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1.
Front Pediatr ; 11: 1130013, 2023.
Article in English | MEDLINE | ID: mdl-36994431

ABSTRACT

Preterm birth is defined as delivery at <37 weeks of gestational age (GA) and exposes 15 million infants worldwide to serious early life diseases. Lowering the age of viability to 22 weeks GA entailed provision of intensive care to a greater number of extremely premature infants. Moreover, improved survival, especially at extremes of prematurity, comes with a rising incidence of early life diseases with short- and long-term sequelae. The transition from fetal to neonatal circulation is a substantial and complex physiologic adaptation, which normally happens rapidly and in an orderly sequence. Maternal chorioamnionitis or fetal growth restriction (FGR) are two common causes of preterm birth that are associated with impaired circulatory transition. Among many cytokines contributing to the pathogenesis of chorioamnionitis-related perinatal inflammatory diseases, the potent pro-inflammatory interleukin (IL)-1 has been shown to play a central role. The effects of utero-placental insufficiency-related FGR and in-utero hypoxia may also be mediated, in part, via the inflammatory cascade. In preclinical studies, blocking such inflammation, early and effectively, holds great promise for improving the transition of circulation. In this mini-review, we outline the mechanistic pathways leading to abnormalities in transitional circulation in chorioamnionitis and FGR. In addition, we explore the therapeutic potential of targeting IL-1 and its influence on perinatal transition in the context of chorioamnionitis and FGR.

2.
Int J Mol Sci ; 24(3)2023 Feb 01.
Article in English | MEDLINE | ID: mdl-36769133

ABSTRACT

Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases.


Subject(s)
Bronchopulmonary Dysplasia , Infant, Newborn, Diseases , Premature Birth , Retinopathy of Prematurity , Infant , Pregnancy , Female , Infant, Newborn , Humans , Interleukin-1 , Infant, Premature , Anti-Inflammatory Agents/therapeutic use , Bronchopulmonary Dysplasia/etiology , Bronchopulmonary Dysplasia/drug therapy , Infant, Newborn, Diseases/drug therapy , Inflammation/complications , Inflammation/drug therapy , Retinopathy of Prematurity/drug therapy
3.
Front Immunol ; 13: 1022104, 2022.
Article in English | MEDLINE | ID: mdl-36389766

ABSTRACT

Background: Bronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity. Methods and analysis: Anakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (240) and 276 weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 240-276 weeks GA. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05280340.


Subject(s)
Bronchopulmonary Dysplasia , Interleukin 1 Receptor Antagonist Protein , Adult , Child , Humans , Infant , Infant, Newborn , Bronchopulmonary Dysplasia/drug therapy , Feasibility Studies , Infant, Extremely Premature , Interleukin 1 Receptor Antagonist Protein/adverse effects , Interleukin-1 , Receptors, Interleukin-1
4.
Sci Transl Med ; 14(639): eaaz8454, 2022 04 06.
Article in English | MEDLINE | ID: mdl-35385341

ABSTRACT

Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1ß and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.


Subject(s)
Bronchopulmonary Dysplasia , Interleukin-13 , Animals , Bronchopulmonary Dysplasia/etiology , Bronchopulmonary Dysplasia/pathology , Bronchopulmonary Dysplasia/prevention & control , Female , Humans , Infant, Newborn , Infant, Premature , Inflammation/complications , Lung/pathology , Mice , Pregnancy
5.
Bio Protoc ; 12(21)2022 Nov 05.
Article in English | MEDLINE | ID: mdl-36816013

ABSTRACT

Bronchopulmonary dysplasia (BPD) and pulmonary hypertension associated with BPD (BPD-PH) are of multifactorial origin and share common risk factors. Most murine models of BPD expose newborn pups to only one of these risk factors-more commonly postnatal hyperoxia-thereby mimicking the vital increased fraction of inspired oxygen (FiO2) that preterm infants in neonatal intensive care units often require. To improve representation of the multifactorial origins of BPD and BPD-PH, we established a double hit model, combining antenatal systemic inflammation followed by postnatal hyperoxia. On embryonic day 14, pups are exposed to systemic maternal inflammation via a single intraperitoneal injection of 150 µg/kg of lipopolysaccharide to the dam. Within 24 h after birth, pups and dams are randomized and exposed to gas with either an FiO2 of 0.21 (room air) or 0.65 (hyperoxia 65%). In our BPD and BPD-PH double hit model, we can obtain multiple readouts from individual pups that include echocardiography, lung histology and immunohistochemistry, ex vivo X-ray micro computed tomography, and pulmonary and plasmatic immunity by RNA, protein, or flow cytometry. This protocol was validated in: Sci Transl Med (2022), DOI: 10.1126/scitranslmed.aaz8454 Graphical abstract Figure 1. Murine double hit model of cardiopulmonary disease. On embryonic day (E)14, pups are exposed to systemic maternal inflammation via a single intraperitoneal injection of 150 µg/kg lipopolysaccharide to the dam. Within 24 h after birth, pups and dams are randomized to be exposed to gas with either a fraction of inspired oxygen (FiO 2 ) of 0.21 (air; 21% O 2 ) or 0.65 (hyperoxia; 65% O 2 ) for a maximum of 28 days. According to the murine stage of lung development ( Schittny, 2017 ), experimental endpoints include postnatal day (D)3, D5, D14, D28, and D60.

6.
Nat Commun ; 11(1): 5794, 2020 11 13.
Article in English | MEDLINE | ID: mdl-33188181

ABSTRACT

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.


Subject(s)
Enterocolitis, Necrotizing/drug therapy , Enterocolitis, Necrotizing/immunology , Adaptive Immunity , Animals , Animals, Newborn , Biomarkers/metabolism , Enterocolitis, Necrotizing/blood , Enterocolitis, Necrotizing/pathology , Homeostasis , Humans , Immunity, Innate , Infant, Newborn , Inflammation Mediators/metabolism , Interleukin-1 , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Lymphocytes/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Toll-Like Receptors/metabolism
7.
Cells ; 9(1)2020 01 10.
Article in English | MEDLINE | ID: mdl-31936823

ABSTRACT

Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages (BMDM), and employing an in vivo endotoxemia model, we studied how IL-37 affects the expression and maturation of IL-1ß and IL-18, inflammasome activation, and pyroptosis in detail. IL-37 inhibited IL-1ß production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect lipopolysaccharide (LPS)-induced mRNA expression of Il18 or inflammasome components, IL-37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, we observed that IL-37 suppresses nigericin- and silica-induced ASC oligomerization/speck formation (a step in inflammasome activation and subsequent caspase-1 activation), and pyroptosis (-50%). In mice subjected to endotoxemia, IL-37 inhibited plasma IL-1ß (-78% compared to wild-type animals) and IL-18 (-61%). Thus, our study adds suppression of inflammasome activity to the portfolio of anti-inflammatory pathways employed by IL-37, highlighting this cytokine as a potential tool for treating inflammasome-driven diseases.


Subject(s)
Inflammasomes/metabolism , Interleukin-1/metabolism , Interleukins/metabolism , Animals , Cells, Cultured , Interleukin-1/analysis , Interleukins/analysis , Mice , Mice, Inbred C57BL , Mice, Transgenic
8.
Front Immunol ; 10: 1480, 2019.
Article in English | MEDLINE | ID: mdl-31354700

ABSTRACT

Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O2. Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4-5 µm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ETA) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Bronchopulmonary Dysplasia/prevention & control , Hypertension, Pulmonary/prevention & control , Interleukin 1 Receptor Antagonist Protein/pharmacology , Vascular Resistance/drug effects , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/pathology , Disease Models, Animal , Endothelin-1/metabolism , Hyperoxia , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Vascular Endothelial Growth Factor A/metabolism
9.
Sleep ; 40(10)2017 10 01.
Article in English | MEDLINE | ID: mdl-28977669

ABSTRACT

Study objectives: In principle, if metabolic rate were to fall during sleep in a patient with obstructive sleep apnea (OSA), ventilatory requirements could be met without increased respiratory effort thereby favoring stable breathing. Indeed, most patients achieve periods of stable flow-limited breathing without respiratory events for periods during the night for reasons that are unclear. Thus, we tested the hypothesis that in patients with OSA, periods of stable breathing occur when metabolic rate (VO2) declines. Methods: Twelve OSA patients (apnea-hypopnea index >15 events/h) completed overnight polysomnography including measurements of VO2 (using ventilation and intranasal PO2) and respiratory effort (esophageal pressure). Results: Contrary to our hypothesis, VO2 did not differ between stable and unstable breathing periods in non-REM stage 2 (208 ± 20 vs. 213 ± 18 mL/min), despite elevated respiratory effort during stable breathing (26 ± 2 versus 23 ± 2 cmH2O, p = .03). However, VO2 was lowered during deeper sleep (244 to 179 mL/min from non-REM stages 1 to 3, p = .04) in conjunction with more stable breathing. Further analysis revealed that airflow obstruction curtailed metabolism in both stable and unstable periods, since CPAP increased VO2 by 14% in both cases (p = .02, .03, respectively). Patients whose VO2 fell most during sleep avoided an increase in PCO2 and respiratory effort. Conclusions: OSA patients typically convert from unstable to stable breathing without lowering metabolic rate. During sleep, OSA patients labor with increased respiratory effort but fail to satisfy metabolic demand even in the absence of overt respiratory events.


Subject(s)
Basal Metabolism/physiology , Continuous Positive Airway Pressure , Oxygen Consumption/physiology , Respiration , Sleep Apnea, Obstructive/physiopathology , Sleep/physiology , Adult , Female , Humans , Male , Middle Aged , Polysomnography , Respiratory Rate/physiology
10.
J Reprod Immunol ; 124: 21-29, 2017 11.
Article in English | MEDLINE | ID: mdl-29035757

ABSTRACT

Bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension (BPD-PH) are chronic inflammatory cardiopulmonary diseases with devastating short- and long-term consequences for infants born prematurely. The immature lungs of preterm infants are ill-prepared to achieve sufficient gas exchange, thus usually necessitating immediate commencement of respiratory support and oxygen supplementation. These therapies are life-saving, but they exacerbate the tissue damage that is inevitably inflicted on a preterm lung forced to perform gas exchange. Together, air-breathing and necessary therapeutic interventions disrupt normal lung development by aggravating pulmonary inflammation and vascular remodelling, thus frequently precipitating BPD and PH via an incompletely understood pathogenic cascade. BPD and BPD-PH share common risk factors, such as low gestational age at birth, fetal growth restriction and perinatal maternal inflammation; however, these risk factors are not unique to BPD or BPD-PH. Occurring in 17-24% of BPD patients, BPD-PH substantially worsens the morbidity and mortality attributable to BPD alone, thus darkening their outlook; for example, BPD-PH entails a mortality of up to 50%. The absence of a safe and effective therapy for BPD and BPD-PH renders neonatal cardiopulmonary disease an area of urgent unmet medical need. Besides the need to develop new therapeutic strategies, a major challenge for clinicians is the lack of a reliable method for identifying babies at risk of developing BPD and BPD-PH. In addition to discussing current knowledge on pathophysiology, diagnosis and treatment of BPD-PH, we highlight emerging biomarkers that could enable clinicians to predict disease-risk and also optimise treatment of BPD-PH in our tiniest patients.


Subject(s)
Bronchopulmonary Dysplasia/epidemiology , Bronchopulmonary Dysplasia/pathology , Hypertension, Pulmonary/epidemiology , Infant, Newborn, Diseases/epidemiology , Infant, Premature/physiology , Premature Birth/epidemiology , Animals , Fetal Development , Humans , Hyperbaric Oxygenation , Hypertension, Pulmonary/pathology , Infant , Infant, Newborn , Infant, Newborn, Diseases/pathology , Inflammation , Premature Birth/pathology , Respiration , Vascular Remodeling
11.
J Cell Mol Med ; 21(6): 1128-1138, 2017 06.
Article in English | MEDLINE | ID: mdl-27957795

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1ß, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.


Subject(s)
Bronchopulmonary Dysplasia/drug therapy , Inflammation/drug therapy , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Protein C/administration & dosage , Animals , Animals, Newborn , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Bronchopulmonary Dysplasia/complications , Bronchopulmonary Dysplasia/pathology , Disease Models, Animal , Female , Humans , Infant , Infant, Newborn , Inflammation/complications , Inflammation/pathology , Interleukin 1 Receptor Antagonist Protein/adverse effects , Lung/drug effects , Lung/pathology , Mice , Pregnancy , Protein C/adverse effects , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology
12.
Eur Respir J ; 48(5): 1351-1359, 2016 11.
Article in English | MEDLINE | ID: mdl-27587554

ABSTRACT

Cheyne-Stokes respiration (CSR) foretells deleterious outcomes in patients with heart failure. Currently, the size of therapeutic intervention is not guided by the patient's underlying pathophysiology. In theory, the intervention needed to resolve CSR, as a control system instability (loop gain >1), can be predicted knowing the baseline loop gain and how much it falls with therapy.In 12 patients with heart failure, we administered an inspiratory carbon dioxide fraction of 1-3% during CSR (n=95 interventions) as a means to reduce loop gain. We estimated the loop gain on therapy (LGtherapy), using the baseline loop gain (using hyperpnoea length/cycle length) and its expected reduction (18% per 1% inspired carbon dioxide), and tested the specific hypothesis that LGtherapy predicts CSR persistence (LGtherapy >1) versus resolution (LGtherapy <1).As predicted, when LGtherapy >1.0, CSR continued during therapy in 23 out of 25 (92%) trials. A borderline loop gain zone (0.8

Subject(s)
Cheyne-Stokes Respiration/physiopathology , Heart Failure/physiopathology , Oxygen Inhalation Therapy/methods , Respiration , Aged , Carbon Dioxide , Humans , Male , Middle Aged , Polysomnography , Sleep , Treatment Outcome
13.
Expert Rev Mol Med ; 18: e12, 2016 06 24.
Article in English | MEDLINE | ID: mdl-27341512

ABSTRACT

Necrotising enterocolitis (NEC) is an uncommon, but devastating intestinal inflammatory disease that predominantly affects preterm infants. NEC is sometimes dubbed the spectre of neonatal intensive care units, as its onset is insidiously non-specific, and once the disease manifests, the damage inflicted on the baby's intestine is already disastrous. Subsequent sepsis and multi-organ failure entail a mortality of up to 65%. Development of effective treatments for NEC has stagnated, largely because of our lack of understanding of NEC pathogenesis. It is clear, however, that NEC is driven by a profoundly dysregulated immune system. NEC is associated with local increases in pro-inflammatory mediators, e.g. Toll-like receptor (TLR) 4, nuclear factor-κB, tumour necrosis factor, platelet-activating factor (PAF), interleukin (IL)-18, interferon-gamma, IL-6, IL-8 and IL-1ß. Deficiencies in counter-regulatory mechanisms, including IL-1 receptor antagonist (IL-1Ra), TLR9, PAF-acetylhydrolase, transforming growth factor beta (TGF-ß)1&2, IL-10 and regulatory T cells likely facilitate a pro-inflammatory milieu in the NEC-afflicted intestine. There is insufficient evidence to conclude a predominance of an adaptive Th1-, Th2- or Th17-response in the disease. Our understanding of the accompanying regulation of systemic immunity remains poor; however, IL-1Ra, IL-6, IL-8 and TGF-ß1 show promise as biomarkers. Here, we chart the emerging immunological landscape that underpins NEC by reviewing the involvement and potential clinical implications of innate and adaptive immune mediators and their regulation in NEC.


Subject(s)
Disease Susceptibility/immunology , Enterocolitis, Necrotizing/etiology , Enterocolitis, Necrotizing/metabolism , Age Factors , Animals , Biomarkers , Clinical Trials as Topic , Disease Models, Animal , Disease Progression , Disease Susceptibility/metabolism , Enterocolitis, Necrotizing/diagnosis , Enterocolitis, Necrotizing/epidemiology , Humans , Immune System/cytology , Immune System/immunology , Immune System/metabolism , Immunity , Immunologic Factors/metabolism , Patient Outcome Assessment , Phenotype , Receptors, Immunologic/metabolism , Receptors, Pattern Recognition/metabolism , Risk Factors , Severity of Illness Index , Signal Transduction
14.
J Appl Physiol (1985) ; 119(3): 299-307, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26023231

ABSTRACT

Systemic maternal inflammation is implicated in preterm birth and bronchopulmonary dysplasia (BPD) and may induce morbidities including reduced pulmonary function, sleep-disordered breathing, and cardiovascular disorders. Here we test the hypothesis that antenatal maternal inflammation per se causes altered alveolar development and increased chemoreflex sensitivity that persists beyond infancy. Pregnant C57BL/6 mice were administered lipopolysaccharide (LPS) (150 µg/kg ip) to induce maternal inflammation or saline (SHAM) at embryonic day 16 (randomized). Pups were weighed daily. On days 7, 28, and 60 (D07, D28, and D60), unrestrained wholebody plethysmography quantified ventilation and chemoreflex responses to hypoxia (10%), hypercapnia (7%), and asphyxia (hypoxic hypercapnia). Lungs were harvested to quantify alveolar number, size, and septal thickness. LPS pups had reduced baseline ventilation per unit bodyweight (∼40%, P < 0.001) vs. SHAM. LPS increased ventilatory responses to hypoxia (D07: 66% vs. 28% increase in ventilation; P < 0.001) hypercapnia (170% vs. 88%; P < 0.001), and asphyxia (249% vs. 154%; P < 0.001); hypersensitive hypoxic responsiveness persisted until D60 (P < 0.001). LPS also increased apnea frequency (P < 0.01). LPS caused thicker alveolar septae (D07, P < 0.001), diminished alveolar number (D28, P < 0.001) vs. SHAM, but effects were minimal by D60. Pups delivered from mothers exposed to antenatal inflammation exhibit deficits in lung structure and hypersensitive responses to respiratory stimuli that persist beyond the newborn period. Antenatal inflammation may contribute to impaired gas exchange and unstable breathing in newborn infants and adversely affect long-term health.


Subject(s)
Inflammation/physiopathology , Lung/physiopathology , Prenatal Exposure Delayed Effects/physiopathology , Pulmonary Gas Exchange , Respiration Disorders/physiopathology , Respiratory Mechanics , Animals , Animals, Newborn , Female , Mice, Inbred C57BL , Pregnancy
15.
Respirology ; 20(5): 819-27, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25939705

ABSTRACT

BACKGROUND AND OBJECTIVE: This study aimed to evaluate the involvement of airway cross-sectional area and shape, and functional residual capacity (FRC), in the genesis of obstructive sleep apnoea (OSA) in patients with supine-predominant OSA. METHODS: Three groups were recruited: (i) supine OSA, defined as a supine apnoea-hyponoea index (AHI) at least twice that of the non-supine AHI; (ii) rapid eye movement (REM) OSA, defined as REM AHI at least twice the non-REM AHI and also selected to have supine AHI less than twice that of the non-supine AHI (i.e. to be non-positional); and (iii) no OSA, defined as an AHI less than five events per hour. The groups were matched for age, gender and body mass index. Patients underwent four-dimensional computed tomography scanning of the upper airway in the supine and lateral decubitus positions. FRC was measured in the seated, supine and lateral decubitus positions. RESULTS: Patients with supine OSA demonstrated a significant decrease in FRC of 340 mL (P = 0.026) when moving from the lateral to supine position compared to controls with no OSA, and REM OSA patients. We found no differences between groups in upper airway size and shape. However, all groups showed a significant change in airway shape with the velopharyngeal airway adopting a more elliptoid shape (with the long axis laterally oriented), with reduced anteroposterior diameter in the supine position. CONCLUSIONS: A fall in FRC when moving lateral to supine in supine OSA patients may be an important triggering factor in the generation of OSA in this patient group.


Subject(s)
Functional Residual Capacity/physiology , Respiratory System , Sleep Apnea, Obstructive , Supine Position , Adult , Aged , Body Mass Index , Female , Humans , Male , Middle Aged , Patient Positioning/methods , Research Design , Respiratory System/diagnostic imaging , Respiratory System/physiopathology , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/physiopathology , Sleep, REM , Tomography, X-Ray Computed/methods
16.
Sleep ; 38(9): 1469-78, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-25761982

ABSTRACT

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) resolves in lateral sleep in 20% of patients. However, the effect of lateral positioning on factors contributing to OSA has not been studied. We aimed to measure the effect of lateral positioning on the key pathophysiological contributors to OSA including lung volume, passive airway anatomy/collapsibility, the ability of the airway to stiffen and dilate, ventilatory control instability (loop gain), and arousal threshold. DESIGN: Non-randomized single arm observational study. SETTING: Sleep laboratory. PATIENTS/PARTICIPANTS: 20 (15M, 5F) continuous positive airway pressure (CPAP)-treated severe OSA patients. INTERVENTIONS: Supine vs. lateral position. MEASUREMENTS: CPAP dial-downs performed during sleep to measure: (i) Veupnea: asleep ventilatory requirement, (ii) passive V0: ventilation off CPAP when airway dilator muscles are quiescent, (iii) Varousal: ventilation at which respiratory arousals occur, (iv) active V0: ventilation off CPAP when airway dilator muscles are activated during sleep, (v) loop gain: the ratio of the ventilatory drive response to a disturbance in ventilation, (vi) arousal threshold: level of ventilatory drive which leads to arousal, (vii) upper airway gain (UAG): ability of airway muscles to restore ventilation in response to increases in ventilatory drive, and (viii) pharyngeal critical closing pressure (Pcrit). Awake functional residual capacity (FRC) was also recorded. RESULTS: Lateral positioning significantly increased passive V0 (0.33 ± 0.76L/min vs. 3.56 ± 2.94L/min, P < 0.001), active V0 (1.10 ± 1.97L/min vs. 4.71 ± 3.08L/min, P < 0.001), and FRC (1.31 ± 0.56 L vs. 1.42 ± 0.62 L, P = 0.046), and significantly decreased Pcrit (2.02 ± 2.55 cm H2O vs. -1.92 ± 3.87 cm H2O, P < 0.001). Loop gain, arousal threshold, Varousal, and UAG were not significantly altered. CONCLUSIONS: Lateral positioning significantly improves passive airway anatomy/collapsibility (passive V0, pharyngeal critical closing pressure), the ability of the airway to stiffen and dilate (active V0), and the awake functional residual capacity without improving loop gain or arousal threshold.


Subject(s)
Posture/physiology , Respiratory System/physiopathology , Sleep Apnea, Obstructive/physiopathology , Arousal/physiology , Continuous Positive Airway Pressure , Female , Humans , Lung/anatomy & histology , Lung/physiology , Male , Middle Aged , Pharynx/physiology , Pressure , Respiration , Respiratory Function Tests , Respiratory System/anatomy & histology , Sleep/physiology , Sleep Apnea, Obstructive/therapy , Supine Position/physiology , Wakefulness/physiology
17.
Diab Vasc Dis Res ; 12(3): 208-16, 2015 May.
Article in English | MEDLINE | ID: mdl-25767181

ABSTRACT

Microvascular complications are now recognized to play a major role in diabetic complications, and understanding the mechanisms is critical. Endothelial dysfunction occurs early in the course of the development of complications; the precise mechanisms remain poorly understood. Mitochondrial dysfunction may occur in a diabetic rat heart and may act as a source of the oxidative stress. However, the role of endothelial cell-specific mitochondrial dysfunction in diabetic vascular complications is poorly studied. Here, we studied the role of diabetes-induced abnormal endothelial mitochondrial function and the resultant endothelial dysfunction. Understanding the role of endothelial mitochondrial dysfunction in diabetic vasculature is critical in order to develop new therapies. We demonstrate that hyperglycaemia leads to mitochondrial dysfunction in microvascular endothelial cells, and that mitochondrial inhibition induces endothelial dysfunction. Additionally, we show that resveratrol acts as a protective agent; resveratrol-mediated mitochondrial protection may be used to prevent long-term diabetic cardiovascular complications.


Subject(s)
Coronary Artery Disease/prevention & control , Coronary Vessels/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/prevention & control , Endothelial Cells/drug effects , Microvessels/drug effects , Mitochondria/drug effects , Stilbenes/pharmacology , Animals , Blood Glucose/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Coronary Artery Disease/blood , Coronary Artery Disease/etiology , Coronary Artery Disease/physiopathology , Coronary Circulation/drug effects , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/complications , Diabetic Angiopathies/blood , Diabetic Angiopathies/etiology , Diabetic Angiopathies/physiopathology , Endothelial Cells/metabolism , Humans , Isolated Heart Preparation , Male , Microcirculation/drug effects , Microvessels/metabolism , Microvessels/physiopathology , Mitochondria/metabolism , Myocardial Contraction/drug effects , Rats, Sprague-Dawley , Resveratrol , Time Factors , Vasodilation/drug effects
18.
Ann Am Thorac Soc ; 11(5): 761-9, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24720558

ABSTRACT

RATIONALE: Patients with obstructive sleep apnea (OSA) experience respiratory events with greater frequency and severity while in the supine sleeping position. Postural modification devices (PMDs) prevent supine sleep, although there is a paucity of guidance to help clinicians decide when to use PMDs for their patients. In order for PMDs to treat OSA effectively, patients must experience respiratory events in the supine sleeping position consistently from night to night and must have a low nonsupine apnea and hypopnea index (AHINS). OBJECTIVES: To document the repeatability of traditionally defined supine predominant OSA on consecutive polysomnography, to determine whether the consistency of the supine-predominant phenotype can be improved by altering the definition of it, and to determine whether a low AHINS is repeatable from night to night. METHODS: We recruited 75 patients for polysomnography on two separate nights. Patients were classified as having supine OSA on each night on the basis of traditional and novel definitions, and the classification systems used were compared on the basis of agreement from night to night. MEASUREMENTS AND MAIN RESULTS: The definition of supine OSA with the highest level of agreement from night to night incorporates a supine AHI (AHIS) to AHINS ratio ≥4:1. In addition, agreement exists for males, but there is poor agreement for female patients, regardless of the definition applied. An AHINS <10 events/hour is highly repeatable from night to night. CONCLUSIONS: Males with an AHIS:AHINS ratio ≥4:1 and an AHINS <10 events/hour represent a consistent supine-predominant OSA phenotype from night to night. This patient group is likely to benefit from treatment with PMD.


Subject(s)
Circadian Rhythm/physiology , Polysomnography/methods , Respiratory Therapy/methods , Sleep Apnea, Obstructive/therapy , Supine Position/physiology , Female , Humans , Male , Middle Aged , Prognosis , Severity of Illness Index , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/physiopathology
19.
Sleep Med Rev ; 18(1): 7-17, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23669094

ABSTRACT

The most striking feature of obstructive respiratory events is that they are at their most severe and frequent in the supine sleeping position: indeed, more than half of all obstructive sleep apnea (OSA) patients can be classified as supine related OSA. Existing evidence points to supine related OSA being attributable to unfavorable airway geometry, reduced lung volume, and an inability of airway dilator muscles to adequately compensate as the airway collapses. The role of arousal threshold and ventilatory control instability in the supine position has however yet to be defined. Crucially, few physiological studies have examined patients in the lateral and supine positions, so there is little information to elucidate how breathing stability is affected by sleep posture. The mechanisms of supine related OSA can be overcome by the use of continuous positive airway pressure. There are conflicting data on the utility of oral appliances, while the effectiveness of weight loss and nasal expiratory resistance remains unclear. Avoidance of the supine posture is efficacious, but long term compliance data and well powered randomized controlled trials are lacking. The treatment of supine related OSA remains largely ignored in major clinical guidelines. Supine OSA is the dominant phenotype of the OSA syndrome. This review explains why the supine position so favors upper airway collapse and presents the available data on the management of patients with supine related OSA.


Subject(s)
Sleep Apnea, Obstructive/etiology , Supine Position , Adult , Continuous Positive Airway Pressure , Humans , Lung/physiopathology , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/therapy , Supine Position/physiology
20.
Proc Natl Acad Sci U S A ; 110(35): 14384-9, 2013 Aug 27.
Article in English | MEDLINE | ID: mdl-23946428

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O2. Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL-1α and IL-1ß on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1α/ß in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.


Subject(s)
Bronchopulmonary Dysplasia/prevention & control , Hyperoxia/complications , Inflammation/complications , Interleukin 1 Receptor Antagonist Protein/physiology , Animals , Bronchopulmonary Dysplasia/etiology , Disease Models, Animal , Female , Humans , Infant, Newborn , Lipopolysaccharides/pharmacology , Lung/drug effects , Lung/immunology , Mice , Mice, Inbred C57BL , Pregnancy
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