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Raghuveer TS, Zackula RE, Lakhotia R, Binder SA. Systemic steroids and bronchopulmonary dysplasia: a systematic review and meta-analysis. J Perinatol 2024:10.1038/s41372-024-02097-w. [PMID: 39223342 DOI: 10.1038/s41372-024-02097-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/29/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
IMPORTANCE It is unclear if systemic steroids decrease the risk of Bronchopulmonary Dysplasia (BPD) while increasing the risk of neurodevelopmental impairment (NDI). OBJECTIVE Conduct a systematic review of randomized controlled trials of systemic steroids to evaluate the risk of BPD, mortality, and NDI in premature infants ≤30 weeks. DATA SOURCES MEDLINE, EBSCOhost, Web of Science, Cochrane Library, Embase, and CINAHL. STUDY SELECTION Randomized clinical trials of Dexamethasone (DEX) or Hydrocortisone (HC) to prevent BPD in premature infants ≤ 30 weeks. DATA EXTRACTION AND SYNTHESIS Data were extracted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Random-effects meta-analyses and multivariable meta-regression were conducted. MAIN OUTCOMES AND MEASURES Primary outcomes were BPD, mortality, and NDI. Secondary outcomes were hypertension, hyperglycemia, sepsis, intestinal perforation, necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). The a priori hypothesis was that steroids would reduce the risk of BPD without increasing NDI. RESULTS There were 6377 preterm infants in the 44 (32 DEX, 13 HC) selected studies. DEX significantly reduced the risk of BPD, RR = 0.66, (95% CI, 0.56-0.78). The most effective DEX regimen was medium cumulative dose (2 to 3 mg/kg), RR = 0.43 (95% CI, 0.29-0.65); day of initiation <8 days: RR = 0.68, (95% CI, 0.59-0.79); and treatment for ≥14 days: RR = 0.67 (95% CI, 0.55-0.80). HC did not significantly decrease the risk of BPD, RR = 0.98, (95% CI, 0.87-1.10). Neither DEX, (RR = 0.92, 95% CI, 0.78-1.09) nor HC (RR = 0.83, 95% CI, 0.68-1.01) decrease the risk of mortality. The risk of CP was not increased by either DEX (RR = 1.09, 95% CI, 0.55-2.17) or HC (RR = 1.18, 95% CI, 0.75-1.87). There were no significant differences between steroids and placebo for MDI/PDI scores. Multivariable meta-regression models showed that DEX significantly reduced the risk of BPD without increased risk of CP. DEX increased the risk of hypertension and hyperglycemia. Studies showed high heterogeneity, differing treatment regimen, missing data and different rates of follow-up. CONCLUSION AND RELEVANCE DEX, but not HC, significantly decreased the risk of BPD. Neither steroid showed an increased risk of NDI or mortality.
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Affiliation(s)
- Talkad S Raghuveer
- Department of Pediatrics, University of Kansas School of Medicine-Wichita, Wichita, KS, USA.
| | - Rosey E Zackula
- Office of Research, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Richa Lakhotia
- Department of Pediatrics, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
- Pediatrix Medical Group of Kansas, Wichita, KS, USA
| | - Stephanie A Binder
- Department of Pediatrics, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
- Pediatrix Medical Group of Kansas, Wichita, KS, USA
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Mukthapuram S, Donaher A, Higano NS, Rowe JA, Tkach JA, Woods JC, Kingma PS. Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Preterm Infants with Bronchopulmonary Dysplasia. Neonatology 2024; 122:76-83. [PMID: 39074457 PMCID: PMC11775235 DOI: 10.1159/000539545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 05/24/2024] [Indexed: 07/31/2024]
Abstract
INTRODUCTION Pulmonary hypertension often complicates bronchopulmonary dysplasia (BPD) and infants with BPD plus pulmonary hypertension experience higher mortality rates. Current methods to evaluate pulmonary hypertension fail to evaluate the primary cause of this disease. We hypothesize that preterm infants with BPD experience altered pulmonary vascular growth and that magnetic resonance imaging (MRI) can be used to assess vascularity in BPD. METHODS In this observational cohort study, preterm infants with BPD (n = 33) and controls (n = 6) received a postnatal chest MRI that included a 2-dimensional time-of-flight acquisition. Semi-automatic segmentation was performed to measure vascularity parameters including vascular volume and density (vascular density = vascular volume/lung volume). RESULTS Vascular volume on MRI increases with post-menstrual age (877.2 mm3/week); however, the vascular density does not significantly change. Vascular volume is higher in infants with more severe BPD (p < 0.002), but vascular density did not significantly change when comparing mild, moderate, and severe BPD. Vascular density in infants with severe BPD requiring tracheostomy trended lower when compared to infants not requiring tracheostomy (0.18 mm3/mm3 vs. 0.27 mm3/mm3, p = 0.06). Vascular density increases with increasing days of inhaled nitric oxide (iNO) therapy in infants with severe BPD (0.02 mm3/mm3/week of iNO, rho = +0.56, p = 0.03). CONCLUSION Neonatal MRI can be used to assess pulmonary vascularity in preterm infants with BPD. Infants with BPD experience altered vascular growth and while higher vascular volume is associated with more severe BPD, lower vascular density trends toward worse clinical outcomes. Vascular density increases with iNO therapy in severe BPD.
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Affiliation(s)
- Shanmukha Mukthapuram
- The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Bronchopulmonary Dysplasia Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Addison Donaher
- The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Nara S Higano
- Cincinnati Bronchopulmonary Dysplasia Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - James A Rowe
- The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Bronchopulmonary Dysplasia Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Jean A Tkach
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jason C Woods
- Cincinnati Bronchopulmonary Dysplasia Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Paul S Kingma
- The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Bronchopulmonary Dysplasia Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Urru SA, Geist M, Carlinger R, Bodrero E, Bruschettini M. Strategies for cessation of caffeine administration in preterm infants. Cochrane Database Syst Rev 2024; 7:CD015802. [PMID: 39045901 PMCID: PMC11267609 DOI: 10.1002/14651858.cd015802.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
BACKGROUND Apnea and intermittent hypoxemia (IH) are common developmental disorders in infants born earlier than 37 weeks' gestation. Caffeine administration has been shown to lower the incidence of these disorders in preterm infants. Cessation of caffeine treatment is based on different post-menstrual ages (PMA) and resolution of symptoms. There is uncertainty about the best timing for caffeine discontinuation. OBJECTIVES To evaluate the effects of early versus late discontinuation of caffeine administration in preterm infants. SEARCH METHODS We searched CENTRAL, PubMed, Embase, and three trial registries in August 2023; we applied no date limits. We checked the references of included studies and related systematic reviews. SELECTION CRITERIA We included randomized controlled trials (RCTs) in preterm infants born earlier than 37 weeks' gestation, up to a PMA of 44 weeks and 0 days, who received caffeine for any indication for at least seven days. We compared three different strategies for caffeine cessation: 1. at different PMAs, 2. before or after five days without symptoms, and 3. at a predetermined PMA versus at the resolution of symptoms. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Primary outcomes were: restarting caffeine therapy, intubation within one week of treatment discontinuation, and the need for non-invasive respiratory support within one week of treatment discontinuation. Secondary outcomes were: number of episodes of apnea in the seven days after treatment discontinuation, number of infants with at least one episode of apnea in the seven days after treatment discontinuation, number of episodes of intermittent hypoxemia (IH) within seven days of treatment discontinuation, number of infants with at least one episode of IH in the seven days after of treatment discontinuation, all-cause mortality prior to hospital discharge, major neurodevelopmental disability, number of days of respiratory support after treatment discontinuation, duration of hospital stay, and cost of neonatal care. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS We included three RCTs (392 preterm infants). Discontinuation of caffeine at PMA less than 35 weeks' gestation versus PMA equal to or longer than 35 weeks' gestation This comparison included one single completed RCT with 98 premature infants with a gestational age between 25 + 0 and 32 + 0 weeks at birth. All infants had discontinued caffeine treatment for five days at randomization. The infants received either an oral loading dose of caffeine citrate (20 mg/kg) at randomization followed by oral maintenance dosage (6 mg/kg/day) until 40 weeks PMA, or usual care (controls), during which caffeine was stopped before 37 weeks PMA. Early cessation of caffeine administration in preterm infants at PMA less than 35 weeks' gestation may result in an increase in the number of IH episodes in the seven days after discontinuation of treatment, compared to prolonged caffeine treatment beyond 35 weeks' gestation (mean difference [MD] 4.80, 95% confidence interval [CI] 2.21 to 7.39; 1 RCT, 98 infants; low-certainty evidence). Early cessation may result in little to no difference in all-cause mortality prior to hospital discharge compared to late discontinuation after 35 weeks PMA (risk ratio [RR] not estimable; 98 infants; low-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, number of episodes of apnea, number of infants with at least one episode of apnea in the seven days after discontinuation of treatment, or number of infants with at least one episode of IH in the seven days after discontinuation of treatment. Discontinuation based on PMA versus resolution of symptoms This comparison included two RCTs with a total of 294 preterm infants. Discontinuing caffeine at the resolution of symptoms compared to discontinuing treatment at a predetermined PMA may result in little to no difference in all-cause mortality prior to hospital discharge (RR 1.00, 95% CI 0.14 to 7.03; 2 studies, 294 participants; low-certainty evidence), or in the number of infants with at least one episode of apnea within the seven days after discontinuing treatment (RR 0.60, 95% CI 0.31 to 1.18; 2 studies; 294 infants; low-certainty evidence). Discontinuing caffeine based on the resolution of symptoms probably results in more infants with IH in the seven days after discontinuation of treatment (RR 0.38, 95% CI 0.20 to 0.75; 1 study; 174 participants; moderate-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, or number of episodes of IH in the seven days after treatment discontinuation. Adverse effects In the Rhein 2014 study, five of the infants randomized to caffeine had the caffeine treatment discontinued at the discretion of the clinical team, because of tachycardia. The Pradhap 2023 study reported adverse events, including recurrence of apnea of prematurity (15% in the short and 13% in the regular course caffeine therapy group), varying severities of bronchopulmonary dysplasia, hyperglycemia, extrauterine growth restriction, retinopathy of prematurity requiring laser treatment, feeding intolerance, osteopenia, and tachycardia, with no significant differences between the groups. The Prakash 2021 study reported that adverse effects of caffeine therapy for apnea of prematurity included tachycardia, feeding intolerance, and potential neurodevelopmental impacts, though most were mild and transient. We identified three ongoing studies. AUTHORS' CONCLUSIONS There may be little or no difference in the incidence of all-cause mortality and apnea in infants who were randomized to later discontinuation of caffeine treatment. However, the number of infants with at least one episode of IH was probably reduced with later cessation. No data were found to evaluate the benefits and harms of later caffeine discontinuation for: restarting caffeine therapy, intubation within one week of treatment discontinuation, or need for non-invasive respiratory support within one week of treatment discontinuation. Further studies are needed to evaluate the short-term and long-term effects of different caffeine cessation strategies in premature infants.
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Affiliation(s)
- Silvana Am Urru
- Hospital Pharmacy Unit, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento, Italy
- Department of Chemistry and Pharmacy, School of Hospital Pharmacy, University of Sassari, Sassari, Italy
| | - Milena Geist
- Institute for Medical Information Processing, Biometry, and Epidemiology - IBE, LMU Munich, Munich, Germany
- Pettenkofer School of Public Health, Munich, Germany
| | | | - Enrico Bodrero
- Neonatal Intensive Care Unit, Ospedale S. Croce e Carle, Cuneo, Italy
| | - Matteo Bruschettini
- Paediatrics, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
- Cochrane Sweden, Department of Research and Education, Lund University, Skåne University Hospital, Lund, Sweden
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Kim C, Kim S, Kim H, Hwang J, Kim SH, Yang M, Ahn SY, Sung SI, Chang YS. Long-term impact of late pulmonary hypertension requiring medication in extremely preterm infants with severe bronchopulmonary dysplasia. Sci Rep 2024; 14:8705. [PMID: 38622180 PMCID: PMC11018761 DOI: 10.1038/s41598-024-58977-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/05/2024] [Indexed: 04/17/2024] Open
Abstract
This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.
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Affiliation(s)
- Chan Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
| | - Sumin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea
| | - Hanna Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
| | - Jieun Hwang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
| | - Seung Hyun Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
| | - Misun Yang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
- Cell and Gene Therapy Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
- Cell and Gene Therapy Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea
- Cell and Gene Therapy Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-ku, Seoul, 06351, Republic of Korea.
- Cell and Gene Therapy Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.
- Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
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Huang Z, Cheng X, Lin B, Zhao J, Huang Z, Xiong X, Yang C, Chen X. Diameter of ductus arteriosus on postnatal Day 7 is associated with late pulmonary hypertension in extremely preterm infants. Pediatr Pulmonol 2023; 58:3523-3529. [PMID: 37712599 DOI: 10.1002/ppul.26686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/16/2023]
Abstract
OBJECTIVES A clinically feasible biomarker for pulmonary hypertension (PH) prediction is still lacking. Thus, we aim to assess the association between ductus arteriosus (DA) diameter and PH in extremely preterm infants. STUDY DESIGN A retrospective case-control study was performed to compare the diameter of DA in infants with and without late PH. Propensity scores were calculated to match the gestational age in two groups with a match ratio of 1:2. The diameter of DA was measured by echocardiography on postnatal Days 3 and 7. RESULTS A total of 91 infants were included in the study. The diagnosis of late PH was made in 32 infants between postnatal life of 28-159 days. Univariable analysis showed that late PH was associated with birth weight, invasive mechanical ventilation, hemodynamically significant PDA (hsPDA), duration of PDA exposure, the rate of surgical ligation, and diameter of DA on postnatal Days 3 and 7. After adjusting for these selected factors, the diameter of DA measured on postnatal Day 7 was independently associated with the risk of late PH (odds ratios: 5.511, 95% confidence interval: 1.552-19.562, p = .008). Receiver operator curve analysis indicated that 1.95 mm in DA diameter on postnatal Day 7 was the cutoff value for late PH with an area under the curve of 0.697. CONCLUSIONS Our findings suggest that DA diameter (larger than or equal to 1.95 mm) on postnatal Day 7 might serve as a predictor for late PH in extremely preterm infants.
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Affiliation(s)
- Zilu Huang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Xiaoqin Cheng
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Bingchun Lin
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Jie Zhao
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Zhifeng Huang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Xiaoyun Xiong
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Chuanzhong Yang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Xueyu Chen
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
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Kelly SB, Tran NT, Polglase GR, Hunt RW, Nold MF, Nold-Petry CA, Olson DM, Chemtob S, Lodygensky GA, Robertson SA, Gunn AJ, Galinsky R. A systematic review of immune-based interventions for perinatal neuroprotection: closing the gap between animal studies and human trials. J Neuroinflammation 2023; 20:241. [PMID: 37864272 PMCID: PMC10588248 DOI: 10.1186/s12974-023-02911-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/28/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. METHODS We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). RESULTS Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. CONCLUSION Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.
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Affiliation(s)
- Sharmony B Kelly
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Nhi T Tran
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
| | - Graeme R Polglase
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Rodney W Hunt
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC, Australia
- Monash Newborn, Monash Children's Hospital, Melbourne, Australia
| | - Marcel F Nold
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC, Australia
- Monash Newborn, Monash Children's Hospital, Melbourne, Australia
| | - Claudia A Nold-Petry
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC, Australia
| | - David M Olson
- Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, Canada
| | - Sylvain Chemtob
- Department of Paediatrics, CHU Sainte Justine Research Centre, University of Montreal, Quebec, Canada
| | - Gregory A Lodygensky
- Department of Paediatrics, CHU Sainte Justine Research Centre, University of Montreal, Quebec, Canada
| | - Sarah A Robertson
- The University of Adelaide, Robinson Research Institute, North Adelaide, SA, Australia
| | - Alistair J Gunn
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Robert Galinsky
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Melbourne, VIC, 3168, Australia.
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.
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Yung D, Jackson EO, Blumenfeld A, Redding G, DiGeronimo R, McGuire JK, Riker M, Tressel W, Berkelhamer S, Eldredge LC. A multidisciplinary approach to severe bronchopulmonary dysplasia is associated with resolution of pulmonary hypertension. Front Pediatr 2023; 11:1077422. [PMID: 37063675 PMCID: PMC10098720 DOI: 10.3389/fped.2023.1077422] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 03/08/2023] [Indexed: 04/18/2023] Open
Abstract
Objective To describe our multidisciplinary bronchopulmonary dysplasia (BPD) consult team's systematic approach to BPD associated pulmonary hypertension (PH), to report our center outcomes, and to evaluate clinical associations with outcomes. Study design Retrospective cohort of 60 patients with BPD-PH who were referred to the Seattle Children's Hospital BPD team from 2018 to 2020. Patients with critical congenital heart disease were excluded. Demographics, comorbidities, treatments, closure of hemodynamically relevant intracardiac shunts, and clinical outcomes including time to BPD-PH resolution were reviewed. Results Median gestational age of the 60 patients was 25 weeks (IQR: 24-26). 20% were small for gestational age (SGA), 65% were male, and 25% received a tracheostomy. With aggressive cardiopulmonary management including respiratory support optimization, patent ductus arteriosus (PDA) and atrial septal defect (ASD) closure (40% PDA, 5% ASD, 3% both), and limited use of pulmonary vasodilators (8%), all infants demonstrated resolution of PH during the follow-up period, including three (5%) who later died from non-BPD-PH morbidities. Neither SGA status nor the timing of PH diagnosis (<36 vs. ≥36 weeks PMA) impacted the time to BPD-PH resolution in our cohort [median 72 days (IQR 30.5-166.5)]. Conclusion Our multidisciplinary, systematic approach to BPD-PH management was associated with complete resolution of PH with lower mortality despite less sildenafil use than reported in comparable cohorts. Unique features of our approach included aggressive PDA and ASD device closure and rare initiation of sildenafil only after lack of BPD-PH improvement with respiratory support optimization and diagnostic confirmation by cardiac catheterization.
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Affiliation(s)
- Delphine Yung
- Division of Cardiology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Emma O. Jackson
- Heart Center, Seattle Children’s Hospital, Seattle, WA, United States
| | - Alyssa Blumenfeld
- Department of Pediatrics, University of Washington, Seattle, WA, United States
| | - Gregory Redding
- Division of Pulmonology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Robert DiGeronimo
- Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, and Seattle Children’s Hospital, Seattle, WA, United States
| | - John K. McGuire
- Division of Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Meredith Riker
- Heart Center, Seattle Children’s Hospital, Seattle, WA, United States
| | - William Tressel
- Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Sara Berkelhamer
- Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, and Seattle Children’s Hospital, Seattle, WA, United States
| | - Laurie C. Eldredge
- Division of Pulmonology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
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8
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Fike CD, Aschner JL. Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future. Pharmaceuticals (Basel) 2023; 16:503. [PMID: 37111262 PMCID: PMC10141152 DOI: 10.3390/ph16040503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023] Open
Abstract
Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.
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Affiliation(s)
- Candice D. Fike
- Department of Pediatrics, University of Utah Health, Salt Lake City, UT 84108, USA
| | - Judy L. Aschner
- Department of Pediatrics, Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ 07601, USA
- Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
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9
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Wang L, Liu Z, Zhang F, Xu H, Wang H, Zhao X. The value of pulmonary artery acceleration time in evaluating pulmonary vascular disease in preterm infants with bronchopulmonary dysplasia. Echocardiography 2023; 40:180-187. [PMID: 36691732 DOI: 10.1111/echo.15513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/15/2022] [Accepted: 11/30/2022] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVES Early screening and dynamic monitoring of pulmonary vascular disease (PVD) in bronchopulmonary dysplasia (BPD) high-risk infants is of great clinical significance. Pulmonary artery acceleration time (PAAT) is a reliable and non-invasive method for assessing PVD in children over 1 year, but to date, few studies have used PAAT to assess pulmonary hemodynamics of preterm infants, especially those with BPD. Through dynamic monitoring the main hemodynamic indicators reflected PVD after birth, this study aimed to assess the value of PAAT in evaluating early PVD in BPD infants. METHODS All 81 preterm infants at risk of BPD were divided into BPD and non-BPD groups according to whether BPD occurred. Clinical characteristics, PAAT, right ventricular ejection time (RVET) and other main hemodynamic indicators at four different time points after birth were studied and compared. RESULTS PAAT and PAAT/RVET increased gradually within 72 h after birth in the BPD group (p < .05), but the curve tended to be flat over time after 72 h (p > .05). At PMA32 and 36 weeks, the PAAT (49.7 ± 4.8 vs. 54.8 ± 5.7, p = .001; 50.0 ± 5.3 vs. 57.0 ± 5.3, p = .001) and PAAT/RVET (.33 ± .04 vs. .35 ± .03, p = .001; .34 ± .03 vs. .37 ± .04, p = .001) in BPD group were significantly lower than those in the non-BPD group. CONCLUSIONS PAAT and PAAT/RVET in the BPD group infants showed different change patterns compared to non-BPD group infants. PAAT can be used as a noninvasive and reliable screening method for screening and dynamic monitoring of PVD in BPD high-risk infants.
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Affiliation(s)
- Liling Wang
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Zhijie Liu
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Fengjuan Zhang
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Haiyan Xu
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Haiyan Wang
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Xueqiang Zhao
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
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10
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Martini S, Corsini I, Corvaglia L, Suryawanshi P, Chan B, Singh Y. A scoping review of echocardiographic and lung ultrasound biomarkers of bronchopulmonary dysplasia in preterm infants. Front Pediatr 2023; 11:1067323. [PMID: 36846161 PMCID: PMC9950276 DOI: 10.3389/fped.2023.1067323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/18/2023] [Indexed: 02/12/2023] Open
Abstract
Despite recent improvements in neonatal care, moderate to severe bronchopulmonary dysplasia (BPD) is still associated with high mortality and with an increased risk of developing pulmonary hypertension (PH). This scoping review provides an updated overview of echocardiographic and lung ultrasound biomarkers associated with BPD and PH, and the parameters that may prognosticate their development and severity, which could be clinically helpful to undertake preventive strategies. A literature search for published clinical studies was conducted in PubMed using MeSH terms, free-text words, and their combinations obtained through appropriate Boolean operators. It was found that the echocardiography biomarkers for BPD, and especially those assessing right ventricular function, are reflective of the high pulmonary vascular resistance and PH, indicating a strong interplay between heart and lung pathophysiology; however, early assessment (e.g., during the first 1-2 weeks of life) may not successfully predict later BPD development. Lung ultrasound indicating poor lung aeration at day 7 after birth has been reported to be highly predictive of later development of BPD at 36 weeks' postmenstrual age. Evidence of PH in BPD infants increases risk of mortality and long-term PH; hence, routine PH surveillance in all at risk preterm infants at 36 weeks, including an echocardiographic assessment, may provide useful information. Progress has been made in identifying the echocardiographic parameters on day 7 and 14 to predict later development of pulmonary hypertension. More studies on sonographic markers, and especially on echocardiographic parameters, are needed for the validation of the currently proposed parameters and the timing of assessment before recommendations can be made for the routine clinical practice.
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Affiliation(s)
- Silvia Martini
- Neonatal Intensive Care Unit, IRCCS AOUBO, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Iuri Corsini
- Division of Neonatology, Careggi University Hospital of Florence, Florence, Italy
| | - Luigi Corvaglia
- Neonatal Intensive Care Unit, IRCCS AOUBO, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Pradeep Suryawanshi
- Department of Neonatology, Bharati Vidyapeeth University Medical College, Pune, India
| | - Belinda Chan
- Division of Neonatology, University of Utah, Salt Lake City, UT, United States
| | - Yogen Singh
- Department of Pediatrics – Division of Neonatology, Loma Linda University School of Medicine, Loma linda, CA, United States
- Neonatology/Pediatric Cardiology, Cambridge University Hospitals, Cambridge, United Kingdom
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11
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Green EA, Garrick SP, Peterson B, Berger PJ, Galinsky R, Hunt RW, Cho SX, Bourke JE, Nold MF, Nold-Petry CA. The Role of the Interleukin-1 Family in Complications of Prematurity. Int J Mol Sci 2023; 24:2795. [PMID: 36769133 PMCID: PMC9918069 DOI: 10.3390/ijms24032795] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/20/2023] [Accepted: 01/22/2023] [Indexed: 02/05/2023] Open
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.
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Affiliation(s)
- Elys A. Green
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
- Monash Newborn, Monash Children’s Hospital, Melbourne, VIC 3168, Australia
| | - Steven P. Garrick
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
| | - Briana Peterson
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
| | - Philip J. Berger
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
| | - Robert Galinsky
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC 3168, Australia
| | - Rod W. Hunt
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
- Monash Newborn, Monash Children’s Hospital, Melbourne, VIC 3168, Australia
| | - Steven X. Cho
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
| | - Jane E. Bourke
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3168, Australia
| | - Marcel F. Nold
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
- Monash Newborn, Monash Children’s Hospital, Melbourne, VIC 3168, Australia
| | - Claudia A. Nold-Petry
- Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
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12
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Galinsky R, Kelly S, Green E, Hunt R, Nold-Petry C, Gunn A, Nold M. Interleukin-1: an important target for perinatal neuroprotection? Neural Regen Res 2023; 18:47-50. [PMID: 35799507 PMCID: PMC9241389 DOI: 10.4103/1673-5374.341044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy. Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth. Multiple pathways are involved in the pathogenesis of perinatal inflammation. However, studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1. In this review, we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury. We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage, and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist, anakinra, as a safe and effective therapeutic intervention. We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment, and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.
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13
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Li J, Zhao J, Yang XY, Shi J, Liu HT. Successful treatment of pulmonary hypertension in a neonate with bronchopulmonary dysplasia: A case report and literature review. World J Clin Cases 2022; 10:11898-11907. [PMID: 36405256 PMCID: PMC9669840 DOI: 10.12998/wjcc.v10.i32.11898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/03/2022] [Accepted: 10/11/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) is a severe complication of bronchopulmonary dysplasia (BPD) in premature neonates and is closely related to prognosis. However, there is no effective and safe treatment for PH due to BPD in infants. Successful treatment for cases of BPD-associated PH with Tadalafil combined with bosentan is rare. This case may make a significant contribution to the literature because PH is difficult to manage as a serious complication of BPD in preterm infants. Mortality is high, especially when it is complicated by heart failure.
CASE SUMMARY An extremely premature neonate with a gestational age of 26+5 wk and birth weight of 0.83 kg was diagnosed with BPD associated with PH; oral sildenafil did not improve the PH. The infant experienced sudden cardiac arrest and serious heart failure with severe PH. After a series of treatments, including cardiopulmonary resuscitation, mechanical ventilation, and inhaled nitric oxide (iNO), the respiratory and circulatory status improved but the pulmonary artery pressure remained high. Then oral sildenafil was replaced with oral tadalafil and bosentan; pulmonary artery pressure improved, and the infant recovered at our hospital. After 2 years of follow-up, she is in good condition, without any cardiovascular complications.
CONCLUSION INO can effectively improve the respiratory and circulatory status of infants with PH associated with premature BPD. B-type natriuretic peptide should be routinely measured during hospitalization to evaluate the risk and prognosis of BPD-associated PH in preterm infants. Tadalafil combined with bosentan for the treatment of PH associated with premature BPD was better than sildenafil in this case. Further studies are needed to explore the efficacy and safety of different vasodilators in the treatment of PH associated with premature BPD.
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Affiliation(s)
- Jiao Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing Zhao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Yan Yang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing Shi
- Neonatal Ward, West China Second University Hospital, Sichuan University, Chengdu 610066, Sichuan Province, China
| | - Hai-Ting Liu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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14
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Lao JC, Bui CB, Pang MA, Cho SX, Rudloff I, Elgass K, Schröder J, Maksimenko A, Mangan NE, Starkey MR, Skuza EM, Sun YBY, Beker F, Collins CL, Kamlin OF, König K, Malhotra A, Tan K, Theda C, Young MJ, McLean CA, Wilson NJ, Sehgal A, Hansbro PM, Pearson JT, Polo JM, Veldman A, Berger PJ, Nold-Petry CA, Nold MF. Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants. Sci Transl Med 2022; 14:eaaz8454. [PMID: 35385341 DOI: 10.1126/scitranslmed.aaz8454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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-1β 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.
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Affiliation(s)
- Jason C Lao
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Christine B Bui
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Merrin A Pang
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Steven X Cho
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Ina Rudloff
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Kirstin Elgass
- Monash Micro Imaging, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Jan Schröder
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.,Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Victoria 3800, Australia.,Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia
| | - Anton Maksimenko
- Imaging and Medical Beamline, Australian Synchrotron, Melbourne, Victoria 3168, Australia
| | - Niamh E Mangan
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia.,Department of Molecular and Translational Science, Monash University, Melbourne, Victoria 3168, Australia
| | - Malcolm R Starkey
- Priority Research Centres for Healthy Lungs and GrowUpWell, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales 2308, Australia.,Department of Immunology and Pathology, Monash University, Melbourne, Victoria 3004, Australia
| | - Elisabeth M Skuza
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Yu B Y Sun
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.,Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Victoria 3800, Australia.,Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia
| | - Friederike Beker
- Mater Research Institute, University of Queensland, Brisbane, Queensland 4101, Australia.,Neonatal Services, Mercy Hospital for Women, Melbourne, Victoria 3084, Australia
| | - Clare L Collins
- Neonatal Services, Mercy Hospital for Women, Melbourne, Victoria 3084, Australia
| | - Omar F Kamlin
- Department of Newborn Research, Royal Women's Hospital, Melbourne, Victoria 3052, Australia.,University of Melbourne, Melbourne, Victoria 3010, Australia.,Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia
| | - Kai König
- Department of Paediatrics, Medicum Wesemlin, Lucerne 6006, Switzerland
| | - Atul Malhotra
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia.,Monash Newborn, Monash Children's Hospital, Melbourne, Victoria 3168, Australia
| | - Kenneth Tan
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Monash Newborn, Monash Children's Hospital, Melbourne, Victoria 3168, Australia
| | - Christiane Theda
- Department of Newborn Research, Royal Women's Hospital, Melbourne, Victoria 3052, Australia.,University of Melbourne, Melbourne, Victoria 3010, Australia.,Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia
| | - Morag J Young
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
| | - Catriona A McLean
- Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria 3004, Australia.,Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria 3800, Australia
| | - Nicholas J Wilson
- CSL Limited, Bio21 Institute, Parkville, Melbourne, Victoria 3052, Australia
| | - Arvind Sehgal
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Monash Newborn, Monash Children's Hospital, Melbourne, Victoria 3168, Australia
| | - Philip M Hansbro
- Priority Research Centres for Healthy Lungs and GrowUpWell, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales 2308, Australia.,Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Ultimo, Sydney, New South Wales 2007, Australia
| | - James T Pearson
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.,Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan.,Victorian Heart Institute, Melbourne, Victoria 3168, Australia
| | - Jose M Polo
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia.,Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Victoria 3800, Australia.,Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia.,Adelaide Centre for Epigenetics, University of Adelaide, Adelaide, South Australia 5005, Australia.,South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Alex Veldman
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia.,Department of Pediatrics, Helios HSK, Wiesbaden 65199, Germany.,Department of Pediatric Cardiology, J. Liebig University, Gießen 35392, Germany
| | - Philip J Berger
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Claudia A Nold-Petry
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia
| | - Marcel F Nold
- Department of Paediatrics, Monash University, Melbourne, Victoria 3168, Australia.,Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria 3168, Australia.,Monash Newborn, Monash Children's Hospital, Melbourne, Victoria 3168, Australia
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15
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Buendía JA, Ramírez Velasquez C, Benjumea-Bedoya D. Bronchopulmonary dysplasia: Incidence and severity in premature infants born at high altitude. Pediatr Pulmonol 2022; 57:470-475. [PMID: 34796697 DOI: 10.1002/ppul.25763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) is the most common cause of chronic lung disease in children born prematurely. There is little information about the epidemiology and severity of BPD places with high altitude. This study aimed to evaluate the frequency of BPD severity levels and the associated risk factors with severity in a cohort of preterm newborns ≤36weeks of gestational age born in Rionegro, Colombia MATERIALS AND METHODS: We carried out a retrospective analytical cohort of preterm newborns without major malformations from Rionegro, Colombia between 2011 and 2018 admitted to neonatal intensive unit at high altitude (2200 m above sea level). The main outcomes were the incidence and severity of BPD. RESULTS The BPD incidence was 23.5% 95% (confidence interval [CI], 19.6-27.7). BPD was grade 1 in 69.9%, grade 2 in 15.5% and grade 3 in 14.5% of patients. After modeling regression analysis, the final variables associated with BPD severity levels were: sepsis (odds ratio [OR], 4.15; 95% CI, 1.33-12.96) and pulmonary hypertension (OR: 3.86; 95% CI, 1.30-11.4). CONCLUSION The incidence of BPD was higher and similar to cities with higher altitudes. In our population, the variables associated with BPD severity levels were: sepsis and pulmonary hypertension. It is necessary to increase the awareness of risk factors, the effect of clinical practices, and early recognition of BPD to reduce morbidity in patients with this pathology.
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Affiliation(s)
- Jefferson A Buendía
- Departamento de farmacología y Toxicologia, Grupo de Investigación en Farmacología y Toxicología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
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16
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Li M, Zhang Z, Joynauth J, Zhan X, Du L. Intrauterine growth restriction neonates present with increased angiogenesis through the Notch1 signaling pathway. Microvasc Res 2022; 140:104308. [PMID: 34995552 DOI: 10.1016/j.mvr.2021.104308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 11/30/2022]
Abstract
Intrauterine growth restriction (IUGR) is associated with increased perinatal mortality and morbidity, and plays an important role in the development of adult cardiovascular diseases. This study brings forward a hypothesis that Human umbilical vein endothelial cells (HUVECs) from IUGR newborns present dysfunctions and varying changes of signaling pathways as compared to the Control group. Similar pathways may also be present in pulmonary or systemic vasculatures. HUVECs were derived from newborns. There were three groups according to the different fetal origins: normal newborns (Control), IUGR from poor maternal nutrition (IUGR1), and pregnancy-induced hypertension (IUGR2). We found that IUGR-derived HUVECs showed a proliferative phenotype compared to those from normal subjects. Interestingly, two types IUGR could cause varying degrees of cellular dysfunction. Meanwhile, the Notch1 signaling pathway showed enhanced activation in the two IUGR-induced HUVECs, with subsequent activation of Akt or extracellular signal regulated protein kinases1/2 (ERK1/2). Pharmacological inhibition or gene silencing of Notch1 impeded the proliferative phenotype of IUGR-induced HUVECs and reduced the activation of ERK1/2 and AKT. In summary, elevated Notch1 levels might play a crucial role in IUGR-induced HUVECs disorders through the activation of ERK1/2 and AKT. These pathways could be potential therapeutic targets for prevention of the progression of IUGR associated diseases later in life.
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Affiliation(s)
- Min Li
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang, China
| | - Zhiqun Zhang
- Department of Neonatology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, China
| | - Jyotsnav Joynauth
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang, China
| | - Xueqin Zhan
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang, China
| | - Lizhong Du
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang, China.
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17
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Tian C, Li D, Fu J. Molecular Mechanism of Caffeine in Preventing Bronchopulmonary Dysplasia in Premature Infants. Front Pediatr 2022; 10:902437. [PMID: 35795332 PMCID: PMC9251307 DOI: 10.3389/fped.2022.902437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/31/2022] [Indexed: 11/24/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic respiratory complication commonly seen in premature infants. Following continuous advances in neonatal intensive care diagnosis and treatment technology, an increasing number of premature babies are being treated successfully. Despite these remarkable improvements, there has been no significant decline in the incidence of BPD; in fact, its incidence has increased as more extremely preterm infants survive. Therefore, in view of the impact of BPD on the physical and mental health of children and the increased familial and social burden on these children, early prevention of BPD is emphasized. In recent decades, the clinical application of caffeine in treating primary apnea in premature infants was shown not only to stimulate the respiratory center but also to confer obvious protection to the nervous and respiratory systems. Numerous clinical cross-sectional and longitudinal studies have shown that caffeine plays a significant role in the prevention and treatment of BPD, but there is a lack of overall understanding of its potential molecular mechanisms. In this review, we summarize the possible molecular mechanisms of caffeine in the prevention or treatment of BPD, aiming to better guide its clinical application.
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Affiliation(s)
- Congliang Tian
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Department of Pediatrics, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Danni Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianhua Fu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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18
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Jin R, Gao Q, Yin C, Zou M, Lu K, Liu W, Zhu Y, Zhang M, Cheng R. The CD146-HIF-1α axis regulates epithelial cell migration and alveolar maturation in a mouse model of bronchopulmonary dysplasia. J Transl Med 2022; 102:794-804. [PMID: 35306530 PMCID: PMC9309096 DOI: 10.1038/s41374-022-00773-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 02/12/2022] [Accepted: 02/13/2022] [Indexed: 11/09/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common challenge in preterm neonates. Retardation of alveolar development characterizes the pulmonary pathology in BPD. In the present study, we explored the roles of the CD146-HIF-1α axis in BPD. We demonstrated that the levels of reactive oxygen species (ROS) and soluble CD146 (sCD1146) were increased in the peripheral blood of preterm neonates with BPD. In alveolar epithelial cells, hyperoxia promoted the expression of HIF-1α and CD146, which reinforced each other. In a mouse model of BPD, by exposing pups to 65% hyperoxia, HIF-1α and CD146 were increased in the pulmonary tissues. Mechanistically, CD146 hindered the migration of alveolar epithelial cells; in contrast, movement was significantly enhanced in CD146-knockout alveolar epithelial cells. As expected, CD146-knockout ameliorated alveolarization and improved BPD disease severity. Taken together, our findings imply that the CD146-HIF-1α axis contributes to alveolarization and that CD146 may be a novel candidate in BPD therapy.
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Affiliation(s)
- Rui Jin
- grid.452511.6Department of Neonatal Medical Center, Children’s Hospital of Nanjing Medical University, Nanjing, China ,Department of Neonatal Medical Center, Lianyungang Maternal and Child Health Hospital, Lianyungang, China
| | - Qianqian Gao
- grid.452511.6Department of Neonatal Medical Center, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Chunyu Yin
- grid.452511.6Department of Neonatal Medical Center, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Mengjia Zou
- grid.452511.6Department of Neonatal Medical Center, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Keyu Lu
- grid.452511.6Department of Neonatal Medical Center, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Liu
- grid.89957.3a0000 0000 9255 8984Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China ,grid.89957.3a0000 0000 9255 8984NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, Nanjing, China
| | - Yuting Zhu
- Department of Neonatology, The Affiliated Wuxi Children’s Hospital of Nanjing Medical University, Wuxi, China
| | - Mingshun Zhang
- Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China. .,NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, Nanjing, China.
| | - Rui Cheng
- Department of Neonatal Medical Center, Children's Hospital of Nanjing Medical University, Nanjing, China.
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19
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Suciu LM, Giesinger RE, Mărginean C, Muntean M, Cucerea M, Făgărășan A, McNamara P. Comparative evaluation of echocardiography indices during the transition to extrauterine life between small and appropriate for gestational age infants. Front Pediatr 2022; 10:1045242. [PMID: 36727000 PMCID: PMC9884809 DOI: 10.3389/fped.2022.1045242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVES To study changes in heart function and hemodynamics during the transitional period in small for gestational (SGA) infants and appropriate (AGA) healthier counterparts. DESIGN A hospital based prospective observational study was performed at a perinatal center. Echocardiograms were performed on the first postnatal day and again at 48 h age. Term SGA infants were compared with those AGA newborns matched for the GA and mode of delivery. RESULTS Eighteen SGA infants were compared with 18 AGA infants [gestation 38 ± 1.5 vs. 38 ± 1.2 weeks, p > 0.05 and birthweight 2331 ± 345 vs. 3332 ± 405 grams, p < 0.05, respectively]. Maternal weight and body mass index was higher among non-affected pregnancies, 61% infants were born vaginally, and no differences in cord blood pH at birth were noted. SGA infants had higher systolic and mean blood pressure at both time points, lower indices of right ventricular (RV) performance [TAPSE (tricuspid annular peak systolic excursion) 7.4 ± 2.8 vs. 9.3 ± 0.7 on day 1, 7.2 ± 2.8 vs. 9.2 ± 0.5 on day 2, p = 0.001], lower pulmonary acceleration time (PAAT) suggestive of elevated pulmonary vascular resistance [56.4 ± 10.5 vs. 65.7 ± 13.2 on day 1, 61.4 ± 12.5 vs. 71.5 ± 15.7 on day 2, p = 0.01] and higher left ventricular (LV) ejection fraction [62.1 ± 7.8 vs. 54.9 ± 5.5 on day 1, 61.9 ± 7.6 vs. 55.8 ± 4.9 on day 2, p = 0.003]. CONCLUSIONS SGA infants had evidence of higher pulmonary vascular resistance, and lower RV performance during the postnatal transition. The relevance and impact of these changes to hemodynamic disease states during the postnatal transition requires prospective investigation.
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Affiliation(s)
- Laura Mihaela Suciu
- Department of Pediatrics, University of Medicine Pharmacy Science and Technology George Emil Palade of Târgu Mureș, Târgu Mureș, Romania
| | - Regan E Giesinger
- Division of Neonatology, Department of Pediatrics, University of Iowa Stead Family Children's Hospital, Iowa, IA, United States
| | - Claudiu Mărginean
- Department of Obstetrics and Gynecology, University of Medicine Pharmacy Science and Technology George Emil Palade of Târgu Mureș, Târgu Mureș, Romania
| | - Mihai Muntean
- Department of Obstetrics and Gynecology, University of Medicine Pharmacy Science and Technology George Emil Palade of Târgu Mureș, Târgu Mureș, Romania
| | - Manuela Cucerea
- Department of Pediatrics, University of Medicine Pharmacy Science and Technology George Emil Palade of Târgu Mureș, Târgu Mureș, Romania
| | - Amalia Făgărășan
- Department of Pediatrics, University of Medicine Pharmacy Science and Technology George Emil Palade of Târgu Mureș, Târgu Mureș, Romania
| | - Patrick McNamara
- Division of Neonatology, Department of Pediatrics, University of Iowa Stead Family Children's Hospital, Iowa, IA, United States
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20
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Yao Q, Shen QL, Huang GY, Hu XH. Relationship between bronchopulmonary dysplasia phenotypes with high-resolution computed tomography score in early preterm infants. Front Pediatr 2022; 10:935733. [PMID: 36204662 PMCID: PMC9530466 DOI: 10.3389/fped.2022.935733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/15/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To assess the relationship between high-resolution computed tomography (HRCT) abnormalities and clinical phenotypes of bronchopulmonary dysplasia (BPD). METHODS A retrospective, single-center study was carried out at the Children's Hospital of Fudan University between 2013 and 2020. Preterm infants born at ≤ 32 weeks' gestation who were diagnosed with BPD and had HRCT between 40 and 50 weeks postmenstrual age (PMA)were included in the study. HRCT images from six pulmonary lobes were scored based on seven types of pulmonary lesions from two categories: hyperaeration lesions and parenchymal lesions. The hyperaeration score (HS) included scores of decreased attenuation, mosaic attenuation, and bulla/bleb, while the parenchymal score (PS) included those of linear lesion, consolidation, bronchial wall thickening, and bronchiectasis. All seven scores were summed up to create the total score (TS). One-way ANOVA testing or Kruskal-Wallis testing was adopted for the comparison of HRCT scores with BPD severity and clinical phenotypes. The correlation between HRCT scores and clinical phenotypes was evaluated by Spearman's correlation analysis. RESULTS A total of 81 cases were included in the study. Cases with more severe BPD had a higher TS (p = 0.01), HS (p = 0.02), PS (p = 0.02), mosaic attenuation score (p = 0.03), bulla/Bleb score (p = 0.03), and linear density score (p = 0.01). TS (r = 0.28), PS (r = 0.35), linear density (r = 0.34), and consolidation (r = 0.24) were correlated with pulmonary hypertension (PH). However, no HRCT score was significantly different between the patients with or without tracheobronchomalacia (TBM). BPD patients with a combination of lung parenchymal disease, PH, and TBM had the highest TS and HS. CONCLUSION HRCT scores correlated with BPD severity and PH in our study. HS might be a useful tool in the assessment of BPD severity while linear densities and consolidation might be helpful in predicting PH.
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Affiliation(s)
- Qiong Yao
- Department of Radiology, Children's Hospital of Fudan University, Shanghai, China
| | - Quan-Li Shen
- Department of Radiology, Children's Hospital of Fudan University, Shanghai, China
| | - Guo-Ying Huang
- Cardiac Center, Children's Hospital of Fudan University, Shanghai, China
| | - Xi-Hong Hu
- Department of Radiology, Children's Hospital of Fudan University, Shanghai, China
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21
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The value of early echocardiographic parameters to predict late pulmonary hypertension in extreme premature infants. PROGRESS IN PEDIATRIC CARDIOLOGY 2021. [DOI: 10.1016/j.ppedcard.2021.101402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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22
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Malnutrition, poor post-natal growth, intestinal dysbiosis and the developing lung. J Perinatol 2021; 41:1797-1810. [PMID: 33057133 DOI: 10.1038/s41372-020-00858-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/07/2020] [Accepted: 09/26/2020] [Indexed: 01/31/2023]
Abstract
In extremely preterm infants, poor post-natal growth, intestinal dysbiosis and bronchopulmonary dysplasia are common, and each is associated with long-term complications. The central hypothesis that this review will address is that these three common conditions are interrelated. Challenges to studying this hypothesis include the understanding that malnutrition and poor post-natal growth are not synonymous and that there is not agreement on what constitutes a normal intestinal microbiota in this evolutionarily new population. If this hypothesis is supported, further study of whether "correcting" intestinal dysbiosis in extremely preterm infants reduces postnatal growth restriction and/or bronchopulmonary dysplasia is indicated.
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23
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Early pulmonary hypertension is a risk factor for bronchopulmonary dysplasia-associated late pulmonary hypertension in extremely preterm infants. Sci Rep 2021; 11:11206. [PMID: 34045608 PMCID: PMC8160152 DOI: 10.1038/s41598-021-90769-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/13/2021] [Indexed: 11/23/2022] Open
Abstract
This study evaluated whether early pulmonary hypertension (PH) in extremely preterm infants (EPIs) at 22–27 weeks of gestation detected clinically with echocardiography at 4–7 postnatal days (PND) is a risk factor for death before 36 weeks post-menstrual age (PMA) or late PH in moderate or severe (m/s) bronchopulmonary dysplasia (BPD) (BPD-PH). We analyzed risk factors for death before 36 weeks PMA or BPD-PH. Among 247 EPIs enrolled, 74 (30.0%) had early PH. Twenty-one (28.4%) infants with early PH and 18 (10.4%) without early PH died before 36 weeks PMA; 14 (18.9%) infants with early PH and 9 (5.2%) without early PH had BPD-PH at 36–38 weeks PMA. Multivariate analysis revealed that early PH (adjusted odds ratio, 6.55; 95% confidence interval, 3.10–13.82, P < 0.05), clinical chorioamnionitis (2.50; 1.18–5.31), intraventricular hemorrhage (grade 3–4) (3.43; 1.26–9.37), and late sepsis (6.76; 3.20–14.28) independently increased the risk of development of death before 36 weeks PMA or BPD-PH. Subgroup analysis among m/s BPD patients revealed that early PH (4.50; 1.61–12.58) and prolonged invasive ventilator care (> 28 days) (4.91; 1.02–23.68) increased the risk for late PH independently. In conclusion, EPIs with early PH at 4–7 PND should be monitored for BPD-associated late PH development.
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24
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Children with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension Treated with Pulmonary Vasodilators-The Pediatric Cardiologist Point of View. CHILDREN-BASEL 2021; 8:children8050326. [PMID: 33922327 PMCID: PMC8145230 DOI: 10.3390/children8050326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/13/2021] [Accepted: 04/19/2021] [Indexed: 11/17/2022]
Abstract
Pulmonary hypertension in children with bronchopulmonary dysplasia (BPD-PH) significantly worsens the prognosis. Pulmonary vasodilators are often used in BPD-PH but the short-term outcome of treatment is not well described. The aim of this study was to evaluate BPD-PH children diagnosed beyond 36 weeks postmenstrual age treated with pulmonary vasodilators (sildenafil, bosentan, or both) and to assess the short and long-term effect of oral pulmonary vasodilators treatment. Twenty patients were included in the study. Cardiology evaluation (WHO-FC, NTproBNP, oxygen saturation, pulmonary to systemic pressure ratio PAP/SAP) was performed at diagnosis and after treatment initiation. In the majority of patients improvement in all evaluated factors was observed. No side effects of vasodilators were observed. PH resolved in 10 patients after a mean of 21.4 months of treatment. Six patients died. The number of poor prognostic factors commonly used to assess patients with pulmonary arterial hypertension (PAH) decreased significantly during BPD-PH treatment. The influence of BPD-PH perinatal risk factors on prognosis was considered but was not confirmed. In conclusion, the treatment of BPD-PH with pulmonary vasodilators was well tolerated and led to a clinical improvement with the possibility of discontinuation without recurrence of PH. Prognostic factors used in pediatric PAH risk stratification also seem to be useful in assessing treatment efficacy and prognosis in patients with BPD-PH.
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25
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Varghese NP, Tillman RH, Keller RL. Pulmonary hypertension is an important co-morbidity in developmental lung diseases of infancy: Bronchopulmonary dysplasia and congenital diaphragmatic hernia. Pediatr Pulmonol 2021; 56:670-677. [PMID: 33561308 DOI: 10.1002/ppul.25258] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/30/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
Bronchopulmonary dysplasia (BPD) following preterm birth and congenital diaphragmatic hernia (CDH) are both forms of developmental lung disease that may result in persistent pulmonary and pulmonary vascular morbidity in childhood. The pulmonary vascular disease (PVD) which accompanies BPD and CDH is due to developmental abnormalities and ongoing perinatal insults. This may be accompanied by evidence of elevated right heart pressures and pulmonary vascular resistance, leading to diagnosis of pulmonary hypertension (PH). The development of PH in these conditions is associated with increased morbidity and mortality in the vulnerable BPD and CDH populations. We present a review of PVD pathogenesis and evaluation in BPD and CDH and discuss management of related sequelae of PH co-morbidity for affected infants.
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Affiliation(s)
| | - Robert H Tillman
- Pediatric Pulmonary Medicine, Atrium Health, Levine Children's Hospital, Charlotte, North Carolina, USA
| | - Roberta L Keller
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
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26
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Yan L, Ren Z, Wang J, Xia X, Yang L, Miao J, Xu F, Gao W, Yang J. The Correlation Between Bronchopulmonary Dysplasia and Platelet Metabolism in Preterm Infants. Front Pediatr 2021; 9:670469. [PMID: 34900853 PMCID: PMC8652141 DOI: 10.3389/fped.2021.670469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 10/04/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Platelets play an important role in the formation of pulmonary blood vessels, and thrombocytopenia is common in patients with pulmonary diseases. However, a few studies have reported on the role of platelets in bronchopulmonary dysplasia. Objective: The objective of the study was to explore the relationship between platelet metabolism and bronchopulmonary dysplasia in premature infants. Methods: A prospective case-control study was performed in a cohort of premature infants (born with a gestational age <32 weeks and a birth weight <1,500 g) from June 1, 2017 to June 1, 2018. Subjects were stratified into two groups according to the diagnostic of bronchopulmonary dysplasia: with bronchopulmonary dysplasia (BPD group) and without bronchopulmonary dysplasia (control group). Platelet count, circulating megakaryocyte count (MK), platelet-activating markers (CD62P and CD63), and thrombopoietin (TPO) were recorded and compared in two groups 28 days after birth; then serial thrombopoietin levels and concomitant platelet counts were measured in infants with BPD. Results: A total of 252 premature infants were included in this study. Forty-eight premature infants developed BPD, 48 premature infants without BPD in the control group who were matched against the study infants for gestational age, birth weight, and admission diagnosis at the age of postnatal day 28. Compared with the controls, infants with BPD had significantly lower peripheral platelet count [BPD vs. controls: 180.3 (24.2) × 109/L vs. 345.6 (28.5) × 109/L, p = 0.001]. Circulating MK count in the BPD group was significantly more abundant than that in the control group [BPD vs. controls: 30.7 (4.5)/ml vs. 13.3 (2.6)/ml, p = 0.025]. The level of CD62p, CD63, and TPO in BPD group was significantly higher than the control group [29.7 (3.1%) vs. 14.5 (2.5%), 15.4 (2.0%) vs. 5.8 (1.7%), 301.4 (25.9) pg/ml vs. 120.4 (14.2) pg/ml, all p < 0.05]. Furthermore, the concentration of TPO was negatively correlated with platelet count in BPD group with thrombocytopenia. Conclusions: Our findings suggest that platelet metabolism is involved in the development of BPD in preterm infants. The possible mechanism might be through increased platelet activation and promoted TPO production by feedback.
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Affiliation(s)
- Longli Yan
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhuxiao Ren
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianlan Wang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xin Xia
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Liling Yang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jiayu Miao
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fang Xu
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Weiwei Gao
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jie Yang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
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27
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Greenough A, Decobert F, Field D, Hallman M, Hummler HD, Jonsson B, Sánchez Luna M, Van Overmeire B, Carnielli VP, Potenziano JL, Mercier JC. Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial. J Perinat Med 2020; 49:104-110. [PMID: 32892178 DOI: 10.1515/jpm-2020-0164] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/08/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.
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Affiliation(s)
| | | | - David Field
- University of Leicester Centre for Medicine, Leicester, UK
| | - Mikko Hallman
- University of Oulu and Oulu University Hospital, Oulu, Finland
| | | | - Baldvin Jonsson
- Karolinska University Hospital and Institute, Stockholm, Sweden
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28
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Gisondo CM, Donn SM. <p>Bronchopulmonary Dysplasia: An Overview</p>. RESEARCH AND REPORTS IN NEONATOLOGY 2020. [DOI: 10.2147/rrn.s271255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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29
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Mesenchymal stem/stromal cells stably transduced with an inhibitor of CC chemokine ligand 2 ameliorate bronchopulmonary dysplasia and pulmonary hypertension. Cytotherapy 2020; 22:180-192. [PMID: 32139242 DOI: 10.1016/j.jcyt.2020.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/21/2020] [Accepted: 01/22/2020] [Indexed: 12/20/2022]
Abstract
Perinatal bronchopulmonary dysplasia (BPD) is defined as lung injury in preterm infants caused by various factors, resulting in serious respiratory dysfunction and high mortality. The administration of mesenchymal stem/stromal cells (MSCs) to treat/prevent BPD has proven to have certain therapeutic effects. However, MSCs can only weakly regulate macrophage function, which is strongly involved in the development of BPD. 7ND-MSCs are MSCs transfected with 7ND, a truncated version of CC chemokine ligand 2 (CCL2) that promotes macrophage activation, using a lentiviral vector. In the present study, we show in a BPD rat model that 7ND-MSC administration, but not MSCs alone, ameliorated the impaired alveolarization evaluated by volume density and surface area in the lung tissue, as well as pulmonary artery remodeling and pulmonary hypertension induced by BPD. In addition, 7ND-MSCs, but not MSCs alone, reduced M1 macrophages and the messenger RNA expressions of interleukin-6 and CCL2 in the lung tissue. Thus, the present study showed the treatment effect of 7ND-MSCs in a BPD rat model, which was more effective than that of MSCs alone.
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30
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Moreira A, Winter C, Joy J, Winter L, Jones M, Noronha M, Porter M, Quim K, Corral A, Alayli Y, Seno T, Mustafa S, Hornsby P, Ahuja S. Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia. Stem Cells Transl Med 2020; 9:221-234. [PMID: 31774626 PMCID: PMC6988765 DOI: 10.1002/sctm.18-0273] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 09/24/2019] [Indexed: 12/12/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a devastating lung condition that develops in premature newborns exposed to prolonged mechanical ventilation and supplemental oxygen. Significant morbidity and mortality are associated with this costly disease and effective therapies are limited. Mesenchymal stem/stromal cells (MSCs) are multipotent cells that can repair injured tissue by secreting paracrine factors known to restore the function and integrity of injured lung epithelium and endothelium. Most preclinical studies showing therapeutic efficacy of MSCs for BPD are administered either intratracheally or intravenously. The purpose of this study was to examine the feasibility and effectiveness of human cord tissue-derived MSC administration given via the intranasal route. Human umbilical cord tissue MSCs were isolated, characterized, and given intranasally (500 000 cells per 20 μL) to a hyperoxia-induced rat model of BPD. Lung alveolarization, vascularization, and pulmonary vascular remodeling were restored in animals receiving MSC treatment. Gene and protein analysis suggest the beneficial effects of MSCs were attributed, in part, to a concerted effort targeting angiogenesis, immunomodulation, wound healing, and cell survival. These findings are clinically significant, as neonates who develop BPD have altered alveolar development, decreased pulmonary vascularization and chronic inflammation, all resulting in impaired tissue healing. Our study is the first to report the intranasal delivery of umbilical cord Wharton's jelly MSCs in experimental BPD is feasible, noninvasive, and an effective route that may bear clinical applicability.
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Affiliation(s)
- Alvaro Moreira
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Caitlyn Winter
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Jooby Joy
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Lauryn Winter
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Maxwell Jones
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Michelle Noronha
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Melissa Porter
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Kayla Quim
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Alexis Corral
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Yasmeen Alayli
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Tyrelle Seno
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Shamimunisa Mustafa
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Peter Hornsby
- Department of Pediatrics, Cellular and Integrative PhysiologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
| | - Sunil Ahuja
- Microbiology and ImmunologyUniversity of Texas Health Science Center San Antonio (UTHSCSA)San AntonioTexas
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Chen LL, Zmuda EJ, Talavera MM, Frick J, Brock GN, Liu Y, Klebanoff MA, Trittmann JK. Dual-specificity phosphatase (DUSP) genetic variants predict pulmonary hypertension in patients with bronchopulmonary dysplasia. Pediatr Res 2020; 87:81-87. [PMID: 31330530 PMCID: PMC6962530 DOI: 10.1038/s41390-019-0502-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/10/2019] [Accepted: 07/10/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND Pulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD. METHODS Preterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve. RESULTS In our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76. CONCLUSION We identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.
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Affiliation(s)
- Lauren L Chen
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Erik J Zmuda
- Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Maria M Talavera
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Pulmonary Hypertension Group, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Jessica Frick
- Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Guy N Brock
- Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Yusen Liu
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Pulmonary Hypertension Group, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Mark A Klebanoff
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Pulmonary Hypertension Group, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Jennifer K Trittmann
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
- Pulmonary Hypertension Group, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
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32
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Yan L, Wang Y, Zhang Z, Xu S, Ullah R, Luo X, Xu X, Ma X, Chen Z, Zhang L, Lv Y, Du L. Postnatal delayed growth impacts cognition but rescues programmed impaired pulmonary vascular development in an IUGR rat model. Nutr Metab Cardiovasc Dis 2019; 29:1418-1428. [PMID: 31653519 DOI: 10.1016/j.numecd.2019.08.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/19/2019] [Accepted: 08/23/2019] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied. METHODS AND RESULTS We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group. CONCLUSION These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR.
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Affiliation(s)
- LingLing Yan
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Wang
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - ZiMing Zhang
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - ShanShan Xu
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Rahim Ullah
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - XiaoFei Luo
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - XueFeng Xu
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - XiaoLu Ma
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zheng Chen
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - LiYan Zhang
- Fujian University of Medicine, NICU, Fuzhou Children's Hospital of Fujian Province, Fuzhou, 350005, Fujian Province, China
| | - Ying Lv
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - LiZhong Du
- Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.
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Bui CB, Kolodziej M, Lamanna E, Elgass K, Sehgal A, Rudloff I, Schwenke DO, Tsuchimochi H, Kroon MAGM, Cho SX, Maksimenko A, Cholewa M, Berger PJ, Young MJ, Bourke JE, Pearson JT, Nold MF, Nold-Petry CA. Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension. Front Immunol 2019; 10:1480. [PMID: 31354700 PMCID: PMC6637286 DOI: 10.3389/fimmu.2019.01480] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
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.
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Affiliation(s)
- Christine B Bui
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | | | - Emma Lamanna
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Kirstin Elgass
- Monash Micro Imaging, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Arvind Sehgal
- Department of Paediatrics, Monash University, Clayton, VIC, Australia.,Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia
| | - Ina Rudloff
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Daryl O Schwenke
- Department of Physiology-Heart Otago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Hirotsugu Tsuchimochi
- Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Maurice A G M Kroon
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.,Department of Pharmacy, Amsterdam UMC, Amsterdam, Netherlands
| | - Steven X Cho
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Anton Maksimenko
- Imaging and Medical Beamline, Australian Synchrotron, Clayton, VIC, Australia
| | - Marian Cholewa
- Centre for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, Rzeszow, Poland
| | - Philip J Berger
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Morag J Young
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Jane E Bourke
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - James T Pearson
- Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.,Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Marcel F Nold
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Claudia A Nold-Petry
- Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Paediatrics, Monash University, Clayton, VIC, Australia
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Neonatal hematological parameters and the risk of moderate-severe bronchopulmonary dysplasia in extremely premature infants. BMC Pediatr 2019; 19:138. [PMID: 31039810 PMCID: PMC6489335 DOI: 10.1186/s12887-019-1515-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 04/18/2019] [Indexed: 11/14/2022] Open
Abstract
Objective To evaluate the association between hematological parameters at birth and the risk of moderate-severe bronchopulmonary dysplasia (BPD) in a cohort of extremely preterm infants. Methods This is a retrospective study of all extremely premature infants admitted to the neonatal intensive care unit, Shenzhen Maternity and Child Healthcare Hospital from January 2016 to May 2018. Extremely prematurity was defined as a delivery at a gestational age ≤ 28 weeks or a birth weight ≤ 1000 g. BPD was diagnosed if oxygen exposure exceeded 28 days and the severity was decided at 36 weeks PMA or discharge. Multivariable analysis was performed to assess the independence of the association between hematological parameters at birth and risk of moderate or severe BPD. Results A total of 115 extremely premature infants were analyzed in this study. The median platelet count, neutrophil and monocyte count at birth were significantly higher in infants with moderate-severe BPD compared to infants without BPD (228 vs 194*109/l, P = 0.004; 5.0 vs 2.95*109/l, P = 0.023; 0.88 vs 0.63*109/l, P = 0.026, respectively) whereas the mean platelet volume was significantly lower in infants with moderate-severe BPD than those without BPD (9.1 vs 9.4 fl, P = 0.002). After adjusting for covariates, the risk of moderate-severe BPD was independently associated with platelet count≥207*109/l (odds ratio 3.794, 95% confidence interval: 1.742–8.266, P = 0.001). Conclusion Our findings suggest that hematologic parameters at birth are different in extremely preterm infants who will develop moderate-severe BPD. A higher platelet count at birth may increase the risk of moderate-severe BPD after extremely premature birth.
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35
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MacKenzie K, Cunningham K, Thomas S, Mondal T, El Helou S, Shah PS, Mukerji A. Incidence, risk factors, and outcomes of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Paediatr Child Health 2019; 25:222-227. [PMID: 32549737 DOI: 10.1093/pch/pxz024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 01/03/2019] [Indexed: 11/13/2022] Open
Abstract
Objectives To determine the incidence and risk factors for pulmonary hypertension (PH) in preterm infants with moderate to severe bronchopulmonary dysplasia (BPD) and to compare short-term outcomes. Methods Preterm infants <32 weeks gestation born August 2013 through July 2015 with moderate to severe BPD at 36 weeks postmenstrual age were categorized into BPD-PH (exposure) and BPD-noPH (control) groups. Results Of 92 infants with BPD, 87 had echocardiographic assessment, of whom 24 (28%) had PH. On multiple logistic regression after adjustment for gestational age and sex, no significant risk factors for PH were identified based on data from this cohort. There were no differences in resource utilization or clinical outcomes including survival to discharge. Conclusion Approximately one out of four patients with moderate to severe BPD were identified as having PH. No significant risk factors for PH were identified. No differences in outcomes were identified for those with and without PH.
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Affiliation(s)
| | - Kathy Cunningham
- Department of Pediatrics, McMaster University, Hamilton, Ontario
| | - Sumesh Thomas
- Department of Pediatrics, University of Calgary, Calgary, Alberta
| | - Tapas Mondal
- Department of Pediatrics, McMaster University, Hamilton, Ontario
| | - Salhab El Helou
- Department of Pediatrics, McMaster University, Hamilton, Ontario
| | - Prakesh S Shah
- Department of Pediatrics, University of Toronto, Toronto, Ontario
| | - Amit Mukerji
- Department of Pediatrics, McMaster University, Hamilton, Ontario
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36
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Leary S, Das P, Ponnalagu D, Singh H, Bhandari V. Genetic Strain and Sex Differences in a Hyperoxia-Induced Mouse Model of Varying Severity of Bronchopulmonary Dysplasia. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:999-1014. [PMID: 30794808 DOI: 10.1016/j.ajpath.2019.01.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 12/21/2018] [Accepted: 01/24/2019] [Indexed: 01/11/2023]
Abstract
Bronchopulmonary dysplasia (BPD) is a disease prevalent in preterm babies with a need for supplemental oxygen, resulting in impaired lung development and dysregulated vascularization. Epidemiologic studies have shown that males are more prone to BPD and have a delayed recovery compared with females, for reasons unknown. Herein, we tried to recapitulate mild, moderate, and severe BPD, using two different strains of mice, in males and females: CD1 (outbred) and C57BL/6 (inbred). Aside from higher body weight in the CD1 strain, there were no other gross morphologic differences with respect to alveolar development between the two strains. With respect to lung morphology after oxygen exposure, females had less injury with better preservation of alveolar chord length and decreased alveolar protein leak and inflammatory cells in the bronchoalveolar lavage fluid. In addition, housekeeping genes, which are routinely used as loading controls, were expressed differently in males and females. In the BPD mouse model, gonadotropin-releasing hormone was increased in females compared with males. Specific miRNAs (miR-146 and miR-34a) were expressed differently in the sexes. In the severe BPD mouse model, administering miR-146 mimic to males attenuated lung damage, whereas administering miR-146 inhibitor to females increased pulmonary injury.
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Affiliation(s)
- Sean Leary
- Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Pragnya Das
- Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Devasena Ponnalagu
- Department of Pharmacology, Physiology and Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Harpreet Singh
- Department of Pharmacology, Physiology and Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Vineet Bhandari
- Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania; Division of Neonatology, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.
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37
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Li J, Shi J, Li P, Guo X, Wang T, Liu A. Genipin attenuates hyperoxia-induced lung injury and pulmonary hypertension via targeting glycogen synthase kinase-3 β in neonatal rats. Nutrition 2019; 57:237-244. [DOI: 10.1016/j.nut.2018.05.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 05/06/2018] [Accepted: 05/25/2018] [Indexed: 12/18/2022]
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Trittmann JK, Bartenschlag A, Zmuda EJ, Frick J, Stewart WCL, Nelin LD. Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia. Acta Paediatr 2018; 107:2158-2164. [PMID: 30267614 PMCID: PMC6226353 DOI: 10.1111/apa.14600] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 08/28/2018] [Accepted: 09/25/2018] [Indexed: 02/03/2023]
Abstract
AIM Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase-1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414) genes has been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients. METHODS Bronchopulmonary dysplasia patients (n = 79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n = 20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data. RESULTS Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data were added to the genetic model, AUC was 0.73. CONCLUSION These findings demonstrate that ROC predictive modelling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia.
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Affiliation(s)
- J K Trittmann
- Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - A Bartenschlag
- Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - E J Zmuda
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - J Frick
- Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | - W C L Stewart
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Battelle Center for Mathematical Medicine, Columbus, OH, USA
| | - L D Nelin
- Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
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Qasim A, Dasgupta S, Aly AM, Jain SK. Sildenafil Use in the Treatment of Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: A Case Series. AJP Rep 2018; 8:e219-e222. [PMID: 30345157 PMCID: PMC6188884 DOI: 10.1055/s-0038-1673343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 04/18/2018] [Indexed: 11/02/2022] Open
Abstract
Objective This article studies the role of sildenafil in reducing myocardial stress (measured by serial N-terminal pro b-type natriuretic peptide [NTproBNP] levels) secondary to bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). Study Design This is a case series of three extremely low birth weight infants with severe BPD at 36 weeks' postmenstrual age. All infants had very elevated NTproBNP (> 2,000 ng/dL) levels and echocardiographic evidence of BPD-PH. Sildenafil was started and infants were followed up every 2 weeks clinically along with NTproBNP levels and echocardiograms. Results After 4 weeks of sildenafil treatment, NTproBNP levels decreased significantly in all infants, echocardiograms showed significant improvement in one infant, and respiratory severity score improved significantly in one infant. All infants tolerated sildenafil. Conclusion Sildenafil reduced NTproBNP levels in all infants with BPD-PH but the echocardiographic findings and respiratory scores did not improve consistently. We speculate that this may be due to a delay in diagnosis and initiation of therapy after irreversible pulmonary changes have set in.
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Affiliation(s)
- Amna Qasim
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | - Soham Dasgupta
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | - Ashraf M Aly
- Division of Pediatric Cardiology, University of Texas Medical Branch, Galveston, Texas
| | - Sunil K Jain
- Division of Neonatology, University of Texas Medical Branch, Galveston, Texas
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40
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Meyer N, Zenclussen AC. Mast cells-Good guys with a bad image? Am J Reprod Immunol 2018; 80:e13002. [DOI: 10.1111/aji.13002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022] Open
Affiliation(s)
- Nicole Meyer
- Experimental Obstetrics and Gynecology; Medical Faculty; Otto-von-Guericke University; Magdeburg Germany
| | - Ana Claudia Zenclussen
- Experimental Obstetrics and Gynecology; Medical Faculty; Otto-von-Guericke University; Magdeburg Germany
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41
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Zhong Y, Catheline D, Houeijeh A, Sharma D, Du L, Besengez C, Deruelle P, Legrand P, Storme L. Maternal omega-3 PUFA supplementation prevents hyperoxia-induced pulmonary hypertension in the offspring. Am J Physiol Lung Cell Mol Physiol 2018; 315:L116-L132. [PMID: 29597832 DOI: 10.1152/ajplung.00527.2017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 16-25% of premature infants with bronchopulmonary dysplasia (BPD), contributing significantly to perinatal morbidity and mortality. Omega-3 polyunsaturated fatty acids (PUFA ω-3) can improve vascular remodeling, angiogenesis, and inflammation under pathophysiological conditions. However, the effects of PUFA ω-3 supplementation in BPD-associated PH are unknown. The present study aimed to evaluate the effects of PUFA ω-3 on pulmonary vascular remodeling, angiogenesis, and inflammatory response in a hyperoxia-induced rat model of PH. From embryonic day 15, pregnant Sprague-Dawley rats were supplemented daily with PUFA ω-3, PUFA ω-6, or normal saline (0.2 ml/day). After birth, pups were pooled, assigned as 12 per litter, randomly assigned to either air or continuous oxygen exposure (fraction of inspired oxygen = 85%) for 20 days, and then euthanized for pulmonary hemodynamic and morphometric analysis. We found that PUFA ω-3 supplementation improved survival, decreased right ventricular systolic pressure and RVH caused by hyperoxia, and significantly improved alveolarization, vascular remodeling, and vascular density. PUFA ω-3 supplementation produced a higher level of total ω-3 in lung tissue and breast milk and was found to reverse the reduced levels of VEGFA, VEGF receptor 2, angiopoietin-1 (ANGPT1), endothelial TEK tyrosine kinase, endothelial nitric oxide synthase, and nitric oxide concentrations in lung tissue and the increased ANGPT2 levels in hyperoxia-exposed rats. The beneficial effects of PUFA ω-3 in improving lung injuries were also associated with an inhibition of leukocyte infiltration and reduced expression of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. These data indicate that maternal PUFA ω-3 supplementation strategies could effectively protect against infant PH induced by hyperoxia.
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Affiliation(s)
- Ying Zhong
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France.,Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine , Hangzhou , China
| | - Daniel Catheline
- Laboratoire de Biochimie et Nutrition Humaine, Institut National de la Recherche Agronomique USC 2012, Institut Supérieur des Sciences Agronomiques, Agroalimentaires, Horticoles et du Paysage, Rennes , France
| | - Ali Houeijeh
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France.,Department of Neonatology, Centre Hospitalier Régional Universitaire de Lille , Lille , France
| | - Dyuti Sharma
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France.,Department of Pediatric Surgery, Centre Hospitalier Régional Universitaire de Lille , Lille , France
| | - Lizhong Du
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine , Hangzhou , China
| | - Capucine Besengez
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France
| | - Philippe Deruelle
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France.,Department of Obstetrics and Gynecology, Centre Hospitalier Régional Universitaire de Lille , Lille , France
| | - Philippe Legrand
- Laboratoire de Biochimie et Nutrition Humaine, Institut National de la Recherche Agronomique USC 2012, Institut Supérieur des Sciences Agronomiques, Agroalimentaires, Horticoles et du Paysage, Rennes , France
| | - Laurent Storme
- Perinatal Environment and Health, UPRES EA 4489, Université de Lille, Centre Hospitalier Régional Universitaire de Lille , Lille , France.,Department of Neonatology, Centre Hospitalier Régional Universitaire de Lille , Lille , France
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42
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Hwang JS, Rehan VK. Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment. Lung 2018; 196:129-138. [PMID: 29374791 DOI: 10.1007/s00408-018-0084-z] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 01/04/2018] [Indexed: 12/16/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is potentially one of the most devastating conditions in premature infants with longstanding consequences involving multiple organ systems including adverse effects on pulmonary function and neurodevelopmental outcome. Here we review recent studies in the field to summarize the progress made in understanding in the pathophysiology, prognosis, prevention, and treatment of BPD in the last decade. The work reviewed includes the progress in understanding its pathobiology, genomic studies, ventilatory strategies, outcomes, and therapeutic interventions. We expect that this review will help guide clinicians to treat premature infants at risk for BPD better and lead researchers to initiate further studies in the field.
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Affiliation(s)
- Jung S Hwang
- Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, Torrance, CA, 90502, USA
| | - Virender K Rehan
- Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, Torrance, CA, 90502, USA.
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43
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Valencia AM, Abrantes MA, Hasan J, Aranda JV, Beharry KD. Reactive Oxygen Species, Biomarkers of Microvascular Maturation and Alveolarization, and Antioxidants in Oxidative Lung Injury. REACTIVE OXYGEN SPECIES (APEX, N.C.) 2018; 6:373-388. [PMID: 30533532 DOI: 10.20455/ros.2018.867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lungs of extremely low gestational age neonates (ELGANs) are deficient in pulmonary surfactant and are incapable of efficient gas exchange necessary for successful transition from a hypoxic intrauterine environment to ambient air. To improve gas exchange and survival, ELGANs often receive supplemental oxygen with mechanical ventilation which disrupts normal lung developmental processes, including microvascular maturation and alveolarization. Factors that regulate these developmental processes include vascular endothelial growth factor and matrix metalloproteinases, both of which are influenced by generation of oxygen byproducts, or reactive oxygen species (ROS). ELGANs are also deficient in antioxidants necessary to scavenge excessive ROS. Thus, the accumulation of ROS in the preterm lungs exposed to prolonged hyperoxia, results in inflammation and development of bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). Despite advances in neonatal care, BPD/CLD remains a major cause of neonatal morbidity and mortality. The underlying mechanisms are not completely understood, and the benefits of current therapeutic interventions are limited. The association between ROS and biomarkers of microvascular maturation and alveolarization, as well as antioxidant therapies in the setting of hyperoxia-induced neonatal lung injury are reviewed in this article.
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Affiliation(s)
- Arwin M Valencia
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saddleback Memorial Hospital, Laguna Hills, CA 92653, USA
| | - Maria A Abrantes
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Kaiser Permanente, Anaheim, CA 92806, USA
| | - Jamal Hasan
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Miller's Children's and Women's Hospital, Long Beach, CA 90806, USA
| | - Jacob V Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.,Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA
| | - Kay D Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.,Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA
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