Lung Injury In Preterm Infants Research Articles

Regulating NLRP3 Inflammasome–Induced Pyroptosis via Nrf2: TBHQ Limits Hyperoxia-Induced Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia

Nuclear factor e2–related factor 2 (Nrf2) plays a key role in cellular resistance to oxidative stress injury. Oxidative stress injury, caused by Nrf2 imbalance, results in increased pyroptosis, DNA damage, and inflammatory activation, which may lead to the arrest of alveolar development and bronchopulmonary dysplasia (BPD) in premature infants under hyperoxic conditions. We established a BPD mouse model to investigate the effects of tert-butylhydroquinone (TBHQ), an Nrf2 activator, on oxidative stress injury, pyroptosis, NLRP3 inflammasome activation, and alveolar development. TBHQ reduced abnormal cell death in the lung tissue of BPD mice and restored the number and normal structure of the alveoli. TBHQ administration activated the Nrf2/heme oxygenase-1 (HO-1) signaling pathway, resulting in the decrease in the following: reactive oxygen species (ROS), activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and IL-18 and IL-1β expression and activation, as well as inhibition of pyroptosis. In contrast, after Nrf2 gene knockout in BPD mice, there was more severe oxidative stress injury and cell death in the lungs, there were TUNEL + and NLRP3 + co-positive cells in the alveoli, the pyroptosis was significantly increased, and the development of alveoli was significantly blocked. We demonstrated that TBHQ may promote alveolar development by enhancing Nrf2-induced antioxidation in the lung tissue of BPD mice and that the decrease in the NLRP3 inflammasome and pyroptosis caused by Nrf2 activation may be the underlying mechanism. These results suggest that TBHQ is a promising treatment for lung injury in premature infants with hyperoxia.

The effect of imposed resistance in neonatal resuscitators on pressure stability and peak flows: a bench test.

The importance of neonatal resuscitator resistance is currently unknown. In this study we investigated peak flows and pressure stability resulting from differences in imposed resistance during positive pressure ventilation(PPV) and simulated spontaneous breathing (SSB) between the r-PAP, low-resistance resuscitator, and Neopuff™, high-resistance resuscitator. In a bench test, 20 inflations during PPV and 20 breaths during SSB were analysed on breath-by-breath basis to determine peak flow and pressure stability using the Neopuff™ with bias gas flow of 8, 12 or 15 L/min and the r-PAP with total gas flow of 15 L/min. Imposed resistance of the Neopuff™ was significantly reduced when the bias gas flow was increased from 8 to 15 L/min, which resulted in higher peak flows during PPV and SSB. Peak flows in the r-PAP were, however, significantly higher and fluctuations in CPAP during SSB were significantly smaller in the r-PAP compared to the Neopuff™ for all bias gas flow levels. During PPV, a pressure overshoot of 3.2 cmH2O was observed in the r-PAP. The r-PAP seemed to have a lower resistance than the Neopuff™ even when bias gas flows were increased. This resulted in more stable CPAP pressures with higher peak flows when using the r-PAP. The traditional T-piece system (Neopuff™) has a higher imposed resistance compared to a new neonatal resuscitator (r-PAP). This study shows that reducing imposed resistance leads to smaller CPAP fluctuations and higher inspiratory and expiratory peak flows. High peak flows might negatively affect lung function and/or cause lung injury in preterm infants at birth. This study will form the rationale for further studies investigating these effects. A possible compromise might be to use the traditional T-piece system with a higher bias gas flow (12 L/min), thereby reducing the imposed resistance and generating more stable PEEP/CPAP pressures, while limiting potentially harmful peak flows.

Severe Intraventricular Hemorrhage is Associated with Lung Injury in Preterm Infants on Mechanical Ventilation.

The aim of this study was to better understand the relationship between intraventricular hemorrhage and the risk of development of early lung disease in extremely low birth weight infants. We hypothesize that infants with severe intraventricular hemorrhage have higher respiratory severity scores than infants with mild/no intraventricular hemorrhage within the first 7 days of life. This was a single center retrospective study conducted on subjects born between 01/01/2018 and 06/30/2021 at the University of Kentucky Children's Hospital NICU. We enrolled preterm infants with gestational age of less than 30 weeks and birth weight of less than 1000 grams who were placed on mechanical ventilation on admission. We found a clinically significant increasing trend of respiratory severity scores within the first week of life in the group of infants with severe intraventricular hemorrhage. This study is first to show that severe intraventricular hemorrhage is associated with higher respiratory severity scores predicting early lung injury in the extremely low birth weight infants placed on a mechanical ventilator within the first 7 days of life.

The importance of lung recruitability: A novel ultrasound pattern to guide lung recruitment in neonates.

Lung Ultrasound (LUS)-guided Lung Recruitment Maneuver (LRM) has been shown to possibly reduce ventilator-induced lung injury in preterm infants. However, to avoid potential hemodynamic and pulmonary side effects, the indication to perform the maneuver needs to be supported by early signs of lung recruitability. Recently, a new LUS pattern (S-pattern), obtained during the reopening of collapsed parenchyma, has been described. This study aims to evaluate if this novel LUS pattern is associated with a higher clinical impact of the LUS-guided LRMs. All the LUS-guided rescue LRMs performed on infants with oxygen saturation/fraction of inspired oxygen (S/F) ratio below 200, were included in this cohort study. The primary outcome was to determine if the presence of the S-pattern is associated with the success of LUS-guided recruitment, in terms of the difference between the final and initial S/F ratio (Delta S/F). We reported twenty-two LUS-guided recruitments, performed in nine patients with a median gestational age of 34 weeks, interquartile range (IQR) 28-35 weeks. The S-pattern could be obtained in 14 recruitments (64%) and appeared early during the procedure, after a median of 2 cmH2O (IQR 1-3) pressure increase. The presence of the S-pattern was significantly associated with the effectiveness of the maneuver as opposed to the cases in which the S-pattern could not be obtained (Delta S/F 110 +/- 47 vs 44 +/- 39, p = 0.01). Our results suggest that the presence of the S-pattern may be an early sign of lung recruitability, predicting LUS-guided recruitment appropriateness and efficacy.

Upregulating carnitine palmitoyltransferase 1 attenuates hyperoxia-induced endothelial cell dysfunction and persistent lung injury

BackgroundBronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury.MethodsLung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or l-carnitine after hyperoxia (50% and 95% O2) followed by air recovery.ResultsWe found that incubation with l-carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with l-carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice.ConclusionsUpregulating Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using l-carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.

14 Diaphragmatic Electrical Activity in Preterm Infants on Non-Invasive High Frequency Oscillatory Ventilation (DEAP-NHFO Study)

Abstract Primary Subject area Neonatal-Perinatal Medicine Background Continuous Positive Airway Pressure (CPAP) is a common form of non-invasive respiratory support for preterm infants. Non-invasive high frequency ventilation (NHFOV) is a relatively new method of non-invasive respiratory support. NHFOV is being increasingly utilized in clinical practice in an attempt to prevent intubation and minimize ventilator-induced lung injury in preterm infants. Preliminary studies suggest superiority of NHFOV over CPAP, but little is known about its mechanism of action and its effect on respiratory control in the newborn. We hypothesize that NHFOV reduces respiratory drive and improves ventilation, resulting in decreased patient diaphragm energy expenditure, which can be assessed by measuring the electrical activity of the diaphragm (Edi). Objectives The objective of this study is to compare the effects of non-invasive respiratory support delivered by nasal CPAP versus NHFOV on respiratory pattern, as assessed by the Edi in very low birth weight (VLBW) preterm infants. Design/Methods In a prospective, randomized, crossover study, 20 preterm infants with birth weights ≤1500 g requiring CPAP were randomized to either NHFOV or CPAP for 105 min, followed by crossover to the other method for the same duration. Edi was continuously measured by a feeding catheter with miniaturized sensors embedded in its wall (Maquet, Solna). The general sequence was 15 minutes for acclimation to the mode, 75 minutes for a feed to be completed, followed by 15 minutes for breath-by-breath analyses of neural breathing pattern. Primary outcome was difference in the peak Edi between CPAP and NHFOV. Secondary outcomes included difference in other measures of respiratory drive: neural respiratory rate, neural inspiratory time, diaphragm energy expenditure, transcutaneous pCO2, number of apnea episodes on the Edi, and episodes of clinically significant apnea. Results No significant differences in Edi timing, Edi min, Edi peak, apnea, or CO2 were observed between the two modes of respiratory support. Conclusion In this cohort of VLBW preterm infants, neural respiratory pattern was not significantly different between NHFOV and CPAP. With this baseline information in stable preterm infants, it would now be important to assess whether these results hold true in infants with more severe lung disease, where NHFOV is often used as escalating support from CPAP.

Minimally invasive surfactant therapy versus intubation for surfactant delivery in preterm infant with RDS: evaluation of safety and efficacy

Background Minimally invasive surfactant therapy (MIST) is a promising mode of administration that offers the potential to limit barotrauma and prevent lung injury in preterm infants with respiratory distress syndrome (RDS). Objective This study assessed the effects of the implementation of MIST on safety and efficacy in infants who met criteria for surfactant administration and were treated by MIST as compared with a historical control group treated with surfactant via an endotracheal tube during mechanical ventilation. Methods This retrospective study included infants born between 2012 and 2017 who met the following inclusion criteria: gestational age 23–36 + 6 weeks, a diagnosis of RDS requiring at least 30% oxygen with or without nasal continuous positive airway pressure (nCPAP). MIST was introduced in 2014 and a comparison was made between the study group who received MIST and the control group who met similar criteria and received surfactant via an endotracheal tube during mechanical ventilation Results No significant differences were found between the groups in baseline and demographic data. Severity of initial disease, assessed by the CRIB II score, was similar in the two groups (control 4.6 ± 2.8, MIST 4.4 ± 2.4, p=.995). The requirement for oxygen during the first 3 d of life was significantly lower (area under the curve [AUC]: p=.001) in the MIST group as assessed by the AUC. Likewise, the mean days of oxygen requirement were significantly lower in the MIST group (Control: 10.3 d, MIST: 5.9 d, p=.04). Only six infants in the MIST group (13%) subsequently required intubation for mechanical ventilation, only one of whom adjacent to the procedure. A modest reduction in duration of ventilation was also noted. Duration of admission was 32 ± 23 d in the control group and 26 ± 21 d in the MIST group, p=.061. No significant differences were found between the groups in the incidence of major morbidities or mortality. No major adverse events related to the procedure were observed. Conclusions Transition to MIST was associated with significantly reduced need for oxygen, mechanical ventilation and surfactant, and a borderline shortened NICU admission.

Enhanced epithelial sodium channel activity in neonatal Scnn1b mouse lung attenuates high oxygen-induced lung injury.

Prolonged oxygen therapy leads to oxidative stress, epithelial dysfunction, and acute lung injury in preterm infants and adults. Heterozygous Scnn1b mice, which overexpress lung epithelial sodium channels (ENaC), and their wild-type (WT) C57Bl6 littermates were utilized to study the pathogenesis of high fraction inspired oxygen ([Formula: see text])-induced lung injury. Exposure to high [Formula: see text] from birth to postnatal (PN) day 11 was used to model oxidative stress. Chronic exposure of newborn pups to 85% O2 increased glutathione disulfide (GSSG) and elevated the GSH/GSSG redox potential (Eh) of bronchoalveolar lavage fluid (BALF). Longitudinal X-ray imaging and Evans blue-labeled-albumin assays showed that chronic 85% O2 and acute GSSG (400 µM) exposures decreased alveolar fluid clearance (AFC) in the WT lung. Morphometric analysis of WT pups insufflated with GSSG (400 µM) or amiloride (1 µM) showed a reduction in alveologenesis and increased lung injury compared with age-matched control pups. The Scnn1b mouse lung phenotype was not further aggravated by chronic 85% O2 exposure. These outcomes support the hypothesis that exposure to hyperoxia increases GSSG, resulting in reduced lung fluid reabsorption due to inhibition of amiloride-sensitive ENaC. Flavin adenine dinucleotide (FADH2; 10 µM) was effective in recycling GSSG in vivo and promoted alveologenesis, but did not impact AFC nor attenuate fibrosis following high [Formula: see text] exposure. In conclusion, the data indicate that FADH2 may be pivotal for normal lung development, and show that ENaC is a key factor in promoting alveologenesis, sustaining AFC, and attenuating fibrotic lung injury caused by prolonged oxygen therapy in WT mice.

Neonatal Proximal Airway Basal Cell Culture as a Potential Model to Study Mechanisms of Lung Injury in Premature Infants

Neonatal Proximal Airway Basal Cell Culture as a Potential Model to Study Mechanisms of Lung Injury in Premature Infants

Mesenchymal stem/stromal cells stably transduced with an inhibitor of CC chemokine ligand 2 ameliorate bronchopulmonary dysplasia and pulmonary hypertension

Perinatal bronchopulmonary dysplasia (BPD) is defined as lung injury in preterm infants caused by various factors, resulting in serious respiratory dysfunction and high mortality. The administration of mesenchymal stem/stromal cells (MSCs) to treat/prevent BPD has proven to have certain therapeutic effects. However, MSCs can only weakly regulate macrophage function, which is strongly involved in the development of BPD. 7ND-MSCs are MSCs transfected with 7ND, a truncated version of CC chemokine ligand 2 (CCL2) that promotes macrophage activation, using a lentiviral vector. In the present study, we show in a BPD rat model that 7ND-MSC administration, but not MSCs alone, ameliorated the impaired alveolarization evaluated by volume density and surface area in the lung tissue, as well as pulmonary artery remodeling and pulmonary hypertension induced by BPD. In addition, 7ND-MSCs, but not MSCs alone, reduced M1 macrophages and the messenger RNA expressions of interleukin-6 and CCL2 in the lung tissue. Thus, the present study showed the treatment effect of 7ND-MSCs in a BPD rat model, which was more effective than that of MSCs alone.

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Permissive Hypercapnia.

Ventilator-induced lung injury is considered to be a main factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Optimizing ventilator strategies may reduce respiratory morbidities in preterm infants. Permissive hypercapnia has been suggested to attenuate lung injury. We aimed to determine if a higher PCO2 target range results in less lung injury compared to the control target range and possibly reduces pro-inflammatory cytokines and acid sphingomyelinase (ASM) in tracheal aspirates (TA), which has not been addressed before. During a multicenter trial of permissive hypercapnia in extremely low birthweight infants (PHELBI), preterm infants (birthweight 400-1,000 g, gestational age 23 0/7-28 6/7 weeks) requiring mechanical ventilation within 24 h of birth were randomly assigned to a high PCO2 target or a control group. The high target group aimed at PCO2 values of 55-65, 60-70, and 65-75 mmHg and the control group at PCO2 values of 40-50, 45-55 and 50-60 mmHg on postnatal days 1-3, 4-6, and 7-14, respectively. TA was analyzed for pro-inflammatory cytokines from postnatal day 2-21. BPD was determined at a postmenstrual age of 36 weeks ± 2 days. Levels of inflammatory cytokines and ASM were similar in both groups: interleukin (IL)-6 (p = 0.14), IL-8 (p = 0.43), IL-10 (p = 0.24), IL-1β (p = 0.11), macrophage inflammatory protein 1α (p = 0.44), albumin (p = 0.41), neuropeptide Y (p = 0.52), leukotriene B4 (p = 0.11), transforming growth factor-β1 (p = 0.68), nitrite (p = 0.15), and ASM (p = 0.94). Furthermore, most inflammatory mediators were strongly affected by the age of the infants and increased from postnatal day 2 to 21. BPD or death was observed in 14 out of 62 infants, who were distributed evenly between both groups. The results suggest that high PCO2 target levels did not result in lower pulmonary inflammatory activity and thus reflect clinical results. This indicates that high PCO2 target ranges are not effective in reducing ventilator-induced lung injury in preterm infants, as compared to control targets. ISRCTN56143743.

Expression and significance of long non-coding RNA metastasis associated in lung denocarcinoma transcript 1 in the process of hyperoxia-induced lung injury in preterm infants

Objective To explore the protective effect of long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) involved in hyperoxia-induced lung injury in preterm infants. Methods This study had downloaded chip data set GSE25286 (Mouse GEO Genome 430 2.0 Array) from gene expression database gene expression omnibus (GEO), according to the state of hyperoxia exposure, the MALAT1 mRNA expression in rats normal lung tissues and hyperoxic lung tissues was compared at day 14th and 29th.In chip data set GSE43830(Human Exon 1.0 ST Arrays) from GEO, the expression of multiple genes[cell division cycle 6(CDC6), death effector domain containing 2(DEDD2), and Cyclin B1(CCNB1)] in WI38 cells (lung fibroblasts) was compared before and after MALAT1 was knockout.At the same time, the peripheral blood samples of premature infants were collected to verify.Totally 40 premature infants were hospitalized in the department of neonatology in our hospital from Jan 2015 to Dec 2016, the peripheral blood samples of 40 premature infants were collected.RNA was extracted and Real time-PCR was performed after reverse transcription, clinical data of these 40 cases were retrospectively analyzed. Results (1) By using Affymetrix Expression console and Affymetrix Transcriptome analysis console software source files of the chip of pretreatment and difference expression gene screening, the expression of lncRNA MALAT1 gene in lung tissues of hyperoxia lung injury mice significantly upregulated[fold change(FC)=2.33, P=0.001]. (2) After MALAT1 in WI38 cell was knockout, MALAT1 expression was significantly reduced(FC=-15.6, P=0.000), the expression of CDC6(FC=-2.37, P=0.001) and CCNB1(FC=-2.16, P=0.002) were down regulated, DEDD2 expression was up regulated(FC=2.46, P=0.000). (3) The results of peripheral blood samples from preterm infants showed that the expression of MALAT1 was significantly increased in preterm infants with hyperoxia-induced lung injury(0.375 5±0.081 9, t=4.634, P=0.015), compared with normal preterm infants(0.273 4±0.067 3). Conclusion Through inhibiting cell apoptosis, lncRNA MALAT1 can protect preterm infants with hyperoxia-induced lung injury, it may provide a new strategy for prevention and treatment of hyperoxia-induced lung injury in premature infants. Key words: Long noncoding RNA; Neonates; Lung injury; Metastasis associated in lung denocarcinoma transcript 1; Hyperoxia

Decrease in delivery room intubation rates after use of nasal intermittent positive pressure ventilation in the delivery room for resuscitation of very low birth weight infants

BackgroundThe literature supports minimizing duration of invasive ventilation to decrease lung injury in premature infants. Neonatal Resuscitation Program recommended use of non-invasive ventilation (NIV) in delivery room for infants requiring prolonged respiratory support. ObjectiveTo evaluate the impact of implementation of non-invasive ventilation (NIV) using nasal intermittent positive pressure ventilation (NIPPV) for resuscitation in very low birth infants. Study designRetrospective study was performed after NIPPV was introduced in the delivery room and compared with infants receiving face mask to provide positive pressure ventilation for resuscitation of very low birth weight infants prior to its use. Data collected from 119 infants resuscitated using NIPPV and 102 infants resuscitated with a face mask in a single institution. The primary outcome was the need for endotracheal intubation in the delivery room. Data was analyzed using IBM SPSS Statistics software version 24. ResultsA total of 31% of infants were intubated in the delivery room in the NIPPV group compared to 85% in the Face mask group (p=<0.001). Chest compression rates were 11% in the NIPPV group and 31% in the Face mask group (p<0.001). Epinephrine administration was also lower in NIPPV group (2% vs. 8%; P=0.03). Only 38% infants remained intubated at 24hours of age in the NIPPV group compared to 66% in the Face mask group (p<0.001). Median duration of invasive ventilation in the NIPPV group was shorter (2days) compared to the Face mask group (11days) (p=0.01). The incidence of air-leaks was not significant between the two groups. ConclusionNIPPV was safely and effectively used in the delivery room settings to provide respiratory support for VLBW infants with less need for intubation, chest compressions, epinephrine administration and subsequent invasive ventilation.

Does lack of glutathione peroxidase 1 gene expression exacerbate lung injury induced by neonatal hyperoxia in mice?

Supplemental oxygen (O2) increases the risk of lung injury in preterm infants, owing to an immature antioxidant system. Our objective was to determine whether impairing antioxidant defense by decreasing glutathione peroxidase 1 (GPx1) gene expression increases the injurious effects of hyperoxia (Hyp). GPx1+/+ and GPx1-/- C57Bl/6J mice were exposed to 21% O2 (Air) or 40% O2 (Hyp) from birth to postnatal day 7 (P7d); they were euthanized on P7d or maintained in air until adulthood [postnatal day 56 (P56d)] to assess short-term and long-term effects, respectively. We assessed lung architecture, three markers of pulmonary oxidative stress (P7d, P56d), macrophages in lung tissue (P7d), immune cells in bronchoalveolar lavage fluid (BALF; P56d), and GPx1-4 and catalase gene expression in lung tissue (P7d, P56d). On P7d, macrophages were decreased by lack of GPx1 expression and further decreased by hyperoxia. GPx1 expression was increased in GPx1+/+Hyp mice and decreased in both GPx1-/- groups. On P56d, heme oxygenase-1 was increased by hyperoxia when GPx1 was absent. There were significantly more immune cells from Hyp groups than from the GPx1+/+Air group and a greater proportion of lymphocytes in GPx1-/-Hyp mice. GPx1 expression was significantly decreased in GPx1-/- mice; GPx2-4 and catalase expression was increased in GPx1-/-Hyp mice compared with other groups. Tissue fraction was decreased in GPx1-/-Air mice; bronchiolar smooth muscle was decreased in GPx1-/- mice. GPx1 does not clearly exacerbate hyperoxia-induced increases in oxidative stress or lung injury but may alter pulmonary immune function. Increased expression of GPx2-4 and catalase in GPx1-/-Hyp mice suggests gene redundancy within the model.

Reduction of Endotracheal Tube Connector Dead Space Improves Ventilation: A Bench Test on a Model Lung Simulating an Extremely Low Birth Weight Neonate.

The reduction of instrumental dead space is a recognized approach to preventing ventilation-induced lung injury in premature infants. However, there are no published data regarding the effectiveness of instrumental dead-space reduction in endotracheal tube (ETT) connectors. We tested the impact of the Y-piece/ETT connector pairs with reduced instrumental dead space on CO2 elimination in a model of the premature neonate lung. The standard ETT connector was compared with a low-dead-space ETT connector and with a standard connector equipped with an insert. We compared the setups by measuring the CO2 elimination rate in an artificial lung ventilated via the connectors. The lung was connected to a ventilator via a standard circuit, a 2.5-mm ETT, and one of the connectors under investigation. The ventilator was run in volume-controlled continuous mandatory ventilation mode. The low-dead-space ETT connector/Y-piece and insert-equipped standard connector/Y-piece pairs had instrumental dead space reduced by 36 and 67%, respectively. With set tidal volumes (VT) of 2.5, 5, and 10 mL, in comparison with the standard ETT connector, the low-dead-space connector reduced CO2 elimination time by 4.5% (P < .05), 4.4% (P < .01), and 7.1% (not significant), respectively. The insert-equipped standard connector reduced CO2 elimination time by 13.5, 25.1, and 16.1% (all P < .01). The low-dead-space connector increased inspiratory resistance by 17.8% (P < .01), 9.6% (P < .05), and 5.0% (not significant); the insert-equipped standard connector increased inspiratory resistance by 9.1, 8.4, and 5.9% (all not significant). The low-dead-space connector decreased expiratory resistance by 6.8% (P < .01) and 1.8% (not significant) and increased it by 1.4% (not significant); the insert-equipped standard connector decreased expiratory resistance by 1.5 and 1% and increased it by 1% (all not significant). The low-dead-space connector increased work of breathing by 4.7% (P < .01), 3.8% (P < .01), and 2.5% (not significant); the insert-equipped standard connector increased it by 0.8% (not significant), 2.5% (P < .01), and 2.8% (P < .01). Both methods of instrumental dead-space reduction led to improvements in artificial lung ventilation. Negative effects on resistance and work of breathing appeared minimal. Further testing in vivo should be performed to confirm the lung model results and, if successful, translated into clinical practice.

Wnt5a reverses the inhibitory effect of hyperoxia on transdifferentiation of alveolar epithelial type II cells to type I cells.

Transdifferentiation of alveolar epithelial type II cells (AECIIs) to type I cells (AECIs) is critical for reestablishment and maintenance of an intact alveolar epithelium. However, this process is frequently destroyed by hyperoxia treatment, which is commonly used in respiratory distress syndrome therapy in preterm infants. Wnt5a is considered to participate in this physiopathologic process, but the clear mechanisms still need to be further investigated. In this study, preterm rats and primary rat AECIIs were exposed to hyperoxia. Hematoxylin and eosin staining was used to examine the histological changes of the lungs. Real-time PCR and western blotting were used to examine Wnt5a expression and biomarkers of AECII and AECI expression. Immunohistochemistry and immunofluorescence were also used to determine the expression and location of selected biomarkers. Furthermore, AECIIs transfected with Wnt5a gene and exogenous Wnt5a were used to examine whether Wnt5a contributes to the transdifferentiation of AECIIs to AECIs. Results showed that hyperoxia inhibited the transdifferentiation of AECIIs to AECIs in vitro, which is represented by biomarkers of two types of cell that remained unchanged. In addition, Wnt5a protein expression was found to be decreased after hyperoxia exposure in vitro and in vivo. Furthermore, both the overexpression of Wnt5a and exogenous Wnt5a addition blocked the inhibitory effect of hyperoxia in vitro. In conclusion, our results suggest that the transdifferentiation of AECIIs to AECIs is impaired by hyperoxia, and this process may be associated with Wnt5a downregulation. Targeting Wnt5a may have the potential for the therapy of lung injury in preterm infants induced by hyperoxia.

CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

Background: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. Objective: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO₂ = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. Results: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. Conclusion: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD.

Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury.

BackgroundThe critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD.ObjectiveTo determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.MethodsC57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A4, or Hyperoxia + Resolvin D1/Lipoxin A4. Resolvin D1 and/or Lipoxin A4 (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ1 and TGFβ2.ResultThe increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A4; while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A4. Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A4 also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ2 (2.1 fold) and Smad3 (1.58 fold).ConclusionThe histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism

Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but it also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade.Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants.

Ventilator-induced lung injury in preterm infants

In preterm infants, the need for intubation and mechanical ventilation is associated with ventilator-induced lung injuries and subsequent bronchopulmonary dysplasia. The aim of the present review was to improve the understanding of the mechanisms of injury that involve cytokine-mediated inflammation to contribute to the development of new preventive strategies. Relevant articles were retrieved from the PubMed database using the search terms "ventilator-induced lung injury preterm", "continuous positive airway pressure", "preterm", and "bronchopulmonary dysplasia". The resulting data and other relevant information were divided into several topics to ensure a thorough, critical view of ventilation-induced lung injury and its consequences in preterm infants. The role of pro-inflammatory cytokines (particularly interleukins 6 and 8 and tumor necrosis factor alpha) as mediators of lung injury was assessed. Evidence from studies conducted with animals and human newborns is described. This evidence shows that brief periods of mechanical ventilation is sufficient to induce the release of pro-inflammatory cytokines. Other forms of mechanical and non-invasive ventilation were also analyzed as protective alternatives to conventional mechanical ventilation. It was concluded that non-invasive ventilation, intubation followed by early surfactant administration and quick extubation for nasal continuous positive airway pressure, and strategies that regulate tidal volume and avoid volutrauma (such as volume guarantee ventilation) protect against ventilator-induced lung injury in preterm infants.