Preeclampsia was a risk factor for pulmonary interstitial emphysema in preterm infants born ≤32 weeks of gestational age.

AIM: This study determined the prenatal and postnatal risk factors for pulmonary interstitial emphysema (PIE) in preterm infants born at up to 32 weeks of gestational age (GA) and their contribution to severe complications. METHODS: We studied 179 preterm infants, who had undergone chest X-rays during the first five days of life at Justus Liebig University Giessen, Germany, between 2016 and 2017. Of these, 33 were retrospectively classified as PIE and 146 as non-PIE. The PIE cases were also matched with 33 non-PIE cases by GA and gender. Risk factors were identified by univariate analyses and multivariable logistic regression. RESULTS: Previously known risk factors for pulmonary interstitial emphysema were confirmed, including GA and birthweight and the associations with adverse outcomes like intraventricular haemorrhage and mortality. We identified preeclampsia and haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome as additional risk factors for PIE (P = .027), and lung impairment was associated with respiratory distress syndrome (P = .001), higher maximum inspired oxygen (P = .014) and needing surfactant (P = .006). CONCLUSION: Preeclampsia and HELLP syndrome were identified as possible additional risk factors for PIE in preterm infants. These conditions should be included in future studies, to identify preterm infants at risk of PIE straight after birth.

MSC Based Therapies to Prevent or Treat BPD-A Narrative Review on Advances and Ongoing Challenges.

Bronchopulmonary dysplasia (BPD) remains one of the most devastating consequences of preterm birth resulting in life-long restrictions in lung function. Distorted lung development is caused by its inflammatory response which is mainly provoked by mechanical ventilation, oxygen toxicity and bacterial infections. Dysfunction of resident lung mesenchymal stem cells (MSC) represents one key hallmark that drives BPD pathology. Despite all progress in the understanding of pathomechanisms, therapeutics to prevent or treat BPD are to date restricted to a few drugs. The limited therapeutic efficacy of established drugs can be explained by the fact that they fail to concurrently tackle the broad spectrum of disease driving mechanisms and by the huge overlap between distorted signal pathways of lung development and inflammation. The great enthusiasm about MSC based therapies as novel therapeutic for BPD arises from the capacity to inhibit inflammation while simultaneously promoting lung development and repair. Preclinical studies, mainly performed in rodents, raise hopes that there will be finally a broadly acting, efficient therapy at hand to prevent or treat BPD. Our narrative review gives a comprehensive overview on preclinical achievements, results from first early phase clinical studies and challenges to a successful translation into the clinical setting.

Oxygen Toxicity to the Immature Lung-Part II: The Unmet Clinical Need for Causal Therapy.

Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.

Oxygen Toxicity to the Immature Lung-Part I: Pathomechanistic Understanding and Preclinical Perspectives.

In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury.

Anti-CCL2 therapy reduces oxygen toxicity to the immature lung.

Oxygen toxicity constitutes a key contributor to bronchopulmonary dysplasia (BPD). Critical step in the pathogenesis of BPD is the inflammatory response in the immature lung with the release of pro-inflammatory cytokines and the influx of innate immune cells. Identification of efficient therapies to alleviate the inflammatory response remains an unmet research priority. First, we studied macrophage and neutrophil profiles in tracheal aspirates of n = 103 preterm infants <29 weeks´ gestation requiring mechanical ventilation. While no differences were present at birth, a higher fraction of macrophages, the predominance of the CD14+CD16+ subtype on day 5 of life was associated with moderate/severe BPD. Newborn CCL-2-/- mice insufficient in pulmonary macrophage recruitment had a reduced influx of neutrophils, lower apoptosis induction in the pulmonary tissue and better-preserved lung morphometry with higher counts of type II cells, mesenchymal stem cells and vascular endothelial cells when exposed to hyperoxia for 7 days. To study the benefit of a targeted approach to prevent the pulmonary influx of macrophages, wildtype mice were repeatedly treated with CCL-2 blocking antibodies while exposed to hyperoxia for 7 days. Congruent with the results in CCL-2-/- animals, the therapeutic intervention reduced the pulmonary inflammatory response, attenuated cell death in the lung tissue and better-preserved lung morphometry. Overall, our preclinical and clinical datasets document the predominant role of macrophage recruitment to the pathogenesis of BPD and establish the abrogation of CCL-2 function as novel approach to protect the immature lung from hyperoxic injury.

Noninvasive Ventilation and Rapid Enteral Feeding Advances in Preterm Infants-2-Year Follow-Up of the STENA-Cohort.

The importance of nutritional supply for somatic growth and neurodevelopmental outcome in very-low-birthweight infants is an established medical strategy for reducing long-term morbidities. Our cohort study on rapid enteral feeding advances using a standardized protocol (STENA) previously demonstrated a 4-day reduction of parenteral nutrition. STENA did not impede the success of noninvasive ventilations strategies but significantly less infants required mechanical ventilation. Most importantly, STENA resulted in improved somatic growth at 36 weeks of gestation. Here, we evaluated our cohort for psychomotor outcomes and somatic growth at 2 years of age. n = 218 infants of the original cohort were followed-up (74.4%). Z-scores for weight and length did not differ but the benefits of STENA for head circumference persisted until the age of 2 years (p = 0.034). Concerning the psychomotor outcome, we neither found any statistically significant differences in the mental developmental index (MDI) (p = 0.738), norin the psychomotor developmental index (PDI) (p = 0.122). In conclusion, our data adds important insights on the topic of rapid enteral feeding advances and confirms the safety of STENA with respect to somatic growth and psychomotor outcome measures.

Compatibility of rapid enteral feeding advances and noninvasive ventilation in preterm infants-An observational study.

AIM: To evaluate safety and clinical outcome of rapid enteral feeding advances in preterm infants <1500 g birthweight (BW). METHODS: In this single-center retrospective cohort study, 293 preterm infants born during 2015-2018 were comparatively analyzed before (n = 145) and after (n = 148) the implementation of a rapid enteral feeding protocol with daily milk increments of 20-30 ml/kg of body weight. Major outcome parameters were focused toward pulmonary morbidities and nutritional variables. RESULTS: Preterm infants in the rapid feeding advancement group were more successfully stabilized on noninvasive ventilation (p < 0.001) never requiring mechanical ventilation. Duration of respiratory support (0.465) and frequency of bronchopulmonary dysplasia (BPD) (p = 0.341) and severe BPD (0.273) did not differ between both groups. Furthermore, patients in the rapid feeding group achieved full volume feedings faster (p < 0.001), regained BW earlier (p = 0.009), and displayed significantly improved somatic growth at 36 weeks gestational age (p < 0.001). There was no increased risk for further morbidities of prematurity including feeding intolerance, necrotizing enterocolitis (NEC), and focal intestinal perforation. CONCLUSION: Rapid enteral feeding advancements in preterm infants <1500 g BW are safe and do not impede stabilization on noninvasive ventilation.

When inflammation meets lung development-an update on the pathogenesis of bronchopulmonary dysplasia.

Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.

TRAIL protects the immature lung from hyperoxic injury.

The hyperoxia-induced pro-inflammatory response and tissue damage constitute pivotal steps leading to bronchopulmonary dysplasia (BPD) in the immature lung. The pro-inflammatory cytokines are considered attractive candidates for a directed intervention but the complex interplay between inflammatory and developmental signaling pathways requires a comprehensive evaluation before introduction into clinical trials as studied here for the death inducing ligand TRAIL. At birth and during prolonged exposure to oxygen and mechanical ventilation, levels of TRAIL were lower in tracheal aspirates of preterm infants <29 weeks of gestation which developed moderate/severe BPD. These findings were reproduced in the newborn mouse model of hyperoxic injury. The loss of TRAIL was associated with increased inflammation, apoptosis induction and more pronounced lung structural simplification after hyperoxia exposure for 7 days while activation of NFκB signaling during exposure to hyperoxia was abrogated. Pretreatment with recombinant TRAIL rescued the developmental distortions in precision cut lung slices of both wildtype and TRAIL-/- mice exposed to hyperoxia. Of importance, TRAIL preserved alveolar type II cells, mesenchymal progenitor cells and vascular endothelial cells. In the situation of TRAIL depletion, our data ascribe oxygen toxicity a more injurious impact on structural lung development. These data are not surprising taking into account the diverse functions of TRAIL and its stimulatory effects on NFκB signaling as central driver of survival and development. TRAIL exerts a protective role in the immature lung as observed for the death inducing ligand TNF-α before.

Bacterial Colonization within the First Six Weeks of Life and Pulmonary Outcome in Preterm Infants <1000 g.

Bronchopulmonary dysplasia (BPD) is a multifactorial disease mainly provoked by pre- and postnatal infections, mechanical ventilation, and oxygen toxicity. In severely affected premature infants requiring mechanical ventilation, association of bacterial colonization of the lung and BPD was recently disclosed. To analyze the impact of bacterial colonization of the upper airway and gastrointestinal tract on moderate/severe BPD, we retrospectively analyzed nasopharyngeal and anal swabs taken weekly during the first 6 weeks of life at a single center in n = 102 preterm infants <1000 g. Colonization mostly occurred between weeks 2 and 6 and displayed a high diversity requiring categorization. Analyses of deviance considering all relevant confounders revealed statistical significance solely for upper airway colonization with bacteria with pathogenic potential and moderate/severe BPD (p = 0.0043) while no link could be established to the Gram response or the gastrointestinal tract. Our data highlight that specific colonization of the upper airway poses a risk to the immature lung. These data are not surprising taking into account the tremendous impact of microbial axes on health and disease across ages. We suggest that studies on upper airway colonization using predefined categories represent a feasible approach to investigate the impact on the pulmonary outcome in ventilated and non-ventilated preterm infants.

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System.

More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.

Epithelial-Mesenchymal Transition in Endometriosis-When Does It Happen?

Epithelial-mesenchymal transition (EMT) is an important process of cell remodeling characterized by the gradual loss of the epithelial phenotype and progressive gain of a mesenchymal phenotype. EMT is not an all-or-nothing process, but instead a transition of epithelial to mesenchymal cells with intermediate cell states. Recently, EMT was described in endometriosis, and many EMT-specific pathways like Twist, Snail, Slug, Zinc finger E-box-binding homeobox 1/2 (ZEB1/2), E/N-cadherin, keratins, and claudins are involved. However, as pointed out in this review, a comparison of the eutopic endometrium of women with and without endometriosis yielded only subtle changes of these EMT markers. Furthermore, only very few alterations in cell-cell contacts could be found but without changes in the epithelial phenotype. This suggests only a partial EMT which is not a prerequisite for the detachment of endometrial cells and, thus, not critical for the first step(s) in the pathogenesis of endometriosis. In contrast, the majority of changes in the EMT-related marker expression were found in the ectopic endometrium, especially in the three endometriotic entities, ovarian, peritoneal, and deep infiltrating endometriosis (DIE), compared with the eutopic endometrium. In this review, we examine the most important EMT pathways described in endometriosis and propose that partial EMT might result from the interaction of endometrial implants with their surrounding microenvironment.

MSC Based Therapies-New Perspectives for the Injured Lung.

Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.

Non-Invasive Ventilation in Neonatology.

BACKGROUND: Invasive mechanical ventilation (IMV) has been replaced by early continuous positive airway pressure (CPAP) in the treatment of respiratory distress syndrome (RDS) in preterm infants aiming to reduce the rate of bronchopulmonary dysplasia (BPD). Subsequently, modern non-invasive ventilation strategies (NIV) were introduced into clinical practice with limited evidence of effects on pulmonary and neurodevelopmental outcomes. METHODS: We performed a selective literature search in PubMed including randomized controlled trials (RCT) (n ≥ 200) and meta-analyses published in the field of NIV in neonatology and follow-up studies focusing on long term pulmonary and neurodevelopmental outcomes. RESULTS: Individual studies do not show a significant risk reduction for the combined endpoint death or BPD in preterm infants caused by early CPAP in RDS when compared to primary intubation. One meta-analysis comparing four studies found CPAP significantly reduces the risk of BPD or death (relative risk: 0.91; 95% confidence interval [0.84;0.99]). Nasal intermittent positive pressure ventilation (NIPPV) as a primary ventilation strategy reduces the rate of intubations in infants with RDS (RR: 0.78 [0.64;0.94]) when compared to CPAP but does not affect the rate of BPD (RR: 0.78 [0.58;1.06]). CONCLUSION: Early CPAP reduces the need for IMV and the risk of BPD or death in preterm infants with RDS. NIPPV may offer advantages over CPAP regarding intubation rates. Networking-based follow-up programs are required to assess the effect of NIV on long term pulmonary and neurodevelopmental outcomes.

The Microbiome and Preterm Birth: A Change in Paradigm with Profound Implications for Pathophysiologic Concepts and Novel Therapeutic Strategies.

Preterm birth poses a global challenge with a continuously increasing disease burden during the last decades. Advances in understanding the etiopathogenesis did not lead to a reduction of prematurely born infants so far. A balanced development of the host microbiome in early life is key for the maturation of the immune system and many other physiological functions. With the tremendous progress in new diagnostic possibilities, the contribution of microbiota changes to preterm birth and the acute and long-term sequelae of prematurity have come into the research focus. This review summarizes the latest advances in the understanding of microbiomes in the amniotic cavity and the female lower genital tract and how changes in microbiota structures contribute to preterm delivery. The exhibition of these highly vulnerable infants to the hostile environment in the neonatal intensive care unit necessarily entails the rapid colonization with a nonbalanced microbiome in a situation where the organism is still very prone and at an early stage of development. The global research efforts to decipher pathologic changes will pave the way to new pre- and postnatal therapeutic concepts.