor necrosis factor-α messenger RNA (mRNA) levels increased in both ventilation groups compared to NV, only animals in the MV group showed a higher number of CD45-positive cells in the lung. In contrast, mean (standard deviations) surfactant protein-B mRNA levels were significantly lower in OLEV, 0.63 (0.38) compared to NV 1.03 (0.32) (p = .023, one-way analysis of variance). In conclusion, a small reduction in pulmonary inflammation after 24 h of support with OLEV suggests potential to reduce preterm lung injury.

Umbilical cord blood-derived therapy for preterm lung injury: a systematic review and meta-analysis.

Lung injuries, such as bronchopulmonary dysplasia (BPD), remain a major complication of preterm birth, with limited therapeutic options. One potential emerging therapy is umbilical cord blood (UCB)-derived therapy. To systematically assess the safety and efficacy of UCB-derived therapy for preterm lung injury in preclinical and clinical studies. A systematic search of MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO International Trials Registry Platform was performed. A meta-analysis was conducted with Review Manager (5.4.1) using a random effects model. Data was expressed as standardized mean difference (SMD) for preclinical data and pooled relative risk (RR) for clinical data, with 95% confidence intervals (CI). Potential effect modifiers were investigated via subgroup analysis. Certainty of evidence was assessed using the GRADE system. Twenty-three preclinical studies and six clinical studies met eligibility criteria. Statistically significant improvements were seen across several preclinical outcomes, including alveolarization (SMD, 1.32, 95%CI [0.99, 1.65]), angiogenesis (SMD, 1.53, 95%CI [0.87, 2.18]), and anti-inflammatory cytokines (SMD, 1.68, 95%CI [1.03, 2.34]). In clinical studies, 103 preterm infants have received UCB-derived therapy for preterm lung injury and no significant difference was observed in the development of BPD (RR, 0.93, 95%CI [0.73, 1.18]). Across both preclinical and clinical studies, administration of UCB-derived therapy appeared safe. Certainty of evidence was assessed as "low." Administration of UCB-derived therapy was associated with statistically significant improvements across several lung injury markers in preclinical studies. Early clinical studies demonstrated the administration of UCB-derived therapy as safe and feasible but lacked data regarding efficacy.

Impact of tidal volume strategy at birth on initiating lung injury in preterm lambs.

Tidal ventilation is essential in supporting the transition to air-breathing at birth, but excessive tidal volume (VT) is an important factor in preterm lung injury. Few studies have assessed the impact of specific VT levels on injury development. Here we used a lamb model of preterm birth to investigate the role of different levels of VT during positive pressure ventilation (PPV) in promoting aeration and initiating early lung injury pathways. VT was delivered as; (i) 7ml/kg throughout (VTstatic), (ii) begun at 3ml/kg and increased to a final VT of 7ml/kg over 3-minutes (VTinc) or (iii) commenced at 7ml/kg, decreased to 3ml/kg and the returned to 7ml/kg (VTalt). VT, inflating pressure, lung compliance and aeration were similar in all groups from 4 minutes, as was post-mortem histology and lung lavage protein concentration. However, transient decrease in VT in the VTalt group caused increased ventilation heterogeneity. Following TMT-based quantitative mass spectrometry proteomics, 1610 proteins were identified in the lung. 3-fold more proteins were significantly altered with VTalt compared with VTstatic or VTinc strategies. Gene set enrichment analysis identified VTalt specific enrichment of immune and angiogenesis pathways and VTstatic enrichment of metabolic processes. Our finding of comparable lung physiology and volutrauma across VT groups challenges the paradigm that there is a need to rapidly aerate the preterm lung at birth. Increased lung injury and ventilation heterogeneity was identified when initial VT was suddenly decreased during respiratory support at birth, further supporting the benefit of a gentle VT approach.

Lung ultrasound detects regional aeration inhomogeneity in ventilated preterm lambs

BackgroundInhomogeneous lung aeration is a significant contributor to preterm lung injury. EIT detects inhomogeneous aeration in the research setting. Whether LUS detects inhomogeneous aeration is unknown. The aim was to determine whether LUS detects regional inhomogeneity identified by EIT in preterm lambs.MethodsLUS and EIT were simultaneously performed on mechanically ventilated preterm lambs. LUS images from non-dependent and dependent regions were acquired and reported using a validated scoring system and computer-assisted quantitative LUS greyscale analysis (Q-LUSMGV). Regional inhomogeneity was calculated by observed over predicted aeration ratio from the EIT reconstructive model. LUS scores and Q-LUSMGV were compared with EIT aeration ratios using one-way ANOVA.ResultsLUS was performed in 32 lambs (~125d gestation, 128 images). LUS scores were greater in upper anterior (non-dependent) compared to lower lateral (dependent) regions of the left (3.4 vs 2.9, p = 0.1) and right (3.4 vs 2.7, p < 0.0087). The left and right upper regions also had greater LUS scores compared to right lower (3.4 vs 2.7, p < 0.0087) and left lower (3.7 vs 2.9, p = 0.1). Q-LUSMGV yielded similar results. All LUS findings corresponded with EIT regional differences.ConclusionLUS may have potential in measuring regional aeration, which should be further explored in human studies.ImpactInhomogeneous lung aeration is an important contributor to preterm lung injury, however, tools detecting inhomogeneous aeration at the bedside are limited.Currently, the only tool clinically available to detect this is electrical impedance tomography (EIT), however, its use is largely limited to research.Lung ultrasound (LUS) may play a role in monitoring lung aeration in preterm infants, however, whether it detects inhomogeneous lung aeration is unknown.Visual LUS scores and mean greyscale image analysis using computer assisted quantitative LUS (Q-LUSMGV) detects regional lung aeration differences when compared to EIT.This suggests LUS reliably detects aeration inhomogeneity warranting further investigation in human trials.

Respiratory strategy at birth initiates distinct lung injury phenotypes in the preterm lamb lung

BackgroundA lack of clear trial evidence often hampers clinical decision-making during support of the preterm lung at birth. Protein biomarkers have been used to define acute lung injury phenotypes and improve patient selection for specific interventions in adult respiratory distress syndrome. The objective of the study was to use proteomics to provide a deeper biological understanding of acute lung injury phenotypes resulting from different aeration strategies at birth in the preterm lung.MethodsChanges in protein abundance against an unventilated group (n = 7) were identified via mass spectrometry in a biobank of gravity dependent and non-dependent lung tissue from preterm lambs managed with either a Sustained Inflation (SI, n = 20), Dynamic PEEP (DynPEEP, n = 19) or static PEEP (StatPEEP, n = 11). Ventilation strategy-specific pathways and functions were identified (PANTHER and WebGestalt Tool) and phenotypes defined using integrated analysis of proteome, physiological and clinical datasets (MixOmics package).Results2372 proteins were identified. More altered proteins were identified in the non-dependent lung, and in SI group than StatPEEP and DynPEEP. Different inflammation, immune system, apoptosis and cytokine pathway enrichment were identified for each strategy and lung region. Specific integration maps of clinical and physiological outcomes to specific proteins could be generated for each strategy.ConclusionsProteomics mapped the molecular events initiating acute lung injury and identified detailed strategy-specific phenotypes. This study demonstrates the potential to characterise preterm lung injury by the direct aetiology and response to lung injury; the first step towards true precision medicine in neonatology.

Role of Protein Thiol-based Redox Modifications in Hyperoxia-induced Preterm Lung Injury

Neutrophils are elevated in critically ill patients during the systemic inflammatory response to trauma and sepsis. The neutrophil-derived enzyme myeloperoxidase generates reactive oxygen species which can react with host tissue resulting in cell damage and dysfunction. Thus, elevated myeloperoxidase in the circulation may be associated with adverse patient outcomes.Circulating myeloperoxidase concentrations were measured in a cohort of 44 critically ill patients, 55% of whom were diagnosed with septic shock, and 44 healthy controls. Intensive care mortality prediction scores (SOFA, SAPS, APACHE) and ICU and hospital mortality were obtained from the patients’ clinical notes. Hematological and biochemical assessments included blood cell counts, lactate, alanine transaminase, creatinine, bilirubin, C-reactive protein, and PaO2. Myeloperoxidase was measured using a commercial ELISA kit and cell free DNA was detected using SytoxGreen™ fluorescence staining.Myeloperoxidase concentrations were significantly higher in critically ill patients than control samples (234 ± 30 ng/ml versus 15 ± 4 ng/ml, p < 0.001), and were elevated in septic shock relative to non-septic patients (302 ± 42 ng/ml versus 156 ± 38 ng/ml, p = 0.02), despite neutrophil counts being comparable between the two subgroups (p = 0.6). Myeloperoxidase correlated with SOFA scores in the critically ill patients (r = 0.395, p = 0.02), and with markers of tissue dysfunction and injury such as lactate (r = 0.572, p < 0.001), log10 alanine transferase (r = 0.392, p = 0.016) and log10 cell free DNA (r = 0.371, p = 0.03). The subgroup of patients with higher than mean APACHE III scores (i.e. >78, n = 16) exhibited significantly elevated myeloperoxidase concentrations in the non-survivors compared with survivors (416 ± 59 ng/ml versus 140 ± 33 ng/mL, p = 0.001). Hospital mortality for the whole cohort was 27%; mortality in the high APACHE III subgroup was 38%, and when combined with higher than mean myeloperoxidase (i.e. >234 ng/mL), mortality increased to 71%.Myeloperoxidase is associated with markers of tissue injury and systemic organ failure, particularly in septic patients. The enzyme is also associated with mortality in patients with higher APACHE III scores, and thus has potential as an additional diagnostic marker to improve mortality prediction.

Inhaled surfactant plus budesonide reduces early preterm lung injury, but is there an effect beyond the lung?

Inhaled surfactant plus budesonide reduces early preterm lung injury, but is there an effect beyond the lung?

Plasma proteomics reveals gestational age-specific responses to mechanical ventilation and identifies the mechanistic pathways that initiate preterm lung injury

The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states; the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma samples taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of individualized respiratory support approaches tailored to both the developmental and pathological state of the lung.

Modelling Bronchopulmonary Dysplasia in Animals: Arguments for the Preterm Rabbit Model.

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.

Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia.

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic.

Preterm human amnion epithelial cells have limited reparative potential

The collection and use of stem cells from the fetal membranes as cell therapy for a variety of lung diseases, including preterm lung disease, have been previously proposed. To date, only cells from term amnion have been assessed. In the setting of a future therapy for the preterm neonate, it would be ideal if autologous cells could be given. However, the reparative and anti-inflammatory actions of stem cells isolated from preterm amnions have not been evaluated. In this study, with a view to developing an autologous cell therapy for preterm lung injury, we compared the differentiation potential and efficacy of term versus preterm human amnion epithelial cells (hAECs) to protect against inflammation and fibrosis in a bleomycin mouse model of lung injury. We found that, unlike term hAECs, preterm hAECs did not differentiate into a lung lineage following culture in small airway growth media. Preterm hAECs also exerted significantly less protective effects than term hAEC following acute lung injury. Specifically, preterm hAEC did not improve Ashcroft scoring or collagen deposition in the lung despite a reduction in activated myofibroblasts. Term hAECs expressed double the levels of HLA-G compared to preterm hAECs. These findings indicate that while hAECs can be isolated from term and preterm amnions in similar numbers, they bear distinctive characteristics, which may impact upon their clinical use.

Human amnion epithelial cells reduce ventilation-induced preterm lung injury in fetal sheep

The objective of the study was to explore whether human amnion epithelial cells (hAECs) can mitigate ventilation-induced lung injury. An established in utero ovine model of ventilation-induced lung injury was used. At day 110 of gestation, singleton fetal lambs either had sham in utero ventilation (IUV) (n = 4), 12 hours of IUV alone (n = 4), or 12 hours of IUV and hAEC administration (n = 5). The primary outcome, structural lung injury, was assessed 1 week later. Compared with sham controls, IUV alone was associated with significant lung injury: increased collagen (P = .03), elastin (P = .02), fibrosis (P = .02), and reduced secondary-septal crests (P = .009). This effect of IUV was significantly mitigated by the administration of hAECs: less collagen (P = .03), elastin (P = .04), fibrosis (P = .02), normalized secondary-septal crests (P = .02). The hAECs were immunolocalized within the fetal lung and had differentiated into type I and II alveolar cells. The hAECs mitigate ventilation-induced lung injury and differentiated into alveolar cells in vivo.