Publications by authors named "Alan H Jobe"

313 Publications

Postnatal steroid management in preterm infants with evolving bronchopulmonary dysplasia.

J Perinatol 2021 May 19. Epub 2021 May 19.

Division of Neonatology, Department of Pediatrics, UH Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting extremely preterm infants. Although mechanical ventilation and oxygen requirements in premature infants are identified as inciting mechanisms for inflammation and the development of BPD over time, data now support an array of perinatal events that may stimulate the inflammatory cascade prior to delivery. Corticosteroids, such as dexamethasone and hydrocortisone, have proven beneficial for the prevention and management of BPD postnatally due to their anti-inflammatory characteristics. This review aims to examine the pharmacologic properties of several corticosteroids, appraise the existing evidence for postnatal corticosteroid use in preterm infants, and assess steroid management strategies to ameliorate BPD. Finally, we aim to provide guidance based on clinical experience for managing adrenal suppression resulting from prolonged steroid exposure since this is an area less well-studied.
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http://dx.doi.org/10.1038/s41372-021-01083-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133053PMC
May 2021

Chorioamnionitis induces hepatic inflammation and time-dependent changes of the enterohepatic circulation in the ovine fetus.

Sci Rep 2021 May 14;11(1):10331. Epub 2021 May 14.

Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200, MD, Maastricht, the Netherlands.

Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h - 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein.
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http://dx.doi.org/10.1038/s41598-021-89542-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121927PMC
May 2021

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

J Pharmacokinet Pharmacodyn 2021 Jun 5;48(3):411-438. Epub 2021 May 5.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, NY, USA.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC/SC to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.
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http://dx.doi.org/10.1007/s10928-021-09755-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099395PMC
June 2021

Neonatal Network Data Based‒Associations Based on Large Numbers that May Be Spurious.

Authors:
Alan H Jobe

J Pediatr 2021 Apr 13. Epub 2021 Apr 13.

Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.04.013DOI Listing
April 2021

An All-Inclusive Perspective on Bronchopulmonary Dysplasia.

J Pediatr 2021 Apr 1. Epub 2021 Apr 1.

University of Miami Miller School of Medicine Division of Neonatology, Miami, FL.

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http://dx.doi.org/10.1016/j.jpeds.2021.03.063DOI Listing
April 2021

Chapter for antenatal steroids - Treatment drift for a potent therapy with unknown long-term safety seminars in fetal and neonatal medicine.

Semin Fetal Neonatal Med 2021 Apr 19;26(2):101231. Epub 2021 Mar 19.

The University of Miami, Miller School of Medicine, Coral Gables, FL, 33124, USA. Electronic address:

This chapter on therapeutic drift with antenatal steroids will make the case that this pilar of treatment to improve the outcomes of preterm infants, despite multiple Randomized Control Trials (RCTs) and meta-analysis, has multiple gaps in solid clinical data to support any expanded use of Antenatal Corticosteroids (ACS). A basic problem is that agents used for ACS have never been evaluated to minimize fetal exposures. Based on the premise that all drug exposure to the fetus should be minimized and only used when necessary, ACS is a potent developmental modulator that has never been evaluated to minimize the dose and duration of fetal exposure. The use of ACS is expanding to late preterm infants where the benefit is modest, to elective C-sections, and periviable fetuses, with minimal RCT data of long-term benefit. Relevant animal experiments demonstrate that much lower doses will induce lung maturation in sheep and primates. Another area of drift in the use of ACS is based on the assumption that the old RCT data accurately predict the magnitude of benefit when ACS is used today with entirely different OB and neonatal care strategies to improve outcomes. We do not have data that demonstrate the effectiveness of ACS in very low resource environments, where most of the preterm mortality occurs. The final concern is the risk of ACS to the infant and child. Short-term risks are minimal but dysmaturation effects of ACS on multiple organ systems (lung, heart, brain, and kidney) may result in disease presentation in later life.
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http://dx.doi.org/10.1016/j.siny.2021.101231DOI Listing
April 2021

Commentary on the Truncated Splice Variant of the GM-CSF Receptor Beta-Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns.

Neonatology 2021 19;118(2):194-197. Epub 2021 Mar 19.

Department of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

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http://dx.doi.org/10.1159/000514639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178199PMC
March 2021

Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells.

Front Med (Lausanne) 2021 22;8:614239. Epub 2021 Feb 22.

Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.

Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.
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http://dx.doi.org/10.3389/fmed.2021.614239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937719PMC
February 2021

Baby's First Cries and Establishment of Gas Exchange in the Lung.

Am J Respir Crit Care Med 2021 Mar 8. Epub 2021 Mar 8.

Childrens Hospital Medical Center, Cincinnati, Ohio, United States.

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http://dx.doi.org/10.1164/rccm.202102-0308EDDOI Listing
March 2021

Intestinal Goblet Cell Loss during Chorioamnionitis in Fetal Lambs: Mechanistic Insights and Postnatal Implications.

Int J Mol Sci 2021 Feb 16;22(4). Epub 2021 Feb 16.

Department of Pediatrics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6202 AZ Maastricht, The Netherlands.

Chorioamnionitis, an important cause of preterm birth, is linked to necrotizing enterocolitis (NEC). NEC is characterized by a disrupted mucus barrier, goblet cell loss, and endoplasmic reticulum (ER) stress of the intestinal epithelium. These findings prompted us to investigate the mechanisms underlying goblet cell alterations over time in an ovine chorioamnionitis model. Fetal lambs were intra-amniotically (IA) exposed to lipopolysaccharides (LPS) for 5, 12, or 24 h, or 2, 4, 8, or 15 d before premature delivery at 125 d gestational age (GA). Gut inflammation, the number, distribution, and differentiation of goblet cells, ER stress, and apoptosis were measured. We found a biphasic reduction in goblet cell numbers 24 h-2 d after, and 15 d after IA LPS exposure. The second decrease of goblet cell numbers was preceded by intestinal inflammation, apoptosis, and crypt ER stress, and increased SAM-pointed domain-containing ETS transcription factor (SPDEF)-positive cell counts. Our combined findings indicated that ER stress drives apoptosis of maturating goblet cells during chorioamnionitis, ultimately reducing goblet cell numbers. As similar changes have been described in patients suffering from NEC, these findings are considered to be clinically important for understanding the predecessors of NEC, and targeting ER stress in this context is interesting for future therapeutics.
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http://dx.doi.org/10.3390/ijms22041946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920290PMC
February 2021

Lung Ultrasound in Early Preterm Life: A Window into the Future?

Am J Respir Crit Care Med 2021 Jun;203(11):1338-1339

Neonatology/Pulmonary Biology Cincinnati Children's Hospital Cincinnati, Ohio and.

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http://dx.doi.org/10.1164/rccm.202101-0091EDDOI Listing
June 2021

Surfactant therapy for COVID-19 related ARDS: a retrospective case-control pilot study.

Respir Res 2021 Jan 18;22(1):20. Epub 2021 Jan 18.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.

Background: COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established.

Methods: We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality.

Results: Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive.

Conclusions: Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.
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http://dx.doi.org/10.1186/s12931-020-01603-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812332PMC
January 2021

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

J Pharmacokinet Pharmacodyn 2021 Apr 3;48(2):261-272. Epub 2021 Jan 3.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University of Buffalo, Buffalo, NY, USA.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/F of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.
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http://dx.doi.org/10.1007/s10928-020-09730-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778726PMC
April 2021

Quality Improvement and Antenatal Steroids.

Authors:
Alan H Jobe

J Pediatr 2021 May 31;232:9-10. Epub 2020 Dec 31.

Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2020.12.073DOI Listing
May 2021

Prenatal inflammation enhances antenatal corticosteroid-induced fetal lung maturation.

JCI Insight 2020 12 17;5(24). Epub 2020 Dec 17.

Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Respiratory complicˆations are the major cause of morbidity and mortality among preterm infants, which is partially prevented by the administration of antenatal corticosteroids (ACS). Most very preterm infants are exposed to chorioamnionitis, but short- and long-term effects of ACS treatment in this setting are not well defined. In low-resource settings, ACS increased neonatal mortality by perhaps increasing infection. We report that treatment with low-dose ACS in the setting of inflammation induced by intraamniotic lipopolysaccharide (LPS) in rhesus macaques improves lung compliance and increases surfactant production relative to either exposure alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death via TP53. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes COL1A1, COL1A2, and COL3A1 and regulators of lung development FGF9 and FGF10. ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term gestation lung. Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a risk of abnormal extracellular matrix development, which may be associated with increased risk of chronic lung disease.
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http://dx.doi.org/10.1172/jci.insight.139452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819743PMC
December 2020

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide.

Pediatr Res 2020 Nov 11. Epub 2020 Nov 11.

School of Women's and Infants' Health, University of Western Australia, Perth, WA, 6009, Australia.

Background: Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS).

Methods: Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared.

Results: Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h.

Conclusions: In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation.

Impact: The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.
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http://dx.doi.org/10.1038/s41390-020-01267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657068PMC
November 2020

Antenatal corticosteroids: a reappraisal of the drug formulation and dose.

Pediatr Res 2021 01 11;89(2):318-325. Epub 2020 Nov 11.

Milad Pharmaceutical Consulting, Plymouth, MI, USA.

We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials. The treatment used in the United States is two intramuscular doses of a mixture of 6 mg betamethasone phosphate (Beta P) and 6 mg betamethasone acetate (Beta Ac). To optimize outcomes with ACS, the goal should be to minimize fetal drug exposure. We have determined that the minimum exposure needed for fetal lung maturation in sheep, monkeys, and humans (based on published cord blood corticosteroid concentrations) is about 1 ng/ml for a 48-h continuous exposure, far lower than the concentration reached by the current dosing. Because the slowly released Beta Ac results in prolonged fetal exposure, a drug containing Beta Ac is not ideal for ACS use. IMPACT: Using sheep and monkey models, we have defined the minimum corticosteroid exposure for a fetal lung maturation. These results should generate new clinical trials of antenatal corticosteroids (ACS) at much lower fetal exposures to ACS, possibly given orally, with fewer risks for the fetus.
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http://dx.doi.org/10.1038/s41390-020-01249-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892336PMC
January 2021

Chorioamnionitis induces changes in ovine pulmonary endogenous epithelial stem/progenitor cells in utero.

Pediatr Res 2020 Oct 18. Epub 2020 Oct 18.

Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.

Background: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools.

Methods: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied.

Results: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs.

Conclusions: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes.

Impact: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes.Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally.This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.
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http://dx.doi.org/10.1038/s41390-020-01204-9DOI Listing
October 2020

A striking result from antenatal exposure to N-acetylcysteine.

Authors:
Alan H Jobe

Pediatr Res 2021 01 21;89(1):14-15. Epub 2020 Sep 21.

Division of Neonatology and Pulmonary Biology, Perinatal Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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http://dx.doi.org/10.1038/s41390-020-01168-wDOI Listing
January 2021

Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function.

Am J Physiol Lung Cell Mol Physiol 2020 08 27;319(2):L239-L255. Epub 2020 May 27.

Perinatal Institute, Section of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene () from fetal pulmonary mesenchymal cells phenocopied defects caused by global deletion, while lung epithelial- or endothelial-specific deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFBs), in part by directly activating extracellular matrix-associated target genes, including , , and and by modulating VEGF, JAK-STAT, and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFBs, which in turn increased proliferation of SOX9+ alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT) and AT cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts, in turn, regulating signals controlling AT/AT progenitor cell proliferation and differentiation and identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.
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http://dx.doi.org/10.1152/ajplung.00459.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473939PMC
August 2020

Variability in the efficacy of a standardized antenatal steroid treatment was independent of maternal or fetal plasma drug levels: evidence from a sheep model of pregnancy.

Am J Obstet Gynecol 2020 12 21;223(6):921.e1-921.e10. Epub 2020 May 21.

Division of Obstetrics and Gynecology, the University of Western Australia, Perth, Western Australia, Australia; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan; School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia.

Background: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%. In some cases, antenatal steroid use is associated with limited benefit and potential harm.

Objective: We hypothesized that individual differences in maternofetal steroid exposure would contribute to observed variability in antenatal steroid treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between maternofetal steroid exposure and antenatal steroid treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation.

Study Design: Ewes carrying a single fetus underwent surgery to catheterize a fetal and maternal jugular vein at 119 days' gestation. Animals recovered for 24 hours before being randomized to either (1) a single maternal intramuscular injection of 2 mL saline (negative control group, n=10) or (2) a single maternal intramuscular injection of 0.25 mg/kg betamethasone phosphate plus acetate (antenatal steroid group, n=20). Serial maternal and fetal plasma samples were collected from each animal after 48 hours before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction.

Results: One animal from the control group and one animal from the antenatal steroid group did not complete their treatment protocol and were removed from analyses. Animals in the antenatal steroid group were divided into a responder subgroup (n=12/19) and a nonresponder subgroup (n=7/19) using a cutoff of partial pressure of arterial CO at 30-minute ventilation within 2 standard deviations of the mean value from saline-treated negative control group animals. Although antenatal steroid improved fetal lung maturation in the undivided antenatal steroid group and in the responder subgroup both physiologically (blood gas- and ventilation-related data) and biochemically (messenger ribonucleic acid expression related to fetal lung maturation), these values did not improve relative to saline-treated control group animals in the antenatal steroid nonresponder subgroup. No differences in betamethasone distribution, clearance, or protein binding were identified between the antenatal steroid responder and nonresponder subgroups.

Conclusion: This study correlated individual maternofetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation that was not significantly different to saline-treated control group animals. These nonresponsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of antenatal steroid therapy is not solely determined by maternofetal drug levels and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid signaling.
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http://dx.doi.org/10.1016/j.ajog.2020.05.032DOI Listing
December 2020

Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep.

Nutrients 2020 May 5;12(5). Epub 2020 May 5.

Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects.
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http://dx.doi.org/10.3390/nu12051312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284867PMC
May 2020

Lack of Evidence for Microbiota in the Placental and Fetal Tissues of Rhesus Macaques.

mSphere 2020 05 6;5(3). Epub 2020 May 6.

Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA

The prevailing paradigm in obstetrics has been the sterile womb hypothesis. However, some are asserting that the placenta, intra-amniotic environment, and fetus harbor microbial communities. The objective of this study was to determine whether the fetal and placental tissues of rhesus macaques harbor bacterial communities. Fetal, placental, and uterine wall samples were obtained from cesarean deliveries without labor (∼130/166 days gestation). The presence of bacteria in the fetal intestine and placenta was investigated through culture. The bacterial burden and profiles of the placenta, umbilical cord, and fetal brain, heart, liver, and colon were determined through quantitative real-time PCR and DNA sequencing. These data were compared with those of the uterine wall as well as to negative and positive technical controls. Bacterial cultures of fetal and placental tissues yielded only a single colony of This bacterium was detected at a low relative abundance (0.02%) in the 16S rRNA gene profile of the villous tree sample from which it was cultured, yet it was also identified in 12/29 background technical controls. The bacterial burden and profiles of fetal and placental tissues did not exceed or differ from those of background technical controls. By contrast, the bacterial burden and profiles of positive controls exceeded and differed from those of background controls. Among the macaque samples, distinct microbial signals were limited to the uterine wall. Therefore, using multiple modes of microbiologic inquiry, there was not consistent evidence of bacterial communities in the fetal and placental tissues of rhesus macaques. Microbial invasion of the amniotic cavity (i.e., intra-amniotic infection) has been causally linked to pregnancy complications, especially preterm birth. Therefore, if the placenta and the fetus are typically populated by low-biomass microbial communities, current understanding of the role of microbes in reproduction and pregnancy outcomes will need to be fundamentally reconsidered. Could these communities be of benefit by competitively excluding potential pathogens or priming the fetal immune system for the microbial bombardment it will experience upon delivery? If so, what properties (e.g., microbial load and community membership) of these microbial communities preclude versus promote intra-amniotic infection? Given the ramifications of the colonization hypothesis, critical evaluation is required. In this study, using multiple modes of microbiologic inquiry (i.e., culture, quantitative real-time PCR [qPCR], and DNA sequencing) and controlling for potential background DNA contamination, we did not find consistent evidence for microbial communities in the placental and fetal tissues of rhesus macaques.
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http://dx.doi.org/10.1128/mSphere.00210-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203455PMC
May 2020

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation.

Front Immunol 2020 3;11:558. Epub 2020 Apr 3.

Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.
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http://dx.doi.org/10.3389/fimmu.2020.00558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145904PMC
March 2021

Chronic Intra-Uterine Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses.

Front Immunol 2020 17;11:189. Epub 2020 Mar 17.

Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.

Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. The loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
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http://dx.doi.org/10.3389/fimmu.2020.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089942PMC
February 2021

Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia.

Am J Respir Crit Care Med 2020 07;202(1):100-111

Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.: Newborn mice were exposed to 75% O for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with or cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.
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http://dx.doi.org/10.1164/rccm.201906-1232OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328311PMC
July 2020

Other causes of fetal brain injury.

Authors:
Alan H Jobe

Am J Obstet Gynecol 2020 08 14;223(2):301. Epub 2020 Mar 14.

Neonatology and Pulmonary Biology, Cincinnati Children's Hospital, Cincinnati, OH. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2020.03.013DOI Listing
August 2020

Dose of budesonide with surfactant affects lung and systemic inflammation after normal and injurious ventilation in preterm lambs.

Pediatr Res 2020 11 17;88(5):726-732. Epub 2020 Feb 17.

School of Women's and Infants' Health, University of Western Australia, Perth, WA, 6009, Australia.

Background: The addition of budesonide (Bud) 0.25 mg/kg to surfactant decreased the lung and systemic responses to mechanical ventilation in preterm sheep and the rates and severity of bronchopulmonary dysplasia (BPD) in preterm infants. We hypothesized that lower budesonide concentrations in surfactant will decrease injury while decreasing systemic corticosteroid exposure.

Methods: Preterm lambs received either (1) protective tidal volume (V) ventilation with surfactant from birth or (2) injurious V ventilation for 15 min and then surfactant treatment. Lambs were further assigned to surfactant mixed with (i) Saline, (ii) Bud 0.25 mg/kg, (iii) Bud 0.1 mg/kg, or (iv) Bud 0.04 mg/kg. All lambs were then ventilated with protective V for 6 h.

Results: Plasma Bud levels were proportional to the dose received and decreased throughout ventilation. In both protective and injurious V ventilation, <4% of Bud remained in the lung at 6 h. Some of the improvements in physiology and markers of injury with Bud 0.25 mg/kg were also found with 0.1 mg/kg, whereas 0.04 mg/kg had only minimal effects.

Conclusions: Lower doses of Bud were less effective at decreasing lung and systemic inflammation from mechanical ventilation. The plasma Bud levels were proportional to dose given and the majority left the lung.
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http://dx.doi.org/10.1038/s41390-020-0809-6DOI Listing
November 2020

50 Years Ago in TheJournalofPediatrics: Commentary: The Use of Assisted Ventilation in the Therapy of Hyaline Membrane Disease.

J Pediatr 2020 02;217:19

Division of Neonatology and Pulmonary Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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http://dx.doi.org/10.1016/j.jpeds.2019.07.069DOI Listing
February 2020