Search

The extracellular matrix (ECM) is an active and dynamic feature of tissues that not only provides gross structure but also plays key roles in cellular responses. The ever-changing microenvironment responds dynamically to cellular and external signals, and in turn influences cell fate, tissue development, and response to environmental injury or microbial invasion. It is therefore paramount to understand how the ECM components interact with each other, the environment and cells, and how they mediate their effects. Among the ECM components that have recently garnered increased attention, proteoglycans (PGs) deserve special note. Recent evidence strongly suggests that they play a crucial role both in health maintenance and disease development. In particular, proteoglycans dictate whether homeostasis or cell death will result from a given injury, by triggering and modulating activation of the innate immune system, via a conserved array of receptors that recognize exogenous (infectious) or endogenous (tissue damage) molecular patterns. Innate immune activation by proteoglycans has important implications for the understanding of cell-matrix interactions in health and disease. In this review, we will summarize the current state of knowledge of innate immune signaling by proteoglycans, discuss the implications, and explore future directions to define progress in this area of extracellular matrix biology.

Objective To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. Study design Data from the Children’s Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. Results Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (

BACKGROUND The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight

To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units.This was a multicenter, retrospective cohort study of infants born ≥37 weeks of gestation in the Children's Hospitals Neonatal Consortium.Out of 67,367 full-term infants admitted in 2010-2016, 4886 (7%) had CLD based on receiving respiratory support at either 28 days of life or discharge. 3286 (67%) were still hospitalized at 28 days receiving respiratory support, with higher mortality risk than those without CLD (10% vs. 2%, p 0.001). A higher proportion received tracheostomy (13% vs. 0.3% vs. 0.4%, p 0.001) and gastrostomy (30% vs. 1.7% vs. 3.7%, p 0.001) compared to infants with CLD discharged home before 28 days and infants without CLD, respectively. The diagnoses and surgical procedures differed significantly between the two CLD subgroups. Small for gestational age, congenital pulmonary, airway, and cardiac anomalies and bloodstream infections were more common among infants with CLD who died or required tracheostomy with home ventilation (p 0.001). Invasive ventilation at 28 days was independently associated with death or tracheostomy and home mechanical ventilation (odds ratio 7.6, 95% confidence interval 5.9-9.6, p 0.0001).Full-term infants with CLD are at increased risk for morbidity and mortality. We propose a severity-based classification for CLD in full-term infants. Future work to validate this classification and its association with early childhood outcomes is necessary.

Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. Neonatal mice were transiently exposed to broad-spectrum antibiotics from birth for either 3- (SE) or 7-days (LE) and were examined at 14-days-old. We found that mice exposed to either SE or LE showed persistent expansion of Proteobacteria (2 log difference, P E. coli into the liver and spleen and were more susceptible K. pneumoniae-induced sepsis. LE mice had a significant and persistent decrease in type 3 innate lymphoid cells (ILC3) in the lamina propria. Reconstitution of the microbiome with mature microbiota by gavage in LE mice following antibiotic exposure resulted in an increase in ILC3 and partial rescue from LOS. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution.

Apart from its known actions as a pulmonary vasodilator, nitric oxide (NO) is a key signal mediator in the neonatal brain. Despite the extensive use of NO for pulmonary artery hypertension (PAH), its actions in the setting of brain hypoxia and ischemia, which co-exists with PAH in 20-30% of affected infants, are not well established. This review focuses on the mechanisms of actions of NO covering the basic, translational, and clinical evidence of its neuroprotective and neurotoxic properties. In this first part, we present the physiology of transport and delivery of NO to the brain and the regulation of cerebrovascular and systemic circulation by NO, as well the role of NO in the development of the immature brain. IMPACT: NO can be transferred from the site of production to the site of action rapidly and affects the central nervous system. Inhaled NO (iNO), a commonly used medication, can have significant effects on the neonatal brain. NO regulates the cerebrovascular and systemic circulation and plays a role in the development of the immature brain. This review describes the properties of NO under physiologic conditions and under stress. The impact of this review is that it describes the effects of NO, especially regarding the vulnerable neonatal brain, and helps understand the conditions that could contribute to neurotoxicity or neuroprotection.

BACKGROUND The hyaluronan (HA) receptors CD44 and RHAMM (CD168) are involved in cellular proliferation, differentiation, and motility. As previously investigated, HA and RHAMM expression in human neonatal lungs correlates to gestational age (GA) and air content. METHODS CD44 immunofluorescence was analyzed in postmortem lung samples from infants (n = 93; 22-41 GA) by digital image analysis together with clinical data, including RHAMM expression, lung air, and HA content by hierarchical clustering. RESULTS Five groups were defined according to RHAMM/CD44 expression, GA, and postnatal age (PNA): extremely to very preterm (EVP; 22-31 GA; Groups 1-2), moderately preterm to term (MPT; 31-41 GA; Groups 3-4), and mixed preterm to term (27-40 GA; Group 5). CD44 correlated linearly with RHAMM in MPT (r = 0.600; p

Background The use of telemedicine to provide care for critically ill newborn infants has significantly evolved over the last two decades. Children's Health System of Texas and University of Texas Southwestern Medical Center established TeleNICU, the first teleneonatology program in Texas. Objective To evaluate the effectiveness of Tele Neonatal Intensive Care Unit (TeleNICU) in extending quaternary neonatal care to more rural areas of Texas. Materials and methods We conducted a retrospective review of TeleNICU consultations from September 2013 to October 2018. Charts were reviewed for demographic data, reasons for consultation, and consultation outcomes. Diagnoses were classified as medical, surgical, or combined. Consultation outcomes were categorized into transferred or retained. Transport cost savings were estimated based on the distance from the hub site and the costs for ground transportation. Results TeleNICU had one hub (Level IV) and nine spokes (Levels I–III) during the study period. A total of 132 direct consultations were completed during the study period. Most consultations were conducted with Level III units (81%) followed by level I (13%) and level II (6%) units. Some common diagnoses included prematurity (57%), respiratory distress (36%), congenital anomalies (25%), and neonatal surgical emergencies (13%). For all encounters, 54% of the patients were retained at the spoke sites, resulting in an estimated cost savings of USD0.9 million in transport costs alone. The likelihood of retention at spoke sites was significantly higher for medical diagnoses compared to surgical diagnoses (89% vs. 11%). Conclusion Telemedicine effectively expands access to quaternary neonatal care for more rural communities, helps in the triage of neonatal transfers, promotes family centered care, and significantly reduces health care costs.

Acute lung injury results in early inflammation and respiratory distress, and later fibrosis. The glycosaminoglycan hyaluronan (HA) and the Receptor for Hyaluronan-Mediated Motility (RHAMM, CD168) have been implicated in the response to acute lung injury. We hypothesized that, compared to wild type (WT) mice, RHAMM knockout (KO) mice would be protected from, whereas mice with macrophage-specific transgenic overexpression of RHAMM (TG) would have worse inflammation, respiratory distress and fibrosis after intratracheal (IT) bleomycin. Compared to WT mice, 10 days after IT bleomycin, RHAMM KO mice had less weight loss, less increase in respiratory rate, and fewer CD45+ cells in the lung. At day 28, compared to injured WT animals, injured RHAMM KO mice had lower M1 macrophage content, as well as decreased fibrosis as determined by trichrome staining, Ashcroft scores and lung HPO content. Four lines of transgenic mice with selective overexpression of RHAMM in macrophages were generated using the Scavenger Receptor A promoter driving a myc-tagged full length RHAMM cDNA. Baseline expression of RHAMM and CD44 was the same in WT and TG mice. By flow cytometry, TG bone marrow-derived macrophages (BMDM) had increased cell surface RHAMM and myc, but equal CD44 expression. TG BMDM also had 2-fold increases in both chemotaxis to HA and proliferation in fetal bovine serum. In TG mice, increased inflammation after thioglycollate-induced peritonitis was restricted to macrophages and not neutrophils. For lung injury studies, non-transgenic mice given bleomycin had respiratory distress with increased respiratory rates from day 7 to 21. However, TG mice had higher respiratory rates from 4 days after bleomycin and continued to increase respiratory rates up to day 21. At 21 days after IT bleomycin, TG mice had increased lung macrophage accumulation. Lavage HA concentrations were 6-fold higher in injured WT mice, but 30-fold higher in injured TG mice. At 21 days after IT bleomycin, WT mice had developed fibrosis, but TG mice showed exaggerated fibrosis with increased Ashcroft scores and HPO content. We conclude that RHAMM is a critical component of the inflammatory response, respiratory distress and fibrosis after acute lung injury. We speculate that RHAMM is a potential therapeutic target to limit the consequences of acute lung injury.

Background Managing critically ill neonates has unique challenges, and the transport team plays an important role in stabilizing and facilitating the transfer of these neonates from lower-level nurseries to tertiary centers, and the use of telemedicine in transport (tele-transport) can potentially benefit patient care. We conducted a multicenter study to assess the readiness for utilizing telemedicine as an adjunct to guide the care of critically ill neonates among physicians and transport team members (TTMs). This is the first multicenter study that explored physicians’ and TTMs’ perceptions of telemedicine usage and its value in neonatal transport. Methods A confidential, voluntary survey on pre-implementation attitudes toward telemedicine usage during neonatal transport was conducted as part of a quality improvement initiative. This survey involved physicians and TTMs from four academic institutions whose responses were entered into an online survey using REDCap®. The survey inquired about satisfaction with the current practice of phone consultation and the perception of using telemedicine to optimize the management of neonates during transport. Results The overall response rate for the survey was 60.1%; 82 of 127 (64.6%) physicians and 64 of 116 (55.2%) TTMs responded to the surveys. Half of the physicians and less than one-fourth of the TTMs had prior experience with telemedicine other than that used on neonatal transport. TTMs expressed greater concern about the inconvenience of video (55% vs. physicians 35% agree or strongly agree) and its time consumption (84% vs. physicians 50%). More than 70% of physicians and less than half of TTMs endorsed the potential for added value and quality improvement with video capability. Almost half of TTMs reported concern about video calls reducing their autonomy in patient care. Physicians expressed confidence in management decisions they would make after video calls (72% confident or very confident) and less confidence (49%) about both the phone assessment by TTMs and their decisions based on phone assessment. In contrast, TTMs were confident or very confident (94%) in both sharing their assessment over the phone and executing patient management after a phone call, compared with 70% for decisions made after video calls. Conclusions Physicians and TTMs had distinct opinions on the use of telemedicine during neonatal transport. Physicians were more likely than TTMs to agree with statements about the potential for improving quality of care, while TTMs were more likely than physicians to say video calls would be time-consuming and inconvenient. We speculate some differences may stem from the TTMs’ concern about losing their autonomy. Therefore, during implementation, it is critical for physicians and TTMs to agree on a shared mental model of indications for telemedicine during transport and its value to the patient care.

Over a century of innovations in technology and medical care have led to the current day capabilities in telemedicine. In this chapter, we discuss the evolution of telemedicine over the last century and highlight various applications in neonatal care. We hope this chapter demonstrates the exponential adoption of telemedicine, particularly in neonatology, and the breadth and depth of the technology being used.

The development, growth, and function of the cardiac, pulmonary, and vascular systems are closely intertwined during both fetal and postnatal life. In utero, placental, environmental, and genetic insults may contribute to abnormal pulmonary alveolarization and vascularization that increase susceptibility to the development of bronchopulmonary dysplasia (BPD) in preterm infants. However, the shared milieu of stressors may also contribute to abnormal cardiac or vascular development in the fetus and neonate, leading to the potential for cardiovascular dysfunction. Further, cardiac or pulmonary maladaptation can potentiate dysfunction in the other organ, amplify the risk for BPD in the neonate, and increase the trajectory for overall neonatal morbidity. Beyond infancy, there is an increased risk for systemic and pulmonary vascular disease including hypertension, as well as potential cardiac dysfunction, particularly within the right ventricle. This review will focus on the cardiovascular antecedents of BPD in the fetus, cardiovascular consequences of preterm birth in the neonate including associations with BPD, and cardiovascular impact of prematurity and BPD throughout the lifespan.

BACKGROUND AND OBJECTIVES Many preterm infants stabilized on continuous positive airway pressure (CPAP) at birth require mechanical ventilation (MV) during the first 72 hours of life, which is defined as CPAP failure. Our objective was to decrease CPAP failure in infants ≤29 weeks’ gestational age (GA). METHODS A quality improvement bundle named OPTISURF was implemented for infants ≤29 weeks’ GA admitted on CPAP, consisting of stepwise escalation of CPAP and less invasive surfactant administration guided by fractional inspired oxygen concentration ≥0.3. The CPAP failure rate was tracked by using control charts. We compared practice and outcomes of a pre–OPTISURF cohort (January 2017 to September 2018) to a post-OPTISURF cohort (October 2018 to December 2019). RESULTS Of the 216 infants ≤29 weeks’ GA admitted to NICU on CPAP, 125 infants belonged to the pre-OPTISURF cohort (OSC) and 91 to the post-OSC. Compared with the pre-OSC, a higher proportion of infants in the post-OSC received CPAP 7 cm H2O within 4 hours of life (7% vs 32%; P < .01). The post-OSC also had lower rates of CPAP failure (54% vs 11%; P < .01), pneumothoraces (8% vs 1%; P < .03), need for MV (58% vs 31%; P < .01), and patent ductus arteriosus treatment (21% vs 9%; P = .02). Additionally, in a subgroup analysis, CPAP failure was lower in the post-OSC among infants 23 to 26 weeks (79% vs 27%; P < .01) and 27 to 29 weeks’ GA (46% vs 3%; P < .01). CONCLUSIONS Implementation of a quality improvement bundle including CPAP optimization and less invasive surfactant administration decreased CPAP failure and need for MV in preterm infants.

Introduction: A patent ductus arteriosus (PDA) in a preterm infant can lead to respiratory insufficiency and chronic lung disease as well as necrotizing enterocolitis due to systemic hypoperfusion. Recently, catheter-based PDA closure has emerged as an appealing alternative to invasive surgical ligation in preterm infants; however, evidence to support this procedure in infancy, particularly in the premature population, is still evolving. Methods: A retrospective chart review was conducted to collect information regarding demographics, neonatal and maternal clinical characteristics, and procedural and post-catheterization data. Inclusion criteria included infants born at Results: Twenty-seven patients were included in our study. Indications for PDA closure in our patient population included hemodynamically significant PDA on echocardiogram, difficulty weaning respiratory support, poor feeding and weight gain, and development of NEC. Median gestational age and weight were 26 weeks and 820 g (ranging from 23 to 30 weeks and 400 to 1540 g, respectively). Most infants tolerated the procedure well and without serious adverse outcomes. One infant developed an intimal flap post-catheterization that resolved without invasive intervention, and 1 infant developed a PAH crisis after PDA closure with resolution of PAH prior to discharge. Statistically significant associations were found between PDA plug closures and decreased oxygen requirements, decreased pulmonary artery hypertension, decreased diuretic requirements, and decreased vasodilator requirements by time of discharge. Conclusions: Successful device closures of PDAs are feasible and safe, and preliminary findings show promising outcomes without mortality or long-term morbidity following transcatheter PDA closure.

We present a preterm infant who developed a fever and mild respiratory disease on the second day of life. Infant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal testing was positive at 24 and 48 hours of life. Placenta histopathology revealed SARS-CoV-2 infection by electron microscopy and immunohistochemistry. Further understanding of the risk factors that lead to in utero transmission of SARS-CoV-2 infection is needed.

Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia-ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of exogenous NO on the developing neonatal brain remain controversial. Inhaled NO (iNO) can be neuroprotective or toxic depending on a variety of factors, including cellular redox state, underlying disease processes, duration of treatment, and dose. This review identifies key gaps in knowledge that should prompt further investigation into the possible role of iNO as a therapeutic agent after injury to the brain. IMPACT: NO is a key signal mediator in the neonatal brain with neuroprotective and neurotoxic properties. iNO, a commonly used medication, has significant effects on the neonatal brain. Dosing, duration, and timing of administration of iNO can affect the developing brain. This review article summarizes the roles of NO in association with various disease processes that impact neonates, such as brain hypoxia-ischemia, asphyxia, retinopathy of prematurity, and neuroinflammation. The impact of this review is that it clearly describes gaps in knowledge, and makes the case for further, targeted studies in each of the identified areas.

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.

Bronchopulmonary dysplasia (BPD), a chronic respiratory disease involving inflammation and aberrant lung development in preterm infants, results from injury to the immature lung caused by exposure to mechanical ventilation, oxygen, and infectious or sterile inflammation. While adaptive immune responses are blunted in premature infants, their innate immune responses are functional and able to mount robust inflammatory responses that exacerbate lung injury. There are multiple nonimmune components of innate immunity that serve to protect the vulnerable host. In addition, a number of mechanisms exist to activate or suppress the innate immune system, including defensins, cathelicidins, and collectins. Further, lung infection or injury produce signals that have pathogen or danger-associated molecular patterns that are recognized by sensors known as pattern recognition receptors in immune cells that either modulate inflammatory responses or signal via specific adapters to assemble intracellular complexes called inflammasomes. These complexes, in turn, activate the enzymatic cleavage of prointerleukin 1 beta (pro-IL1s) to mature IL1s, the cytokine that drives the innate immune cascade to result in a robust inflammatory response. This chapter will explore the innate immune system and its contribution to the development of BPD and examine novel targets and potential therapeutic approaches being contemplated to prevent or limit the severity of this devastating disease.

Cytokines modulate fetal well-being and contribute to parturition. Their origin in fetal blood, whether maternal, placental or fetal, at the time of parturition remains unclear.To determine fetal and placental contributions to circulating fetal cytokines by measuring umbilical arterial (UmA) and venous (UmV) concentration differences in uncomplicated term pregnancies in the absence and presence of labor.Term uncomplicated pregnancies were assessed: Group 1 were not in labor and delivered by elective cesarean section (n = 20); Group 2 delivered vaginally following uncomplicated pregnancy and labor (n = 30). UmA and UmV blood was collected before delivery of the placenta to measure circulating cytokines. Placental tissue was collected for histology and to determine cytokine contents and localization.Group 1 UmA and UmV IL-10 concentrations were similar (504 ± 15 and 468 ± 16 pg/ml, respectively; P ≥ 0.1); other cytokines were below level of detection. During labor, IL-10 concentrations increased 15-34%, but placental contents decreased. Group 2 UmA IL-6 and IL-8 concentrations increased (P 0.001) to 16.7 ± 1.6 and 18.4 ± 4.3 pg/ml, respectively, but were less (P 0.001) in UmV, 0.29 ± 0.2 and 0.74 ± 0.3 pg/ml, respectively, demonstrating placental clearances ≥97%. This was associated with6-fold increases in placental IL-6/IL-8 contents (P 0.001) and chorioamniotic infiltration of activated maternal neutrophils. IL-6 and IL-10 were localized to villous syncytiotrophoblasts.In uncomplicated term pregnancies fetal circulating IL-10 is likely of placental origin, whereas IL-6/IL-8 are derived from the fetus, increase during parturition, and circulating levels are modulated by non-saturable placental clearance, revealing a novel pathway for fetal-placental crosstalk and signaling.

Objective To evaluate the impact of the Neonatal Resuscitation Program (NRP)-recommended low oxygen strategy (LOX) on neonatal morbidities, mortality, and neurodevelopmental outcomes in neonates born preterm. Study design In March 2011, Parkland Hospital changed from a high oxygen strategy (HOX) of resuscitation with initial 100% oxygen and targeting 85%-94% oxygen saturation for delivery room resuscitation to a LOX with initial 21% oxygen and titrating oxygen to meet NRP-recommended transitional target saturations. Neonates ≤28 weeks' gestational age born between August 2009 and April 2012 were identified. In this retrospective, observational study, neonates exposed to LOX vs HOX were compared for short-term morbidity, mortality, and long-term neurodevelopmental outcomes. Regression analysis was performed to control for confounding variables. Results Of 199 neonates, 110 were resuscitated with HOX and 89 with LOX. Compared with HOX, neonates exposed to LOX had lower oxygen exposure in the delivery room (5.2 ± 1.5 vs 7.8 ± 2.8 [∑FiO 2 × time min ], P P = .01), and had lower odds of developing bronchopulmonary dysplasia (aOR 0.4 [0.2, 0.9]). There was no difference in mortality (17 [20%] vs 20 [18%]), but neonates exposed to LOX had greater motor composite scores on Bayley Scales of Infant and Toddler Development–Third edition assessment (91 [85, 97] vs 88 [76, 94], P Conclusion The NRP-recommended LOX strategy was associated with improved respiratory morbidities and neurodevelopmental outcomes with no increase in mortality. Prospective trials to confirm the optimal oxygen strategy for the resuscitation of neonates born preterm are needed.

Teleneonatology, encompassing all telemedicine applications in neonatal medicine, is evolving with innovative applications for use in all aspects of neonatal care. In this chapter, we discuss the key components of and a framework for the development, implementation and evaluation of a program based on existing literature and our own program. We also review some important barriers to implementation and potential solutions. We hope that this review will serve as a guide for those seeking to develop and implement other new teleneonatology programs.

Objective To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). Study design Infants with sBPD in the Children’s Hospitals Neonatal Database who had echocardiograms 34–44 weeks’ postmenstrual age (PMA) were included. SP and RVSP were categorized normal, abnormal (flattened/bowed SP or RVSP > 40 mmHg) or missing. Results Of 1157 infants, 115 infants (10%) died. Abnormal SP or RVSP increased mortality (SP 19% vs. 8% normal/missing, RVSP 20% vs. 9% normal/missing, both p

Cell-matrix interactions are fundamental to many developmental, homeostatic, immune and pathologic processes. Hyaluronan (HA), a critical component of the extracellular matrix (ECM) that regulates normal structural integrity and development, also regulates tissue responses during injury, repair, and regeneration. Though simple in its primary structure, HA regulates biological responses in a highly complex manner with balanced contributions from its molecular size and concentration, synthesis versus enzymatic and/or oxidative-nitrative fragmentation, interactions with key HA binding proteins and cell associated receptors, and its cell context-specific signaling. This review highlights the different, but inter-related factors that dictate the biological activity of HA and introduces the overarching themes that weave throughout this special issue of Matrix Biology on hyaluronan.

To develop a prediction model to identify infants admitted on continuous positive airway pressure (CPAP) requiring intubation within seventy-two hours of life (HOL). Infants born ≤29 weeks’ gestational age between 2013 and April 2018 were randomly assigned to either a modeling cohort (MC) or a validation cohort (VC) in a 2:1 ratio. Variables available within two HOL were compared between the CPAP failure group (CFG) and the CPAP success group (CSG). Of the 189 infants in the MC, 50% failed CPAP. Compared to CSG, infants in the CFG had lower antenatal steroid exposure, birth weight, higher radiographic severe respiratory distress syndrome (RDS) and fraction of inspired oxygen (FiO2). A forward stepwise logistic regression modeling in both MC and VC showed that FiO2 >0.3 and radiographic severe RDS predicted CPAP failure. FiO2 >0.3 within two HOL and radiographic severe RDS predicts CPAP failure in preterm infants.

Maternal obesity and a high-fat diet (HFD) during the perinatal period have documented short- and long-term adverse outcomes for offspring. However, the mechanisms of maternal HFD effects on neonatal offspring are unclear. While the effects of maternal HFD exposure during pregnancy on the offspring are increasingly being appreciated, we do not know if maternal HFD alters the microbiota or affects neonatal susceptibility to inflammatory conditions, nor the mechanisms involved. In this study, we show that the offspring of mothers exposed to HFD develop a unique microbiota, marked by expansion of Firmicutes, and an increase in IL-17-producing type 3 innate lymphoid cells (ILC3s). The expansion of ILC3s was recapitulated through neocolonization with HFD microbiota alone. Further, the HFD offspring were susceptible to a neonatal model of inflammation that was reversible with IL-17 blockade. Collectively, these data suggest a previously unknown and unique role for ILC3s in the promotion of an early inflammatory susceptibility in the offspring of mothers exposed to HFD.

Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30-50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory response and ends in aberrant lung development with dysregulated angiogenesis and alveolarization. Significant morbidity and mortality are associated with this most common chronic lung disease of childhood. Thus, any therapies that decrease the incidence or severity of this condition would have significant impact on morbidity, mortality, human costs, and healthcare expenditure. It is clear that an inflammatory response and the elaboration of growth factors and cytokines are associated with the development of BPD. Numerous approaches to control the inflammatory process leading to the development of BPD have been attempted. This review will examine the anti-inflammatory approaches that are established or hold promise for the prevention or treatment of BPD.

Introduction Hyaluronan (HA) and the receptor for hyaluronan-mediated motility (RHAMM) may play an important role in lung development. We examined the expression of HA content and RHAMM during postnatal lung development by analyzing human lung specimens from newborn infants with a variety of lung diseases at different gestational (GA) and postnatal (PNA) ages. Materials and methods Ninety-four patients were evaluated. Immunohistochemical RHAMM expression was studied with digital image analysis, followed by hierarchical cluster analysis of both these data and clinical data to define subgroups. The air content of the lung was determined by computerized analysis. HA content was estimated by radiometric assay. Results Cluster analysis defined six distinct patient groups (Group 1-2: 34-41 weeks GA; Group 3-5: 23-27 weeks GA; Group 6: mixed population). Group 1-5 showed individual patterns in RHAMM expression and HA content (Group 1: high RHAMM/low HA; Group 2: low RHAMM/low HA; Group 3: low RHAMM/low HA; Group 4: low RHAMM/high HA; Group 5: high RHAMM/high HA). HA content decreased with increasing PNA independently of GA. Negative correlation was observed between air content and RHAMM expression in the bronchiolar epithelium irrespective of clustered groups. Lung hypoplasia appeared in two distinctive groups, with significant differences in lung development and RHAMM expression. Conclusions RHAMM expression may show dynamic changes during pathological processes in the neonatal lung. The distribution of RHAMM in the lung tissue is heterogeneous with a predominance to the bronchiolar epithelium. We found a negative correlation between lung air content and RHAMM expression in bronchiolar epithelium.

To estimate the risk of death or tracheostomy placement (D/T) in infants with severe bronchopulmonary dysplasia (sBPD) born32 weeks' gestation referred to regional neonatal intensive care units.We conducted a retrospective cohort study in infants born32 weeks' gestation with sBPD in 2010-2011, using the Children's Hospital Neonatal Database. sBPD was defined as the need for FiO2 ⩾ 0.3, nasal cannula support2 l min(-1) or positive pressure at 36 weeks' post menstrual age. The primary outcome was D/T before discharge. Predictors associated with D/T in bivariable analyses (P0.2) were used to develop a multivariable logistic regression equation using 80% of the cohort. This equation was validated in the remaining 20% of infants.Of 793 eligible patients, the mean gestational age was 26 weeks' and the median age at referral was 6.4 weeks. D/T occurred in 20% of infants. Multivariable analysis showed that later gestational age at birth, later age at referral along with pulmonary management as the primary reason for referral, mechanical ventilation at the time of referral, clinically diagnosed pulmonary hypertension, systemic corticosteroids after referral and occurrence of a bloodstream infection after referral were each associated with D/T. The model performed well with validation (area under curve 0.86, goodness-of-fit χ(2), P = 0.66).Seven clinical variables predicted D/T in this large, contemporary cohort with sBPD. These results can be used to inform clinicians who counsel families of affected infants and to assist in the design of future prospective trials.

OBJECTIVE: To determine whether a limited oxygen strategy (LOX) versus a high oxygen strategy (HOX) during delivery room resuscitation decreases oxidative stress in preterm neonates. METHODS: A randomized trial of neonates of 24 to 34 weeks’ gestational age (GA) who received resuscitation was performed. LOX neonates received room air as the initial resuscitation gas, and fraction of inspired oxygen (Fio2) was adjusted by 10% every 30 seconds to achieve target preductal oxygen saturations (Spo2) as described by the 2010 Neonatal Resuscitation Program guidelines. HOX neonates received 100% O2 as initial resuscitation gas, and Fio2 was adjusted by 10% to keep preductal Spo2 at 85% to 94%. Total hydroperoxide (TH), biological antioxidant potential (BAP), and the oxidative balance ratio (BAP/TH) were analyzed in cord blood and the first hour of life. Secondary outcomes included delivery room interventions, respiratory support on NICU admission, and short-term morbidities. RESULTS: Forty-four LOX (GA: 30 ± 3 weeks; birth weight: 1678 ± 634 g) and 44 HOX (GA: 30 ± 3 weeks; birth weight: 1463 ± 606 g) neonates were included. LOX decreased integrated excess oxygen (∑Fio2 × time [min]) in the delivery room compared with HOX (401 ± 151 vs 662 ± 249; P < .01). At 1 hour of life, BAP/TH was 60% higher for LOX versus HOX neonates (13 [9–16] vs 8 [6–9]) µM/U.CARR, P < .01). LOX decreased ventilator days (3 [0–64] vs 8 [0–96]; P < .05) and reduced the incidence of bronchopulmonary dysplasia (7% vs 25%; P < .05). CONCLUSIONS: LOX is feasible and results in less oxygen exposure, lower oxidative stress, and decreased respiratory morbidities and thus is a reasonable alternative for resuscitation of preterm neonates in the delivery room.

Objectives To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. Study design This was a multicenter, retrospective cohort study of 1677 infants born Results Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P Conclusions Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born32 weeks' gestation with sBPD. The association between center and the primary outcome of D/T was analyzed by multivariable modeling. Hypothesized diagnoses/practices were included to determine if these explained any observed ICV in D/T.D/T occurred in 280 (20%) of 1383 eligible infants from 21 centers. ICV was significant for D/T (range 2-46% by center, P0.001) and tracheostomy placement (n=187, range 2-37%, P0.001), but not death (n=93, range 0-19%, P=0.08). This association persisted in multivariable analysis (adjusted center-specific odds ratios for D/T varied 5.5-fold, P=0.009).ICV in D/T is apparent among infants with sBPD. These results highlight that the indications for tracheostomy (and subsequent chronic ventilation) remain uncertain.

Objective— Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. Approach and Results— Neointimal hyperplasia was induced in Has3 -deficient mice by ligation of the carotid artery. HA in the media of Has3 -deficient mice was decreased 28 days after ligation, and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both, the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings, immunoblotting of endothelial nitric oxide synthase, and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted toward a mitigated differential regulation of various signaling pathways in Has3 -deficient mice in response to ligation that were related to vascular smooth muscle cell (VSMC) migration, including focal adhesions, integrins, mitogen-activated protein kinase, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in VSMC supported the migratory phenotype of VSMC in response to platelet-derived growth factor BB in vitro. Accordingly, knockdown of HAS3 reduced the migratory response to platelet-derived growth factor BB and in addition decreased the expression of PDGF-B mRNA. Conclusions— HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases platelet-derived growth factor BB–mediated migration, and in turn enhances neointimal hyperplasia in vivo.

The innate immune system protects the host from bacterial and viral invasion. Surfactant protein A (SPA), a lung-specific collectin, stimulates macrophage chemotaxis. However, the mechanisms regulating this function are unknown. Hyaluronan (HA) and its receptors RHAMM (receptor for HA-mediated motility, CD168) and CD44 also regulate cell migration and inflammation. We therefore examined the role of HA, RHAMM, and CD44 in SPA-stimulated macrophage chemotaxis. Using antibody blockade and murine macrophages, SPA-stimulated macrophage chemotaxis was dependent on TLR2 but not the other SPA receptors examined. Anti-TLR2 blocked SPA-induced production of TGFβ. In turn, TGFβ1-stimulated chemotaxis was inhibited by HA-binding peptide and anti-RHAMM antibody but not anti-TLR2 antibody. Macrophages from TLR2(-/-) mice failed to migrate in response to SPA but responded normally to TGFβ1 and HA, effects that were blocked by anti-RHAMM antibody. Macrophages from WT and CD44(-/-) mice had similar responses to SPA, whereas those from RHAMM(-/-) mice had decreased chemotaxis to SPA, TGFβ1, and HA. In primary macrophages, SPA-stimulated TGFβ production was dependent on TLR2, JNK, and ERK but not p38. Pam3Cys, a specific TLR2 agonist, stimulated phosphorylation of JNK, ERK, and p38, but only JNK and ERK inhibition blocked Pam3Cys-stimulated chemotaxis. We have uncovered a novel pathway for SPA-stimulated macrophage chemotaxis where SPA stimulation via TLR2 drives JNK- and ERK-dependent TGFβ production. TGFβ1, in turn, stimulates macrophage chemotaxis in a RHAMM and HA-dependent manner. These findings are highly relevant to the regulation of innate immune responses by SPA with key roles for specific components of the extracellular matrix.

An increase in hyaluronan (HA) synthesis, cellular uptake, and metabolism occurs during the remodeling of tissue microenvironments following injury and during disease processes such as cancer. We hypothesized that multimodality HA-based probes selectively target and detectably accumulate at sites of high HA metabolism, thus providing a flexible imaging strategy for monitoring disease and repair processes. Kinetic analyses confirmed favorable available serum levels of the probe following intravenous (i.v.) or subcutaneous (s.c.) injection. Nuclear (technetium-HA, (99m)Tc-HA, and iodine-HA, (125)I-HA), optical (fluorescent Texas Red-HA, TR-HA), and magnetic resonance (gadolinium-HA, Gd-HA) probes imaged liver ((99m)Tc-HA), breast cancer cells/xenografts (TR-HA, Gd-HA), and vascular injury ((125)I-HA, TR-HA). Targeting of HA probes to these sites appeared to result from selective HA receptor-dependent localization. Our results suggest that HA-based probes, which do not require polysaccharide backbone modification to achieve favorable half-life and distribution, can detect elevated HA metabolism in homeostatic, injured, and diseased tissues.

The pharmacodynamics and elimination kinetics of escalating doses (1.5-12 mg/kg) of hyaluronan (HA) infu- sions were studied in healthy human volunteers. Metabolic breakdown of serum HA and associated adverse events were monitored throughout the study. The HA-binding capacities of circulating CD4+ and CD8+ T lymphocytes, CD19+ B- lymphocytes and CD14+ peripheral blood monocytes (PBMC) were also quantified. Breakdown of infused HA into small fragments (