Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.

Background:  Increased adhesivity of red blood cells (RBCs) to endothelial cells (ECs) may contribute to organ dysfunction in malaria, sickle cell disease, and diabetes. RBCs normally export nitric oxide (NO)-derived vascular signals, facilitating blood flow. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO upon the oxygenation-linked allosteric transition in hemoglobin.

2022 Year in review: Neonatal pulmonology.

This review outlines some of the major contributions to Neonatal Pulmonology published in 2022 in Pediatric Pulmonology in the areas of lung ultrasound, prevention and treatment of bronchopulmonary dysplasia, and pulmonary function outcomes of neonatal lung disease.

2020 year in review: Neonatal pulmonology.

Pediatric Pulmonology publishes original research, reviews, and case reports related to a wide range of children's respiratory disorders. This review summarizes the past year's publications in the topic area of neonatal pulmonology, in the context of selected literature from other journals relevant to the discipline.

Retraction Note: Intra-amniotic LPS amplifies hyperoxia-induced airway hyperreactivity in neonatal rats.

This paper has been retracted at the request of the authors.

2018 year in review: Part 2 of 4: Neonatal lung disease.

Pediatric Pulmonology publishes original research, reviews and case reports related to a wide range of children's respiratory disorders. This review (Part 2 of a 4-part series) summarizes the past year's publications in the topic area of neonatal lung diseases, in the context of selected literature from other journals relevant to the discipline.

2017 pediatric pulmonology year in review part 2-neonatology.

The articles published in 2017 in topic areas relevant to neonatal pulmonology are reviewed in Part 2 of the Year-in-Review.

Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner.

Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia and in adult rodents.

Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD.

Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O from birth by following hyperoxia with intermittent hypoxia (IH).

Early-Life Intranasal Colonization with Nontypeable Haemophilus influenzae Exacerbates Juvenile Airway Disease in Mice.

Accumulating evidence suggests a connection between asthma development and colonization with nontypeable Haemophilus influenzae (NTHi). Specifically, nasopharyngeal colonization of human infants with NTHi within 4 weeks of birth is associated with an increased risk of asthma development later in childhood. Monocytes derived from these infants have aberrant inflammatory responses to common upper respiratory bacterial antigens compared to those of cells derived from infants who were not colonized and do not go on to develop asthma symptoms in childhood.

Bronchopulmonary dysplasia impairs L-type amino acid transporter-1 expression in human and baboon lung.

Bronchopulmonary dysplasia (BPD) is an inflammatory lung disorder common in premature infants who undergo mechanical ventilation with supplemental oxygen. Inhaled nitric oxide (iNO) has been used to prevent experimental and clinical BPD. Earlier studies showed that NO effects in alveolar epithelial cells (AEC) are mediated by S-nitrosothiol uptake via L-type amino acid transporter-1 (LAT1).

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability.

The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.

Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively).

Neonatal lung function and therapeutics.

Respiratory diseases are increasingly recognized as having their origins during perinatal and early postnatal lung development, a time of significant adaptation to large changes in redox conditions as well as to mechanical forces. This Forum of the journal presents a Forum highlighting studies of the interplay between reactive oxygen/nitrogen species and the systems that have evolved to degrade them or exploit them, as well as the cellular repair processes which respond to early life redox stress in the lung. This group of authors suggests new understandings of these events that may point the way to improved therapeutic approaches.

Hyperoxia inhibits nitric oxide treatment effects in alveolar epithelial cells via effects on L-type amino acid transporter-1.

Aims: The aims of this study were to determine hyperoxia effects on S-nitrosothiol (SNO) accumulation and L-type amino acid transporter 1 (LAT1) expression/function in alveolar epithelium and to determine whether hyperoxia impairs exogenous nitric oxide (NO) treatment effects in alveolar epithelium through effects on LAT1 expression and/or function.

Results: SNO accumulation in vitro and in vivo after NO treatment was dependent on the LAT1 system transport. Hyperoxia (60% or 90%) impaired NO effects on SNO accumulation and soluble guanylyl cyclase activation in proportion to the magnitude of hyperoxia and the duration of exposure, up to 12 h, in type I-like (R3/1) and type II-like (L2) rat and human (A549) alveolar epithelial cells.

Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring.

Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation.

Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice.

Background: Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown.

Objectives: We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood.

Intra-amniotic LPS amplifies hyperoxia-induced airway hyperreactivity in neonatal rats.

Background: We previously showed that intra-amniotic lipopolysaccharide (LPS) amplifies alveolar hypoplasia induced by postnatal hyperoxia. We determined whether the priming effect of intra-amniotic LPS amplifies hyperoxia-induced airway hyperreactivity (AHR).

Methods: LPS or normal saline was injected into the amniotic cavities of pregnant rats at the 20th day of gestation.

S-nitrosothiol transport via PEPT2 mediates biological effects of nitric oxide gas exposure in macrophages.

The pharmacological effects of nitric oxide (NO) administered as a gas are dependent on the conversion to S-nitrosocysteine, and as such are largely mediated by the L-type amino-acid transporters (LATs) in several cell types. The dipeptide transporter PEPT2 has been proposed as a second route for S-nitrosothiol (SNO) transport, but this has never been demonstrated. Because NO governs important immune functions in alveolar macrophages, we exposed rat alveolar macrophages (primary and NR8383 cells) to NO gas at the air-liquid interface ± LPS stimulation in the presence of PEPT2 substrate Cys-Gly (or the LAT substrate L-Cys) ± transporter competitors.

The outdoor air pollution and brain health workshop.

Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

Innate immune activation by inhaled lipopolysaccharide, independent of oxidative stress, exacerbates silica-induced pulmonary fibrosis in mice.

Acute exacerbations of pulmonary fibrosis are characterized by rapid decrements in lung function. Environmental factors that may contribute to acute exacerbations remain poorly understood. We have previously demonstrated that exposure to inhaled lipopolysaccharide (LPS) induces expression of genes associated with fibrosis.

Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner.

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17.