Chronic Lung Disease Of Infancy Research Articles

Hypoxia Inducible Factor-1α in SM22α Expressing Cells Modulates Alveolarization.

Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Infants with BPD have larger and fewer alveoli, pathology that can persist into adulthood. Though hypoxia inducible factor-1α (HIF-1α) plays a significant role in mediating pulmonary angiogenesis and alveolarization, the cell specific role of HIF-1α remains incompletely understood. To determine whether HIF-1α, in a mesenchymal cells (MC) subset, mediates postnatal alveolarization. We generated mice with cell-specific deletion of HIF-1α by crossing SM22α-promoter-driven Cre mice with HIF-1αflox/flox mice (SM22α- HIF-1α-/-), determined SM22α-expressing cell identity using single cell RNA-seq, and interrogated clinical samples from preterm infants. Measurement and Main Outcomes: Deletion of HIF-1α in SM22α expressing cells had no effect on lung structure at day (d) 3 of life. However, at 8d there were fewer and larger alveoli, a difference that persisted into adulthood. Microvascular density, elastin organization, and peripheral branching of the lung vasculature were decreased in SM22α-HIF-1α-/-, compared to control, mice. Single cell RNA-seq demonstrated that 3 MC subtypes (myofibroblasts, airway and vascular smooth muscle cells (VSMC)) express SM22α. Pulmonary VSMC from SM22α- HIF-1α-/- had decreased angiopoetin 2 expression and, in co-culture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoetin-2. Angiopoetin-2 expression in the tracheal aspirates of preterm infants was inversely correlated with overall time on mechanical ventilation, a marker of disease severity. SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoetin-2 expression.

Bronchopulmonary dysplasia – associated pulmonary hypertension: An updated review

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in infants and the commonest complication of prematurity. Advances in respiratory and overall neonatal care have increased the survival of extremely low gestational age newborns, leading to the continued high incidence of BPD. Pulmonary hypertension (PH) represents the severe form of the pulmonary vascular disease associated with BPD, and affects almost one-third of infants with moderate to severe BPD. PH responds suboptimally to pulmonary vasodilators and increases morbidity and mortality in BPD infants. An up-to-date knowledge of the pathogenesis, pathophysiology, diagnosis, treatment, and outcomes of BPD-PH can be helpful to develop meaningful and novel strategies to improve the outcomes of infants with this disorder. Therefore, our multidisciplinary team has attempted to thoroughly review and summarize the latest advances in BPD-PH in preventing and managing this morbid lung disorder of preterm infants.

Characteristics of infants requiring mechanical reventilation in those previously ventilated during the neonatal period

Background. Factors predisposing ventilated neonates to the risk for reventilation during infancy are largely unknown.Objective. To identify factors that predispose previously mechanically ventilated neonates to reventilation.Methods. Mechanically ventilated infants at the Inkosi Albert Luthuli Central Hospital paedicatric intensive care unit (PICU), SouthAfrica, who were also ventilated during the neonatal period were compared with age-, gender-, timing-, and site-matched controls whowere not reventilated during infancy. Neonatal and postnatal records of the two cohorts and data on their clinical presentation andoutcomes of the ICU admission were collected and analysed using descriptive and comparative statistics.Results. Thirty-one reventilated index cases were identified at the PICU over a 15-month period and were matched with 31non-reventilated controls. Ex-preterm babies (n=26; 84%), males (n=19; 61.3%), chronic lung disease (CLD) of infancy (n=5; 16.7%)and prolonged neonatal length of stay (LOS) were common neonatal factors in reventilated neonates. Pneumonia (n=22; 71%), sepsis(n=11; 35.5%) and upper airway obstruction (UAO) (n=8; 25.8%) were common reasons for reventilation in neonates. There were noHIV-positive cases. Of the 31 reventilated cases, 5 (16.1%) demised and 15 (57.6%) survivors had morbidities, commonly seizures (n=8;30.8%) and short bowel syndrome (n=3; 11.5%).Conclusion. Pre-term birth, male, CLD of infancy and prolonged LOS were associated with an increased risk for mechanical reventilationin infancy. Pneumonia, sepsis, CLD of infancy and UAO were common indications for reventilation post neonatal ICU discharge.

SM22α cell-specific HIF stabilization mitigates hyperoxia-induced neonatal lung injury.

Though survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically, BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIFs) may be protective in the context of hyperoxia-induced lung injury, but the cell-specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22α-expressing cells can limit hyperoxia-induced neonatal lung injury. We generated SM22α-specific HIF-1α-stabilized mice (SM22α-PHD1/2-/- mice) by cross-breeding SM22α-promotor-driven Cre recombinase mice with prolyl hydroxylase PHD1flox/flox and PHD2flox/flox mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22α-specific HIF-1α stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In SM22α-PHD1/2-/- mice, pulmonary artery endothelial cells (PAECs) were more proliferative and pulmonary arteries expressed more collagen IV compared with control mice, even under hyperoxic conditions. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in SM22α-PHD1/2-/- compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from SM22α-PHD1/2-/- mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from SM22α-PHD1/2+/+ mice. Addition of Ang2 recombinant protein further augmented tube formation for both PHD1/2+/+ and PHD1/2-/- PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1α expression in SM22α-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22α-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1α stabilization to prevent neonatal lung injury.

Risk factors that affect the degree of bronchopulmonary dysplasia in very preterm infants: a 5-year retrospective study

BackgroundBronchopulmonary dysplasia (BPD) is one of the most common adverse consequence of premature delivery and the most common chronic lung disease in infants. BPD is associated with long-term lung diseases and neurodevelopmental disorders that can persist into the adulthood. The adverse consequences caused by severe BPD are more serious. However, there were few studies on the risk factors for severe BPD.MethodsThis is a retrospective study of preterm infants born less than 32-week gestational age (GA) and diagnosed with BPD.ResultsA total of 250 preterm infants with a diagnosis of BPD and GA < 32 weeks were included (137 boys [54.8%] and 113 girls [45.2%]). The birth weight ranged from 700 g to 2010 g and the mean birth weight was 1318.52 g (255.45 g). The GA ranged from 25 weeks to 31 weeks and 6 days (mean, 30 weeks). The number of cases of mild, moderate and severe BPD were 39 (15.6%), 185 (74.0%) and 26 (10.4%), respectively. There were significant differences in the rate of small for gestational age (SGA), intrauterine asphyxia, pulmonary hemorrhage, neonatal respiratory distress syndrome (NRDS), circulatory failure, pulmonary hypertension, patent ductus arteriosus (PDA), pulmonary surfactant (PS), aminophylline, caffeine, glucocorticoids, tracheal intubation, diuretics, and parenteral nutrition length among the three groups (P < 0.05). The time of parenteral nutrition (aOR = 3.343, 95%CI: 2.198 ~ 5.085) and PDA (aOR =9.441, 95%CI: 1.186 ~ 75.128) were independent risk factors for severe BPD compared with mild BPD. PDA (aOR = 5.202, 95%CI: 1.803 ~ 15.010) and aminophylline (aOR = 6.179, 95%CI: 2.200 ~ 17.353) were independent risk factors for severe BPD, while caffeine (aOR = 0.260, 95%CI: 0.092 ~ 0.736) was the protective factor for severe BPD compared with moderate BPD. The time of parenteral nutrition (aOR = 2.972, 95%CI: 1.989 ~ 4.440) and caffeine (aOR = 4.525, 95%CI: 1.042 ~ 19.649) were independent risk factors for moderate BPD compared with mild BPD. Caffeine (aOR = 3.850, 95%CI: 1.358 ~ 10.916) was the independent risk factor for moderate BPD, while PDA (aOR = 0.192, 95%CI: 0.067 ~ 0.555) and aminophylline (aOR = 0.162, 95%CI: 0.058 ~ 0.455) were protective factors for moderate BPD compared with severe BPD. The time of parenteral nutrition (aOR = 0.337, 95%CI: 0.225 ~ 0.503) and caffeine (aOR = 0.221, 95%CI: 0.051 ~ 0.960) were protective factors for mild BPD compared with moderate BPD. The time of parenteral nutrition (aOR = 0.299, 95%CI: 0.197 ~ 0.455) and PDA (aOR = 0.106, 95%CI: 0.013 ~ 0.843) were protective factors for mild BPD compared with severe BPD.ConclusionThe time of parenteral nutrition is the risk factor of moderate and severe BPD. PDA and aminophylline are risk factors for severe BPD. The role of caffeine in the severity of BPD is uncertain, and SGA is not related to the severity of BPD. Severe or moderate BPD can be avoided by shortening duration of parenteral nutrition, early treatment of PDA, reducing use of aminophylline and rational use of caffeine.Trial registrationRetrospectively registered.

Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.

BackgroundPremature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD.MethodsA multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations.ResultsThe panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD.ConclusionsThe panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.

Predictors of pulmonary function at 6 years of age in infants with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a major complication of premature birth and the most common cause of chronic lung disease in infancy. Previous studies have shown that children with a history of BPD have impaired lung function in childhood compared to their term counterparts. However, little is known about potential modifiable factors that alter lung function trajectories and subsequent respiratory morbidity in this population. To identify potential modifiable risk factors for the development of impaired lung function in patients with a history of prematurity and bronchopulmonary dysplasia. Growth parameters (birth, 2 years old, 6 years old) and pulmonary function testing (6 years old) were retrospectively reviewed for subjects (n = 598) recruited from an outpatient BPD clinic who were born ≤36 weeks gestation and were≥5 years of age. Of the 598 recruited subjects, 88 (14.7%) performed adequate pulmonary function testing at approximately 6 years of age. The mean forced expiratory volume in 1 s global lung initiative (GLI) Z-score was -1.31 with lower values associated with Nissen fundoplication. The mean forced vital capacity GLI Z-score was -0.72 with lower values associated with higher amounts of oxygen required at time of initial hospital discharge and Nissen fundoplication. Our study found that children with BPD have lower predicted lung function values. Although growth parameters at age 2 and 6 years did not correlate with lung function values at 6 years of age; use and greater requirement for supplemental oxygen and the presence of a Nissen fundoplication at discharge were associated with lower lung function. Prospective studies should focus on identifying modifiable risk factors that could minimize the impact of BPD on later lung function.

“Reactance inversion” at low frequencies in a child undergoing treatment of a cystic fibrosis exacerbation

IntroductionImpulse oscillometry (IOS) employs high frequency sinusoidal or impulse pressure and flow waveforms to interrogate the mechanical properties of the respiratory system. It has special applications to preschool and younger children who may have difficulty performing the repetitive forced expiratory maneuvers required for spirometry.Case presentationWe present a case illustrating improvements of respiratory system mechanics measured by IOS in a 6‐year‐old child with cystic fibrosis (CF) who demonstrated clinical and radiological improvement after a course of therapy with hospitalization and intravenous antibiotics, and initiation of a cystic fibrosis transmembrane regulator (CFTR) protein corrector/potentiator agent. We also report a new finding: observed lower than expected reactance at low compared to high frequencies (“reactance inversion”).ConclusionReactance inversion may reflect parallel pathway inhomogeneities in resistance and elastance or intrabreath airway inertance changes in young children with CF. Further study is needed in children with airway obstruction due to asthma, cystic fibrosis, and chronic lung disease of infancy to demonstrate the prevalence of this finding and whether it is specific to a measurement device.

Massive subcutaneous emphysema and pneumomediastinum in acute bronchiolitis: a pediatric case with a history of chronic lung disease of infancy

Massive subcutaneous emphysema and pneumomediastinum in acute bronchiolitis: a pediatric case with a history of chronic lung disease of infancy

Pulmonary hypertension during respiratory syncytial virus bronchiolitis: a risk factor for severity of illness.

Respiratory syncytial virus infection is the most frequent cause of acute lower respiratory tract disease in infants. A few reports have suggested that pulmonary hypertension is associated with increased severity of respiratory syncytial virus infection. We sought to determine the association between the pulmonary hypertension detected by echocardiography during respiratory syncytial virus bronchiolitis and clinical outcomes. We retrospectively reviewed 154 children admitted with respiratory syncytial virus bronchiolitis who had an echocardiography performed during the admission. The association between pulmonary hypertension and clinical outcomes including mortality, intensive care unit (ICU) admission, prolonged ICU stay (&gt;10 days), tracheal intubation, and need of high frequency oscillator ventilation was evaluated. Echocardiography detected pulmonary hypertension in 29 patients (18.7%). Pulmonary hypertension was observed more frequently in patients with congenital heart disease (CHD) (n = 11/33, 33%), chronic lung disease of infancy (n = 12/25, 48%), prematurity (&lt;37 weeks gestational age, n = 17/59, 29%), and Down syndrome (n = 4/10, 40%). The presence of pulmonary hypertension was associated with morbidity (p &lt; 0.001) and mortality (p = 0.02). However, in patients without these risk factors (n = 68), pulmonary hypertension was detected in five patients who presented with shock or poor perfusion. Chronic lung disease was associated with pulmonary hypertension (OR = 5.9, 95% CI 2.2-16.3, p = 0.0005). Multivariate logistic analysis demonstrated that pulmonary hypertension is associated with ICU admission (OR = 6.4, 95% CI 2.2-18.8, p = 0.0007), intubation (OR = 4.7, 95% CI 1.8-12.3, p = 0.002), high frequency oscillator ventilation (OR = 8.4, 95% CI 2.95-23.98, p &lt; 0.0001), and prolonged ICU stay (OR = 4.9, 95% CI 2.0-11.7, p = 0.0004). Pulmonary hypertension detected by echocardiography during respiratory syncytial virus infection was associated with increased morbidity and mortality. Chronic lung disease was associated with pulmonary hypertension detected during respiratory syncytial virus bronchiolitis. Routine echocardiography is not warranted for previously healthy, haemodynamically stable patients with respiratory syncytial virus bronchiolitis.

EPO enhances the protective effects of MSCs in experimental hyperoxia-induced neonatal mice by promoting angiogenesis.

Bronchopulmonary dysplasia (BPD) is the most common type of chronic lung disease in infancy; however, there is no effective treatment for it. In the present study, a neonatal mouse BPD model was established by continuous exposure to high oxygen (HO) levels. Mice were divided randomly into 5 groups: control, BPD, EPO, MSCs, and MSCs+EPO. At 2 weeks post-treatment, vessel density and the expression levels of endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), and its receptor C-X-C chemokine receptor type 4 (CXCR4) were significantly increased in the MSC+EPO group compared with the EPO or MSCs group alone; moreover, EPO significantly enhanced MSCs proliferation, migration, and anti-apoptosis ability in vitro. Furthermore, the MSCs could differentiate into cells that were positive for the type II alveolar epithelial cell (AECII)-specific marker surfactant protein-C, but not positive for the AECI-specific marker aquaporin 5. Our present results suggested that MSCs in combination with EPO could significantly attenuate lung injury in a neonatal mouse model of BPD. The mechanism may be by the indirect promotion of angiogenesis, which may involve the SDF-1/CXCR4 axis.

Long-term ventilation for children with chronic lung disease of infancy.

Modern medical advances have resulted in an increased survival after extremely preterm birth. However, some infants will develop severe bronchopulmonary dysplasia (BPD) and fail to wean from invasive or noninvasive positive pressure support. It remains unclear which infants will benefit from tracheostomy placement for chronic ventilation. Once the decision to pursue chronic ventilation has been made, questions remain with respect to the timing of tracheotomy surgery, optimal strategies for mechanical ventilation, and multidisciplinary care in both the inpatient and outpatient settings. The appropriate time for weaning mechanical ventilation and tracheostomy decannulation has similarly not been determined. Although there remains a paucity of randomized controlled trials involving infants with severe BPD, a growing body of evidence suggests that chronic ventilation via tracheostomy is beneficial to support the growth and development of severely affected preterm children. However, delivering such care is not without risk. Chronic ventilation via tracheostomy requires complex care coordination and significant resource utilization. When chronic respiratory insufficiency limits a preterm infant's ability to grow and develop, chronic invasive ventilation may facilitate neurodevelopmental progress and may lead to an improved long-term outcome.

Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.

Increasing Immunization Rates in Infants with Severe Chronic Lung Disease: A Quality Improvement Initiative.

Immunizations provide important protection from serious childhood illnesses. Infant chronic lung disease (CLD) is a serious complication of prematurity and predisposes premature infants to respiratory morbidity, rehospitalization, and mortality. This high-risk group is especially vulnerable to infections, such as invasive pneumococcal disease, influenza, and bronchiolitis. Our purpose for this project was to increase 2-, 4-, and 6-month immunization rates in eligible infants with CLD in the NICU by 30% through December 2016. A multidisciplinary team developed weekly targeted rounds to identify eligible patients with outstanding immunizations. Exclusion criteria included the following: (1) a fraction of inspired oxygen requirement of >80%, (2) pulmonary hypertensive crisis, (3) positive blood culture results or if within 48 hours of a sepsis evaluation, (4) if within 5 days of a surgical or interventional procedure, (5) receiving steroid treatment (not including a physiologic hydrocortisone dose for adrenal insufficiency), (6) a CLD team consensus of contraindication, and (7) parental refusal. The project managed 60 patients from March 2016 to December 2016. Immunization of eligible patients increased from 44% to 75% and was sustained for the next 6 months. The average number of days from admission to immunization record review decreased from 71 days at baseline to 27 days. The implementation of (1) an in-hospital immunization record review, (2) an e-mail reminder, (3) a weekly multidisciplinary eligibility discussion, and (4) an updated rounding tool was successful in increasing and sustaining immunization rates in this population of infants with CLD. The multidisciplinary CLD meeting was a novel opportunity to discuss immunization eligibility and safety monitoring.

Hyperoxia-induced lung injury increases CDKN1A levels in a newborn rat model of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common, chronic lung disease of infants. Presently, high oxygen exposure and mechanical ventilation considerably influence the development of BPD. To clarify the pathological mechanisms of this disease, we developed a hyperoxia-induced BPD rat model and investigated the role of CDKN1A in the pathogenesis of BPD. Newborn rats were randomly assigned to the hyperoxia (85% O2) and control (normoxia, 21% O2) groups. Lung tissues were collected on days 1, 3, 7, 14, or 21 after the start of hyperoxia or normoxia exposure. The expression of CDKN1A was detected by immunohistochemistry, western blot, and real-time PCR. Starting from day 3, CDKN1A mRNA expression was higher in the hyperoxia group. From day 7, the radial alveolar count was significantly different between the two groups, and on day 14, the hyperoxia group had high CDKN1A protein expression compared to the control group. These results suggest that increased CDKN1A expression may be involved in the pathogenesis of BPD through alveolarization and lung retardation.

Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants that is characterized by interrupted lung development. Postnatal sepsis causes BPD, yet the contributory mechanisms are unclear. To address this gap, studies have used lipopolysaccharide (LPS) during the alveolar phase of lung development. However, the lungs of infants who develop BPD are still in the saccular phase of development, and the effects of LPS during this phase are poorly characterized. We hypothesized that chronic LPS exposure during the saccular phase disrupts lung development by mechanisms that promote inflammation and prevent optimal lung development and repair. Wild-type C57BL6J mice were intraperitoneally administered 3, 6, or 10 mg/kg of LPS or a vehicle once daily on postnatal days (PNDs) 3-5. The lungs were collected for proteomic and genomic analyses and flow cytometric detection on PND6. The impact of LPS on lung development, cell proliferation, and apoptosis was determined on PND7. Finally, we determined differences in the LPS effects between the saccular and alveolar lungs. LPS decreased the survival and growth rate and lung development in a dose-dependent manner. These effects were associated with a decreased expression of proteins regulating cell proliferation and differentiation and increased expression of those mediating inflammation. While the lung macrophage population of LPS-treated mice increased, the T-regulatory cell population decreased. Furthermore, LPS-induced inflammatory and apoptotic response and interruption of cell proliferation and alveolarization was greater in alveolar than in saccular lungs. Collectively, the data support our hypothesis and reveal several potential therapeutic targets for sepsis-mediated BPD in infants.

Bronchopulmonary dysplasia: Pathogenesis and treatment.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease of infancy, which mostly affects premature infants with significant morbidity and mortality. Premature infants who require to be treated for conditions including respiratory distress syndrome have a higher risk of developing BPD. In spite of the improvement in clinical methods, the incidence of BPD has not reduced. In the present review, the pathogenesis of BPD is described along with the treatments available at present and the role of nursing in the management of BPD. Emerging preventive therapies for BPD are also discussed, including the use of recombinant human superoxide dismutase, which has been proven effective in reducing respiratory injury and its long-term effects.

Bronchial hyper-responsiveness in preterm-born subjects: A systematic review and meta-analysis.

Preterm-born survivors have increased respiratory symptoms and decreased lung function, but the nature of bronchial hyper-responsiveness (BHR) is unclear. We conducted a systematic review and meta-analysis for BHR in preterm-born survivors including those with and without chronic lung disease in infancy (CLD) comparing results to term-born subjects. We searched eight databases up to December 2016. Included articles compared BHR in preterm-born and term-born subjects. Studies reporting BHR as decreases in forced expiratory volume in 1second (FEV1 ) after provocation stimuli were included. The analysis used Review Manager V5.3. From 10638 titles, 265 full articles were screened, and 28 included in a descriptive analysis. Eighteen articles were included in a meta-analysis as they reported the proportion of subjects who had BHR. Pooled odds ratio (OR) estimates (95% confidence interval) for BHR comparing the preterm and term-born groups was 1.88 (1.32, 2.66). The majority of the studies reported BHR after a methacholine challenge or an exercise test. Odds ratio was 1.89 (1.12, 3.19) after methacholine challenge and 2.59 (1.50, 4.50) after an exercise test. Nine of fifteen articles reporting BHR in CLD subjects were included in a meta-analysis. Differences for BHR including for methacholine (OR 4.35; 2.36, 8.03) and exercise (OR 5.13; 1.82, 14.47) were greater in the CLD group compared to the term group. Preterm-born subjects especially those who had CLD had increased rates of BHR to direct (methacholine) and indirect (exercise) stimuli compared to term-born subjects suggesting subgroups might benefit from anti-inflammatory or bronchodilator therapies.

Lung omics signatures in a bronchopulmonary dysplasia and pulmonary hypertension-like murine model.

Bronchopulmonary dysplasia (BPD), the most common chronic lung disease in infants, is associated with long-term morbidities, including pulmonary hypertension (PH). Importantly, hyperoxia causes BPD and PH; however, the underlying mechanisms remain unclear. Herein, we performed high-throughput transcriptomic and proteomic studies using a clinically relevant murine model of BPD with PH. Neonatal wild-type C57BL6J mice were exposed to 21% oxygen (normoxia) or 70% oxygen (hyperoxia) during postnatal days (PNDs) 1-7. Lung tissues were collected for proteomic and genomic analyses on PND 7, and selected genes and proteins were validated by real-time quantitative PCR and immunoblotting analysis, respectively. Hyperoxia exposure dysregulated the expression of 344 genes and 21 proteins. Interestingly, hyperoxia downregulated genes involved in neuronal development and maturation in lung tissues. Gene set enrichment and gene ontology analyses identified apoptosis, oxidoreductase activity, plasma membrane integrity, organ development, angiogenesis, cell proliferation, and mitophagy as the predominant processes affected by hyperoxia. Furthermore, selected deregulated proteins strongly correlated with the expression of specific genes. Collectively, our results identified several potential therapeutic targets for hyperoxia-mediated BPD and PH in infants.

Genipin attenuates hyperoxia-induced lung injury and pulmonary hypertension via targeting glycogen synthase kinase-3 β in neonatal rats.

Bronchopulmonary dysplasia is the most common chronic lung disease of infancy and is associated with pulmonary hypertension (PH). Inhibition of glycogen synthase kinase (GSK)-3 β has been shown to attenuate lung injury and PH in hyperoxia-exposed newborn rats. Genipin has been widely used for the treatment of inflammatory diseases. The aim of this study was to show that genipin decreased the expression of GSK-3 β in lung tissues of hyperoxia-exposed rat pups. We established models of hyperoxia-exposed rat pups, evaluated lung injury and pulmonary hypertension and detected the mRNA and protein expression of key molecules. Hyperoxia resulted in the reduction of survival rate and histologic injury of lung tissues; an increase of the messenger RNA (mRNA) expression of transforming growth factor-β1, extracellular matrix proteins collagen-I and fibronectin, and α-smooth muscle actin; an increase of right ventricular (RV) systolic pressure and the weight ratio of RV to left ventriclar (LV) plus septum (S) (RV/LV + S) were inhibited by genipin. Genipin also decreased the levels of tumor necrosis factor-α, interleukin-1 β, and interleukin-6 in both bronchoalveolar lavage fluid and lung tissues after hyperoxia exposure. In addition, genipin inhibited p65 nuclear factor-κB nuclear translocation and matrix metalloproteinase-2 and -9 expression. Moreover, hyperoxia resulted in an increase of methane dicarboxylic aldehyde content and a decrease of superoxide dismutase activity, catalytic subunit of glutamate-cysteine ligase, modified subunit of glutamate-cysteine ligase, and nuclear factor erythroid 2-related factor 2 expression were inhibited by genipin. All these effects induced by genipin were blocked by upregulation of GSK-3 β. Genipin downregulated GSK-3 β expression, decreased nuclear factor-κB translocation, increased nuclear factor erythroid 2-related factor 2 expression, attenuated inflammation and oxidative stress, leading to amelioration of lung injury and PH in hyperoxia-exposed rat pups. Overall, genipin may provide a novel therapeutic option for preventing and treating infants with bronchopulmonary dysplasia.