RhIGF-1 Therapy: A Silver Bullet for Bronchopulmonary Dysplasia Prevention?
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ABSTRACT:
SUBMITTER: Plosa EJ
PROVIDER: S-EPMC7193858 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
rhIGF-1 Therapy: A Silver Bullet for Bronchopulmonary Dysplasia Prevention?
Plosa Erin J EJ Benjamin John T JT
American journal of respiratory and critical care medicine 20200501 9
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Project description:BackgroundThis study aimed to determine whether postnatal treatment with recombinant human IGF-1 (rhIGF-1)/binding peptide 3 (BP3) ameliorates lung injury and prevents pulmonary hypertension (PH) in bronchopulmonary dysplasia (BPD) models.MethodsWe used two models of BPD in this study: one model that was associated with chorioamnionitis (CA), stimulated by intra-amniotic fluid and exposure to lipopolysaccharide (LPS), whereas the other was exposed to postnatal hyperoxia. Newborn rats were treated with rhIGF-1/BP3 (0.2 mg/Kg/d) or saline via intraperitoneal injection. The study endpoints included the wet/dry weight (W/D) ratio of lung tissues, radial alveolar counts (RACs), vessel density, right ventricular hypertrophy (RVH), lung resistance, and lung compliance. Hematoxylin and eosin (H&E) and Masson staining were used to evaluate the degree of lung injury and pulmonary fibrosis. IGF-1 and eNOS expression were detected using western blotting or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The levels of SP-C, E-cadherin, N-cadherin, FSP1, and Vimentin in the lung tissues were detected by immunofluorescence.ResultsLPS and hyperoxia treatment increased lung injury and pulmonary fibrosis, enhanced RVH and total respiratory resistance, and decreased RAC, pulmonary vascular density and pulmonary compliance in young mice (all p < 0.01). Simultaneously, LPS and hyperoxia induced an increase in epithelial-mesenchymal transition (EMT) in airway epithelial cells. However, rhIGF-1/BP3 treatment reduced lung injury and pulmonary fibrosis, decreased RVH and total respiratory resistance, and enhanced RAC, pulmonary vascular density and pulmonary compliance, as well as inhibited EMT in airway epithelial cells in LPS and hyperoxia treated mice.ConclusionPostnatal rhIGF-1/BP3 treatment relieved the effects of LPS or hyperoxia on lung injury and prevented RVH, providing a promising strategy for the treatment of BPD.
| S-EPMC10273711 | biostudies-literature
Project description:Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown.Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia.Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02-20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro.Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation.Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.
| S-EPMC7193843 | biostudies-literature
Project description:IntroductionAs more infants are surviving at younger gestational ages, bronchopulmonary dysplasia (BPD) remains as a frequent neonatal complication occurring after preterm birth. The multifactorial nature of the disease process makes BPD a challenging condition to treat. While multiple pharmacologic therapies have been investigated over the past two decades, there have been limited advances in the field. Often multiple therapies are used concurrently without clear evidence of efficacy, with potential for significant side effects from drug-drug interactions.MethodsSystematic literature review.ConclusionAlthough there is physiologic rationale for the use of many of these therapies, none of them has single-handedly altered the incidence, severity, or progression of BPD. Future research should focus on developing clinically significant end-points (short and long term respiratory assessments), investigating biomarkers that accurately predict risk and progression of disease, and creating appropriate stratification models of BPD severity. Applying a multi-modal approach to the study of new and existing drugs should be the most effective way of establishing the optimal prevention and treatment regimens for BPD.
| S-EPMC4329808 | biostudies-literature
Project description:BackgroundLow levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes.MethodsGroup 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs.ResultsGroup 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs.ConclusionsThree days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity.ImpactPreterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.
| S-EPMC9968819 | biostudies-literature
Project description: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.
| S-EPMC5856637 | biostudies-literature
Project description:A growing understanding of endogenous nitric oxide (NO) biology is helping to explain how and when exogenous NO may confer benefit or harm; this knowledge is also helping to identify new better-targeted NO-based therapies. In this review, results of the bronchopulmonary dysplasia clinical trials that used inhaled NO in the preterm population are placed in context, the biologic basis for novel NO therapeutics is considered, and possible future directions for NO-focused clinical and basic research in developmental lung disease are identified.
| S-EPMC3437658 | biostudies-other
Project description:Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1β, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.
| S-EPMC5431131 | biostudies-literature
Project description:Scientific and technological advances in perinatology and neonatology have led to an increased rate of survival and decreased incidences of various neonatal morbidities. However, the incidence of bronchopulmonary dysplasia has remained almost the same for years in very-low-birth-weight preterm infants. Although bronchopulmonary dysplasia is the leading cause of chronic respiratory morbidity in small preterms, no substantial improvement has been achieved in prevention and treatment strategies to date. Currently, postnatal very-low-dose corticosteroids, caffeine, and vitamin A seem to be the drugs of choice, and stem cell therapy appears to be the most promising treatment modality for the future. In this guideline, which was prepared by the Turkish Neonatal Society, recent evidence-based recommendations for the prevention and treatment of bronchopulmonary dysplasia are summarized.
| S-EPMC6568289 | biostudies-literature
Project description:ImportanceBronchopulmonary dysplasia (BPD) rates in the United States remain high and have changed little in the last decade.ObjectiveTo develop a consistent BPD prevention bundle in a systematic approach to decrease BPD.Design, setting, and participantsThis quality improvement study included 484 infants with birth weights from 501 to 1500 g admitted to a level 3 neonatal intensive care unit in the Kaiser Permanente Southern California system from 2009 through 2019. The study period was divided into 3 periods: 1, baseline (2009); 2, initial changes based on ongoing cycles of Plan-Do-Study-Act (2010-2014); and 3, full implementation of successive Plan-Do-Study-Act results (2015-2019).InterventionsA BPD prevention system of care bundle evolved with a shared mental model that BPD is avoidable.Main outcomes and measuresThe primary outcome was BPD in infants with less than 33 weeks' gestational age (hereafter referred to as BPD <33). Other measures included adjusted BPD <33, BPD severity grade, and adjusted median postmenstrual age (PMA) at hospital discharge. Balancing measures were adjusted mortality and adjusted mortality or specified morbidities.ResultsThe study population included 484 infants with a mean (SD) birth weight of 1070 (277) g; a mean (SD) gestational age of 28.6 (2.9) weeks; 252 female infants (52.1%); and 61 Black infants (12.6%). During the 3 study periods, BPD <33 decreased from 9 of 29 patients (31.0%) to 3 of 184 patients (1.6%) (P < .001 for trend); special cause variation was observed. The standardized morbidity ratio for the adjusted BPD <33 decreased from 1.2 (95% CI, 0.7-1.9) in 2009 to 0.4 (95% CI, 0.2-0.8) in 2019. The rates of combined grades 1, 2, and 3 BPD decreased from 7 of 29 patients (24.1%) to 17 of 183 patients (9.3%) (P < .008 for trend). Grade 2 BPD rates decreased from 3 of 29 patients (10.3%) to 5 of 183 patients (2.7%) (P = .02 for trend). Adjusted median PMA at home discharge decreased by 2 weeks, from 38.2 (95% CI, 37.3-39.1) weeks in 2009 to 36.8 (95% CI, 36.6-37.1) weeks during the last 3 years (2017-2019) of the full implementation period. Adjusted mortality was unchanged, whereas adjusted mortality or specified morbidities decreased significantly.Conclusions and relevanceA sustained low rate of BPD was observed in infants after the implementation of a detailed BPD system of care.
| S-EPMC8239950 | biostudies-literature
Project description: Not available
| S-EPMC10015219 | biostudies-literature