Neonatal Chronic Lung Disease Research Articles

Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury.

Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury.Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress.Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor.Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic lung disease, but may also protect adult survivors of BPD from sequelae later in life.

Maternal hypertensive disorders are associated with increased use of respiratory support but not chronic lung disease or poorer neurodevelopmental outcomes in preterm neonates at

To assess whether maternal hypertensive disorders in pregnancies result in higher respiratory requirements, risk of chronic lung disease (CLD) and poorer neurodevelopmental outcome in <29-week premature neonates. This is a multicentre, retrospective cohort study, within a geographically defined area in Australia, served by a network of 10 neonatal intensive care units (NICUs), consisting of infants <29 weeks of gestational age who were admitted to NICUs between 1998 and 2004. Outcome measures included hospital survival, perinatal complications and functional disability at 2-3 years follow-up. A total of 2549 mothers and infants were included in the study; 379 (14.9%) mothers had hypertensive disorders during pregnancy. Follow-up data were obtained for 1473 (74.8%) infants at 2-3 years. Infants exposed to pre-eclampsia had a higher need for supplemental surfactant therapy (odds ratio (OR): 2.004, 95% confidence interval (CI): 1.51-2.66), longer duration of mechanical ventilation (7.0 days vs. 4.0 days), were associated with a higher incidence of CLD (OR: 1.40, 95% CI: 1.12-1.76) and received post-natal steroids for CLD (OR: 1.82, 95% CI: 1.43-2.31) and home oxygen (OR: 1.47, 95% CI: 1.11-1.95). Multivariable analysis showed that hypertensive disease of pregnancy was not significantly associated with the development of CLD in this cohort (OR: 1.103, 95% CI: 0.845-1.441). Multivariable analysis of long-term neurodevelopmental data available for the 1473 follow-up infants showed no significant difference in outcomes with or without exposure to maternal hypertensive disease. Maternal hypertensive disease of pregnancy does not increase the risk of CLD or long-term neurodevelopmental complications in infants born at <29 weeks of gestation.

Labour room Continuous Positive Airway Pressure (LR CPAP) in preterm neonates

Early continuous positive airway pressure (CPAP) has proven to be beneficial in reducing ventilator dependence and subsequent chronic lung disease in neonates suffering from Respiratory distress syndrome (RDS). However, the efficacy of initiating labour room (LR) CPAP has not been determined prospectively in resource limited settings like India. Hence the objective of the present study was to study the efficacy of LR CPAP in preterm neonates with RDS in resource limited Indian settings. This was a prospective observational study including preterm neonates (26-34 weeks with RDS) carried out over a period of 6 months (January to June 2016) when the CPAP was initiated in LR. The outcome was compared with a similar population during the corresponding period of the previous year when CPAP was initiated in NICU. The historical controls were retrieved from case records and matched for gestational age and birth weight with the study population. There was 36% absolute risk reduction in the need for surfactant and 56% for mechanical ventilation in the LR CPAP group respectively. LR CPAP reduces the need for mechanical ventilation and surfactant in preterm neonates with RDS in resource limited settings.

A review of chronic lung disease in neonates at Charlotte Maxeke Johannesburg Academic Hospital from 1 January 2013 to 31 December 2014

Background. Chronic lung disease (CLD) remains a significant morbidity in preterm babies despite advances in neonatal care. The use of postnatal corticosteroids (PNCSs) to treat CLD remains controversial. Objectives. To describe the clinical characteristics of babies with CLD at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and to explore the use of PNCSs for the prevention and treatment of CLD. Methods. This was a 2-year retrospective review of neonates admitted to CMJAH. Neonates who were in hospital for ≥28 days were included. Comparisons were made between neonates with evolving CLD and those with no CLD. Results. A total of 485 neonates were analysed: 237 had evolving CLD and 245 did not have CLD. Overall incidence of evolving CLD was 5%. More neonates with CLD than those without CLD needed resuscitation at birth (48.5% v. 39.8%; p =0.02) and had low 5-minute Apgar scores (17.2% v. 10.6%; p =0.001). Neonates with CLD had increased prevalence of patent ductus arteriosus (30.4% v. 7.7%; p =0.001) and late-onset sepsis (56.5% v. 23.6%; p =0.001). The mortality rate was also higher in CLD babies (10.2 v. 2.4%; p =0.001). Necrotising enterocolitis (NEC) (29.2% v. 8%; p =0.005) and sepsis (83.3% v. 53.8%; p =0.008) were associated with increased mortality. The use of PNCSs was associated with less NEC (3.5% v. 17.2%; p =0.001) and improved survival (95.6% v. 81.7%; p =0.001). Conclusions. CLD remains a common morbidity in neonates despite advances in neonatal care. The use of PNCSs was shown to have short-term benefits. To get the most out of PNCS use for CLD, further studies need to be conducted to determine the safest type of steroid, safe doses and the duration of treatment.

Abnormal findings in brainstem auditory evoked response at 36–37 weeks of postconceptional age in babies with neonatal chronic lung disease

AimTo examine brainstem auditory function at 36–37weeks of postconceptional age in preterm infants who are diagnosed to have neonatal chronic lung disease (CLD). Study designPreterm infants, born at 31 and less weeks of gestation, were studied at 36–37weeks of postconceptional age when they were diagnosed to have neonatal CLD. Brainstem auditory evoked response (BAER) was recorded and analyzed at different click rates. ResultsCompared with healthy controls at the same postconceptional age, the CLD infants showed a slightly increase in BAER wave V latency. However, the I-V, and III–V interpeak intervals in the CLD infants were significantly increased. The III–V/I–III interval ratio was also significantly increased. The amplitudes of BAER waves III and V in the CLD infants tended to be reduced. These BAER findings were similar at all 21, 51 and 91/s clicks, although the abnormalities tended to be more significant at higher than at low click rates. ConclusionAt 36–37weeks of postconceptional age, BAER was abnormal in preterm infants who were diagnosed to have neonatal CLD. This suggests that at time when the diagnosis of CLD is made there is functional impairment, reflecting poor myelination, in the brainstem auditory pathway in preterm infants with neonatal CLD.

Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants.

Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with an increased risk of developing chronic lung disease. To evaluate supplementation with vitamin A on the incidence of death or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birth weight (VLBW) infants compared with a control (placebo or no supplementation), and to consider the effect of the supplementation route, dose, and timing. For the original review and subsequent updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Science Citation Index, and the Oxford Database of Perinatal Trials. The reference lists of relevant trials, paediatric and nutrition journals, and conference abstracts and proceedings were handsearched up to 2010.For the 2016 update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1 May 2016), EMBASE (1 May 2016), and CINAHL (1 May 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birth weight ≤ 1500 grams or less than 32 weeks' gestation). Two review authors screened the search results, extracted data, and assessed the trials for risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data. Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD -0.07, 95% CI -0.13 to -0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate-quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD -0.05, 95% CI -0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low-quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.

MEDICATION MANAGEMENT OF THE EXTREMELY PREMATURE NEONATE – THE IMPACT OF A SPECIALIST PHARMACIST

AimTo present a case of an extremely premature infant and the role that the specialist neonatal pharmacist has on the quality of care of these patients.MethodInterventions and recommendations made by...

IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development.

Inflammation in the developing preterm lung leads to disrupted airway morphogenesis and chronic lung disease in human neonates. However, the molecular mechanisms linking inflammation and the pathways controlling airway morphogenesis remain unclear. In this article, we show that IL-1β released by activated fetal lung macrophages is the key inflammatory mediator that disrupts airway morphogenesis. In mouse lung explants, blocking IL-1β expression, posttranslational processing, and signaling protected the formation of new airways from the inhibitory effects ofEscherichia coliLPS. Consistent with a critical role for IL-1β, mice expressing a gain-of-functionNlrp3allele and subsequent overactive inflammasome activity displayed abnormal saccular-stage lung morphogenesis and died soon after birth. Although the early-stage fetal lung appeared capable of mounting an NF-κB-mediated immune response, airway formation became more sensitive to inflammation later in development. This period of susceptibility coincided with higher expression of multiple inflammasome components that could increase the ability to release bioactive IL-1β. Macrophages fromNlrp3gain-of-function mice also expressed higher levels of more mature cell surface markers, additionally linking inflammasome activation with macrophage maturation. These data identify developmental expression of the inflammasome and IL-1β release by fetal lung macrophages as key mechanisms and potential therapeutic targets for neonatal lung disease.

Bronchopulmonary Dysplasia Within and Beyond the Neonatal Unit.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity or chronic neonatal lung disease, is a major cause of respiratory illness in premature babies. Newborn babies survive at gestational ages of 23 to 26 weeks, earlier than when BPD was first described. New mechanisms of lung injury have therefore emerged and the clinical and pathological characteristics of pulmonary involvement have changed. Improved neonatal intensive care unit modalities have increased survival rates; the overall prevalence of the condition, however, has not changed. Management of evolving BPD aims at minimizing lung injury. Management of established, especially severe BPD, still poses significant clinical challenge as these babies need long-term oxygen therapy (LTOT) for variable length of time. We aim to give an overview of management of established BPD with particular focus on weaning home oxygen therapy at our local center in the United Kingdom. On the basis of most recent evidence, we concluded that an integrated pathway for managing babies on LTOT is very important after discharge from neonatal unit. A structured weaning pathway for premature babies on home oxygen improves outcome. The management of severe BPD and related complications, particularly during the first 2 years of life, remains a continuing challenge for parents and healthcare providers. The most beneficial respiratory support strategy to minimize lung injury and/or promote lung healing remains unclear and requires further investigation.

An Assessment Tool for Babies Requiring Continuous Positive Airway Pressure or High Flow

A trend towards an increased use of nasal continuous positive airway pressure (nCPAP) has arisen from several studies that have provided evidence of decreased lung damage and reduced incidence of chronic lung disease in neonates [1,2]. Nasal CPAP is an effective treatment modality for neonates with bronchopulmonary dysplasia (BPD) and respiratory disease [3]. External or internal complications of nCPAP and High Flow can be relatively frequent and close surveillance for potential complications must be considered during nCPAP and High flow use.

Fitness to Fly Testing in Patients with Congenital Heart and Lung Disease

During commercial air travel passengers are exposed to a low ambient cabin pressure, comparable to altitudes of 5000 to 8000 ft (1524 to 2438 m). In healthy passengers this causes a fall in partial pressure of oxygen, which results in relative hypoxemia, usually without symptoms. Patients with congenital heart or lung disease may experience more severe hypoxemia during air travel. This systematic review provides an overview of the current literature focusing on whether it is safe for patients with congenital heart or lung disease to fly. The Pubmed database was searched and all studies carried out at an (simulated) altitude of 5000-8000 ft (1524-2438 m) for a short time period (several hours) and related to patients with congenital heart or lung disease were reviewed. Included were 11 studies. These studies examined patients with cystic fibrosis, neonatal (chronic) lung disease and congenital (a)cyanotic heart disease during a hypoxic challenge test, in a hypobaric chamber, during commercial air travel, or in the mountains. Peripheral/arterial saturation, blood gases, lung function, and/or the occurrence of symptoms were listed. Based on the current literature, it can be concluded that air travel is safe for most patients. However, those at risk of hypoxia can benefit from supplemental in-flight oxygen. Therefore, patients with congenital heart and lung disease should be evaluated carefully prior to air travel to select the patients at risk for hypoxia using the current studies and guidelines.

Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease.

Supplemental oxygen after premature birth results in aberrant airway, alveolar, and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia, and development of wheeze and asthma, pulmonary hypertension, and chronic obstructive pulmonary disease in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway has significant beneficial effects on disease development in animal models, so far this could not be translated to the clinic. Oxidative stress reduces the NO-sGC-cGMP pathway by oxidizing heme-bound sGC, resulting in inactivation or degradation of sGC. Reduced sGC activity and/or expression is associated with pathology due to premature birth, oxidative stress-induced lung injury, including impaired alveolar maturation, smooth muscle cell (SMC) proliferation and contraction, impaired airway relaxation and vasodilation, inflammation, pulmonary hypertension, right ventricular hypertrophy, and an aggravated response toward hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca(2+) responses were significantly elevated in hyperoxia-exposed fetal human airway SMCs compared with normoxic controls and that this hyperoxia-induced increase in the response was strongly reduced by NO-independent stimulation and activation of sGC. These recent studies highlight the therapeutic potential of sGC modulators in the treatment of preterm infants for respiratory distress with supplemental oxygen. Such treatment is aimed at improving aberrant alveolar and vascular development of the neonatal lung and preventing the development of wheezing and asthma in survivors of premature birth. In addition, these studies highlight the suitability of fetal human airway SMCs as a translational model for pathological airway changes in the neonate.

Living and managing with the long-term implications of neonatal chronic lung disease: The experiences and perspectives of children and their parents

ObjectiveThe purpose of the study was to investigate children's perspectives of living with chronic lung disease (CLD) and their parents' long-term experiences of caring for them. BackgroundCLD caused by prematurity of birth is associated with continuing respiratory, neuro-developmental and psychosocial issues. Methods10 children (6–15 years old) with CLD and 12 parents were involved in semi-structured qualitative interviews. Data were analyzed using thematic analysis. ResultsCLD was described as ‘getting easier over time’ and that you ‘learnt to live with it.’ Expertise was acquired in controlling symptoms and recognizing the onset of illness, despite expressed uncertainty of the nature of the condition. Children experienced difficulties engaging in peer activities and encountered cases of teasing and isolation at school. ConclusionCLD was reported as becoming easier over time to live with. Despite this, children experienced challenges engaging in peer activities and families described difficulties interacting with health and education services.

Animal Models, Learning Lessons to Prevent and Treat Neonatal Chronic Lung Disease.

Bronchopulmonary dysplasia (BPD) is a unique injury syndrome caused by prolonged injury and repair imposed on an immature and developing lung. The decreased septation and decreased microvascular development phenotype of BPD can be reproduced in newborn rodents with increased chronic oxygen exposure and in premature primates and sheep with oxygen and/or mechanical ventilation. The inflammation caused by oxidants, inflammatory agonists, and/or stretch injury from mechanical ventilation seems to promote the anatomic abnormalities. Multiple interventions targeted to specific inflammatory cells or pathways or targeted to decreasing ventilation-mediated injury can substantially prevent the anatomic changes associated with BPD in term rodents and in preterm sheep or primate models. Most of the anti-inflammatory therapies with benefit in animal models have not been tested clinically. None of the interventions that have been tested clinically are as effective as anticipated from the animal models. These inconsistencies in responses likely are explained by the antenatal differences in lung exposures of the developing animals relative to very preterm humans. The animals generally have normal lungs while the lungs of preterm infants are exposed variably to intrauterine inflammation, growth abnormalities, antenatal corticosteroids, and poorly understood effects from the causes of preterm delivery. The animal models have been essential for the definition of the mediators that can cause a BPD phenotype. These models will be necessary to develop and test future-targeted interventions to prevent and treat BPD.

Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.

Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

A breath of fresh air on the mesenchyme: impact of impaired mesenchymal development on the pathogenesis of bronchopulmonary dysplasia.

The early mouse embryonic lung, with its robust and apparently reproducible branching pattern, has always fascinated developmental biologists. They have extensively used this embryonic organ to decipher the role of mammalian orthologs of Drosophila genes in controlling the process of branching morphogenesis. During the early pseudoglandular stage, the embryonic lung is formed mostly of tubes that keep on branching. As the branching takes place, progenitor cells located in niches are also amplified and progressively differentiate along the proximo-distal and dorso-ventral axes of the lung. Such elaborate processes require coordinated interactions between signaling molecules arising from and acting on four functional domains: the epithelium, the endothelium, the mesenchyme, and the mesothelium. These interactions, quite well characterized in a relatively simple lung tubular structure remain elusive in the successive developmental and postnatal phases of lung development. In particular, a better understanding of the process underlying the formation of secondary septa, key structural units characteristic of the alveologenesis phase, is still missing. This structure is critical for the formation of a mature lung as it allows the subdivision of saccules in the early neonatal lung into alveoli, thereby considerably expanding the respiratory surface. Interruption of alveologenesis in preterm neonates underlies the pathogenesis of chronic neonatal lung disease known as bronchopulmonary dysplasia. De novo formation of secondary septae appears also to be the limiting factor for lung regeneration in human patients with emphysema. In this review, we will therefore focus on what is known in terms of interactions between the different lung compartments and discuss the current understanding of mesenchymal cell lineage formation in the lung, focusing on secondary septae formation.

G397(P) Hypoxic challenge testing – which children are we assessing?

Aim Hypoxic challenge testing (HCT) is the method used to assess whether a patient with stable respiratory disease requires in-flight oxygen. A national guideline, published by British Thoracic Society in 2011, makes recommendations on which children ought to undergo HCT prior to undertaking air travel. Identified are: infants under 1 year with neonatal history of chronic lung disease, children with CF/chronic lung disease old enough for spirometry whose FEV1 This audit aimed to define which patients had undergone hypoxic challenge tests and compared this against the patient groups identified in the BTS guideline. Methods A large tertiary children’s hospital in the UK conducted a retrospective audit of hypoxic challenge tests carried out between 2012 and 2014. Information was collected on age, diagnosis, when the patient last required long-term oxygen, lung function around the time of the test and the outcome of the test. Results 31 HCTs from 25 patients were audited. The average age was 6.3 years (6 months-16.5 years). Of the 22 patients who passed the HCT, three were recommended in the guideline to have HCT. Of the nine patients who did not pass HCT, two were within the recommendations. These five patients, who were within the recommendations, were three children with CF/chronic lung disease with FEV1 Of the nine children who did not pass the HCT, seven fell outside the recommended groups. Five were ex-preterm children older than one year had history of neonatal chronic lung disease, one had SMA Type 2, one had muscular dystrophy, one had severe kyphoscoliosis and one had severe restrictive lung disease following PNET. Conclusion Results show that clinicians are choosing to preform hypoxic challenge tests on patient outside of the recommendations. A larger proportion who failed the hypoxic challenge test were not defined within the BTS guidelines. With advancing technology the demographics of our respiratory paediatric patient population is evolving. It is therefore prudent to reconsider the paediatric recommendations.

Utility of large-animal models of BPD: chronically ventilated preterm lambs.

This paper is focused on unique insights provided by the preterm lamb physiological model of bronchopulmonary dysplasia (BPD). Connections are also made to insights provided by the former preterm baboon model of BPD, as well as to rodent models of lung injury to the immature, postnatal lung. The preterm lamb and baboon models recapitulate the clinical setting of preterm birth and respiratory failure that require prolonged ventilation support for days or weeks with oxygen-rich gas. An advantage of the preterm lamb model is the large size of preterm lambs, which facilitates physiological studies for days or weeks during the evolution of neonatal chronic lung disease (CLD). To this advantage is linked an integrated array of morphological, biochemical, and molecular analyses that are identifying the role of individual genes in the pathogenesis of neonatal CLD. Results indicate that the mode of ventilation, invasive mechanical ventilation vs. less invasive high-frequency nasal ventilation, is related to outcomes. Our approach also includes pharmacological interventions that test causality of specific molecular players, such as vitamin A supplementation in the pathogenesis of neonatal CLD. The new insights that are being gained from our preterm lamb model may have important translational implications about the pathogenesis and treatment of BPD in preterm human infants.

Bronchopulmonary dysplasia - an overview about pathophysiologic concepts.

Neonatal chronic lung disease in the preterm infant, i.e. bronchopulmonary dysplasia (BPD) is characterized by impaired pulmonary development with its effects persisting into adulthood. Triggered in the immature lung by infectious complications, oxygen toxicity and the impact of mechanical ventilation, a sustained inflammatory response, extensive remodeling of the extracellular matrix, increased apoptosis as well as altered growth factor signaling characterize the disease. The current review focuses on selected pathophysiologic processes and their interplay in disease development. Furthermore, the potential of both, acute and long-term changes to the pulmonary scaffold and the cellular interface in concert with dysregulated growth factor signaling to affect aging and repair processes in the adult lung is discussed.

Bronchopulmonary dysplasia early changes leading to long-term consequences.

Neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, is characterized by impaired pulmonary development resulting from the impact of different risk factors including infections, hyperoxia, and mechanical ventilation on the immature lung. Remodeling of the extracellular matrix, apoptosis as well as altered growth factor signaling characterize the disease. The immediate consequences of these early insults have been studied in different animal models supported by results from in vitro approaches leading to the successful application of some findings to the clinical setting in the past. Nonetheless, existing information about long-term consequences of the identified early and most likely sustained changes to the developing lung is limited. Interesting results point towards a tremendous impact of these early injuries on the pulmonary repair capacity as well as aging related processes in the adult lung.