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1.
Int J Mol Sci ; 24(3)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36769133

RESUMO

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.


Assuntos
Displasia Broncopulmonar , Doenças do Recém-Nascido , Nascimento Prematuro , Retinopatia da Prematuridade , Lactente , Gravidez , Feminino , Recém-Nascido , Humanos , Interleucina-1 , Recém-Nascido Prematuro , Anti-Inflamatórios/uso terapêutico , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/tratamento farmacológico , Doenças do Recém-Nascido/tratamento farmacológico , Inflamação/complicações , Inflamação/tratamento farmacológico , Retinopatia da Prematuridade/tratamento farmacológico
2.
J Cell Mol Med ; 21(6): 1128-1138, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27957795

RESUMO

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.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína C/administração & dosagem , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação/complicações , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Gravidez , Proteína C/efeitos adversos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia
3.
Eur Respir J ; 48(5): 1351-1359, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27587554

RESUMO

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

Assuntos
Respiração de Cheyne-Stokes/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Oxigenoterapia/métodos , Respiração , Idoso , Dióxido de Carbono , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Sono , Resultado do Tratamento
4.
Expert Rev Mol Med ; 18: e12, 2016 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-27341512

RESUMO

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.


Assuntos
Suscetibilidade a Doenças/imunologia , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/metabolismo , Fatores Etários , Animais , Biomarcadores , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças/metabolismo , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/epidemiologia , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade , Fatores Imunológicos/metabolismo , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Receptores Imunológicos/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Fatores de Risco , Índice de Gravidade de Doença , Transdução de Sinais
5.
Proc Natl Acad Sci U S A ; 110(35): 14384-9, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23946428

RESUMO

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.


Assuntos
Displasia Broncopulmonar/prevenção & controle , Hiperóxia/complicações , Inflamação/complicações , Proteína Antagonista do Receptor de Interleucina 1/fisiologia , Animais , Displasia Broncopulmonar/etiologia , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
6.
Respirology ; 20(5): 819-27, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25939705

RESUMO

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.


Assuntos
Capacidade Residual Funcional/fisiologia , Sistema Respiratório , Apneia Obstrutiva do Sono , Decúbito Dorsal , Adulto , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Posicionamento do Paciente/métodos , Projetos de Pesquisa , Sistema Respiratório/diagnóstico por imagem , Sistema Respiratório/fisiopatologia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/fisiopatologia , Sono REM , Tomografia Computadorizada por Raios X/métodos
7.
BMC Gastroenterol ; 13: 69, 2013 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-23607370

RESUMO

BACKGROUND: Intestinal ischemia-reperfusion injury (IRI) can occur in clinical scenarios such as organ transplantation, trauma and cardio-pulmonary bypass, as well as in neonatal necrotizing enterocolitis or persistent ductus arteriosus. Pharmacological protection by pretreating ("preconditioning") with opioids attenuates IRI in a number of organs. Remifentanil appears particularly attractive for this purpose because of its ultra-short duration of action and favorable safety profile. To date, little is known about opioid preconditioning of the intestine. METHODS: Young adult C57BL/6J mice were randomly assigned to receive tail vein injections of 1 µg/kg of remifentanil or normal saline and underwent either ischemia-reperfusion of the intestine or a sham laparotomy. Under isoflurane anesthesia, the mice were subjected to intestinal ischemia-reperfusion by occlusion (clamping) of the superior mesenteric artery for 30 min, followed by unclamping and 60 min of reperfusion. After completion of this protocol, tissue injury and lipid peroxidation in jejunum and ileum were analyzed by histology and malondialdehyde (MDA), respectively. Systemic interleukin (IL)-6 was determined in the plasma by ELISA. RESULTS: Pretreatment with remifentanil markedly reduced intestinal IRI (P < 0.001): In the ileum, we observed a more than 8-fold decrease in injured villi (4% vs 34% in saline-pretreated animals). In fact, the mucosa in the remifentanil group was as healthy as that of sham-operated animals. This protective effect was not as pronounced in the jejunum, but the percentage of damaged villi was still reduced considerably (18% vs 42%). There was up to 3-fold more tissue MDA after intestinal ischemia-reperfusion than after sham laparotomy, but this increase in lipid peroxidation was prevented by preconditioning with remifentanil (P < 0.05). The systemic inflammatory response triggered by intestinal IRI was significantly attenuated in mice pretreated with remifentanil (159 vs 805 pg/ml of IL-6 after saline pretreatment, with 92 pg/ml in the sham groups). After sham operations, no difference was detected between the saline- and remifentanil-pretreatments in any of the parameters investigated. CONCLUSION: Preconditioning with remifentanil attenuates intestinal IRI and the subsequent systemic inflammatory response in mice. We therefore suggest that prophylaxis with this ultra-short-acting opioid may be advantageous in various clinical scenarios of human IRI.


Assuntos
Analgésicos Opioides/uso terapêutico , Íleo/irrigação sanguínea , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Piperidinas/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Analgésicos Opioides/farmacologia , Animais , Íleo/metabolismo , Íleo/patologia , Interleucina-6/sangue , Jejuno/metabolismo , Jejuno/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Remifentanil , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
8.
Clin Exp Pharmacol Physiol ; 40(4): 253-61, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23448535

RESUMO

The prevalence of type 1 diabetes (T1D) is increasing worldwide and is associated with significant microvessel complications, of which nephropathy, retinopathy and neuropathy are the most commonly studied. Although clinically evident microvascular complications of diabetes are rarely seen in childhood, early vascular abnormalities develop during childhood and accelerate during puberty. Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis, which is regulated by endothelial nitric oxide synthase (NOS3) at several levels. Together, VEGF and NOS3 play an important role in the pathogenesis of the microvascular complications of diabetes. Genetic variations in NOS3 and VEGF critically regulate endothelial survival and function and increase the susceptibility of patients to develop severe microvessel complications. Identification of the risk factors for and improved understanding of the subclinical signs of these diabetic microvascular complications will enable implementation of therapeutic strategies, potentially changing the course of vascular complications and improving the prognosis of children, adolescents and young adults with diabetes. Moreover, early detection of these variations may have a prognostic value or may suggest interventional approaches to regulate these proteins in patients with diabetes.


Assuntos
Vasos Coronários/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/genética , Óxido Nítrico Sintase Tipo III/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Predisposição Genética para Doença , Humanos , Microvasos/fisiopatologia , Polimorfismo Genético , Adulto Jovem
9.
Front Pediatr ; 11: 1130013, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36994431

RESUMO

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.

10.
Am J Respir Crit Care Med ; 184(9): 1067-75, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21816941

RESUMO

RATIONALE: Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES: To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2π/(2πDR - sin2πDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS: After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS: In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS: Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy.


Assuntos
Respiração de Cheyne-Stokes/prevenção & controle , Pressão Positiva Contínua nas Vias Aéreas , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Animais , Respiração de Cheyne-Stokes/diagnóstico , Respiração de Cheyne-Stokes/etiologia , Respiração de Cheyne-Stokes/mortalidade , Respiração de Cheyne-Stokes/fisiopatologia , Retroalimentação Fisiológica , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Humanos , Modelos Animais , Consumo de Oxigênio , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Volume de Ventilação Pulmonar , Resultado do Tratamento
11.
Bio Protoc ; 12(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36816013

RESUMO

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.

12.
Front Immunol ; 13: 1022104, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389766

RESUMO

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.


Assuntos
Displasia Broncopulmonar , Proteína Antagonista do Receptor de Interleucina 1 , Adulto , Criança , Humanos , Lactente , Recém-Nascido , Displasia Broncopulmonar/tratamento farmacológico , Estudos de Viabilidade , Lactente Extremamente Prematuro , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Interleucina-1 , Receptores de Interleucina-1
13.
Sci Transl Med ; 14(639): eaaz8454, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35385341

RESUMO

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.


Assuntos
Displasia Broncopulmonar , Interleucina-13 , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/prevenção & controle , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação/complicações , Pulmão/patologia , Camundongos , Gravidez
14.
Am J Respir Crit Care Med ; 182(7): 961-9, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20522790

RESUMO

RATIONALE: Brief recurrent apneas in preterm infants and adults can precipitate rapid and severe arterial O(2) desaturation for reasons that remain unclear. OBJECTIVES: We tested a mathematically derived hypothesis that when breathing terminates apnea, mixed-venous hypoxemia continues into the subsequent apnea; as a result, there is a surge in pulmonary O(2) uptake that rapidly depletes the finite alveolar O(2) store, thereby accelerating arterial O(2) desaturation. METHODS: Recurrent apneas were simulated in an experimental lamb model. Pulmonary O(2) uptake was calculated from continuously measured arterial and mixed-venous O(2) saturation and cardiac output. MEASUREMENTS AND MAIN RESULTS: Direct measurements revealed that asynchrony in the desaturation and resaturation of arterial and venous blood gave rise to dips and surges in O(2) uptake. After desaturation to 50%, a typical nadir in preterm infants, O(2) uptake surged to a peak of 176.9 ± 7.8% of metabolic rate. During subsequent apneas, desaturation rate was increased two- to threefold greater than during isolated apneas, in direct proportion to the magnitude of the surge in O(2) uptake (P < 0.001; R(2) = 0.897). Application of our mathematical model to a published recording of cyclic apneas in a preterm infant precisely reproduced the accelerated desaturation rates of up to 15% · s(-1) observed clinically. CONCLUSIONS: Rapid depletion of alveolar O(2) stores by surges in O(2) uptake almost completely explains the acceleration of desaturation that occurs during recurrent apnea. This powerful mechanism is likely to explain the severity of intermittent hypoxemia that is associated with neurocognitive and cardiovascular morbidities in preterm infants and adults.


Assuntos
Apneia/fisiopatologia , Hipóxia/fisiopatologia , Recém-Nascido Prematuro , Animais , Animais Recém-Nascidos , Humanos , Recém-Nascido , Modelos Lineares , Modelos Biológicos , Oxiemoglobinas/metabolismo , Alvéolos Pulmonares/irrigação sanguínea , Troca Gasosa Pulmonar , Recidiva , Ovinos
15.
J Theor Biol ; 264(3): 657-62, 2010 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-20362590

RESUMO

Ventilation-perfusion (V/Q) mismatch is a prominent feature of preterm infants and adults with lung disease. V/Q mismatch is known to cause arterial hypoxemia under steady-state conditions, and has been proposed as the cause of rapid arterial oxygen desaturation during apnea. However, there is little evidence to support a role for V/Q mismatch in the dynamic changes in arterial oxygenation that occur during apnea. Using a mathematical model, we quantified the effect of V/Q mismatch on the rate of desaturation during apnea to ascertain whether it could lead to rates of up to 10%s(-1) as observed in preterm infants. We used a lung-body model for the preterm infant that incorporated 50 parallel alveolar-capillary units that were ventilated and perfused with the severity of V/Q mismatch (sigma) defined conventionally according to sigma=S.D. of the distribution of V/Q ratios. Average desaturation rate 10s from apnea onset was strongly elevated with worsening V/Q mismatch as a result of an earlier desaturation of low V/Q units compared with high V/Q units. However, V/Q mismatch had little impact after apnea onset, with peak desaturation rate only substantially increased if mismatching caused a lowered resting arterial O(2) saturation. In conclusion, V/Q mismatch causes a more immediate onset of desaturation during apnea, and therefore places preterm infants and adults with lung disease at risk of hypoxemic dips. However, V/Q mismatch does not accelerate desaturation rate beyond apnea onset and cannot, therefore, explain the rapid desaturation observed during recurrent apnea in preterm infants.


Assuntos
Apneia/fisiopatologia , Recém-Nascido Prematuro/fisiologia , Modelos Biológicos , Ventilação Pulmonar/fisiologia , Humanos , Recém-Nascido , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Consumo de Oxigênio , Respiração
16.
PLoS Comput Biol ; 5(12): e1000588, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19997495

RESUMO

Rapid arterial O(2) desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O(2) desaturation during apnea (Sa(O)2) is complicated by the non-linear O(2) dissociation curve, falling pulmonary O(2) uptake, and by the fact that O(2) desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O(2) consumption accelerates Sa(O)2throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar P(O)2causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates Sa(O)2during stage 1, and finally, total blood O(2) capacity (blood volume and hemoglobin content) alone determines Sa(O)2during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.


Assuntos
Doenças do Prematuro/metabolismo , Modelos Cardiovasculares , Oxigênio/metabolismo , Fenômenos Fisiológicos Respiratórios , Apneia do Sono Tipo Central/metabolismo , Biologia Computacional , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Troca Gasosa Pulmonar
17.
Respirology ; 15(2): 326-35, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20199643

RESUMO

UNLABELLED: This article investigates a new acoustic device to assess the behaviour of the upper airway in patients with OSA. Currently there is no simple non-invasive method to perform such measurements. As such this paper describes the device in probing the patency of the airway during sleep and increasing the efficiency of diagnosing OSA. BACKGROUND AND OBJECTIVE: OSA is a common disorder resulting in health and economic burdens. Currently identifying OSA in patients involves expensive techniques that require overnight studies in a laboratory setting with qualified staff. This paper tests a new acoustic device (AirwayClear (AC)) for assessing upper airway patency in human subjects with OSA. We hypothesize that obstructive apnoeas would be detected equally well with AC and polysomnography (PSG). METHODS: Twenty-three patients with severe OSA underwent an overnight CPAP titration study. We introduced pseudorandom noise (600-1200 Hz) using AC to the patient's nasal mask during 1 h of subtherapeutic CPAP. AC determined a measure of airway patency based on the level of pseudorandom noise reaching a sternal notch sensor. The ability of AC to detect obstructive respiratory events was compared with standard PSG. RESULTS: Three hundred and twenty-two obstructive events (obstructive and mixed apnoeas) were identified by PSG. AC scored 80% as complete obstructions and 16% as partial obstructions. Conversely, AC detected 281 complete obstructions. PSG recognized 84% as apnoeas and scored 11% as hypopnoeas. Of the 204 hypopnoeas identified with PSG, AC indicated the airway was partially or completely obstructed in 69% of patients. A Bland-Altman analysis for the apnoeas from the two measures showed a mean difference of 2.3 events/h and 95% confidence intervals of +/-15.5 events/h. CONCLUSIONS: We conclude that AC is able to track airway patency and to identify airway closure in patients with OSA.


Assuntos
Acústica , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/etiologia , Testes Diagnósticos de Rotina/instrumentação , Síndromes da Apneia do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Adulto , Obstrução das Vias Respiratórias/fisiopatologia , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Síndromes da Apneia do Sono/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia
18.
Cells ; 9(1)2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936823

RESUMO

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.


Assuntos
Inflamassomos/metabolismo , Interleucina-1/metabolismo , Interleucinas/metabolismo , Animais , Células Cultivadas , Interleucina-1/análise , Interleucinas/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
19.
Nat Commun ; 11(1): 5794, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188181

RESUMO

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.


Assuntos
Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/imunologia , Imunidade Adaptativa , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Enterocolite Necrosante/sangue , Enterocolite Necrosante/patologia , Homeostase , Humanos , Imunidade Inata , Recém-Nascido , Mediadores da Inflamação/metabolismo , Interleucina-1 , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Toll-Like/metabolismo
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