losartan-potassium and Enterocolitis--Necrotizing

Recombinant erythropoietin (rEPO) has erythropoiesis and anti-inflammatory properties that might help reduce lung injury in preterm infants.. To conduct a systematic review and meta-analysis to evaluate the possible role of rEPO in altering the risk of bronchopulmonary dysplasia (BPD).. PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched to identify randomized controlled trials (RCTs) that evaluated the effects of rEPO for the prevention of BPD in preterm infants.. Fourteen studies (3199 infants) were included. Our results could not demonstrate a significant effect of rEPO on the incidence of BPD36 (risk ratio [RR]: 0.97, 95% confidence interval [CI]: 0.87-1.09, p = 0.63, I. Our results suggest that rEPO does not affect the risk of developing BPD in preterm infants. Adequately powered RCTs are required to further confirm these findings.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Sepsis

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes.. There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings.. • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants.. • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

Topics: Anemia, Neonatal; Enterocolitis, Necrotizing; Erythropoietin; Female; Fetal Diseases; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Randomized Controlled Trials as Topic

Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gastrointestinal Tract; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Retinopathy of Prematurity; Sepsis

Fetal erythropoietin (EPO), in addition to regulating erythropoiesis, has also tissue-protective properties based on its anti-inflammatory, anti-apoptotic, antioxidant, and neurotrophic effects. Notably, EPO concentrations needed for tissue protection are 100-1000 times higher than concentrations needed for regulating erythropoiesis. This dual effect of EPO is based on EPO-receptor (EPO-R) isoforms, which differ structurally and functionally. We hypothesize in this Integrated Mechanism Review that during severe fetal hypoxia the observed, but poorly understood, marked increases of fetal plasma EPO concentrations occur to protect the brain, heart, and other vital fetal organs. We further hypothesize that the concurrent marked increases of EPO in the amniotic fluid during fetal hypoxia, occur to protect newborn infants from necrotizing enterocolitis. This review presents experimental and clinical evidence in support of these hypotheses and points out unknown or poorly understood functions of EPO in the fetus. If these novel hypotheses are correct, the importance of fetal EPO as an antenatal hypoxia biomarker will become apparent. It will also likely point the way to important diagnostic and therapeutic fetal and neonatal interventions.

Topics: Amniotic Fluid; Animals; Biomarkers; Brain; Enterocolitis, Necrotizing; Erythropoietin; Female; Fetal Blood; Fetal Diseases; Hematopoiesis; Humans; Hypoxia; Infant, Newborn; Inflammation; Intestines; Neuroprotection; Pregnancy; Protein Isoforms; Reactive Oxygen Species

Neonatal anemia is a common disorder, particularly in (very) preterm neonates. Management of neonatal anemia is based principally on red blood cell (RBC) transfusion. Although the use of blood products is nowadays widespread in neonatal medicine, evidence on the potential benefit is extremely limited. Recent studies suggest that RBC transfusions in newborns may be associated with an increased risk for necrotizing enterocolitis, transfer of infectious agents and negative effects on neurodevelopmental outcome. Whether the benefits of RBC transfusions outweigh the risks is controversial and requires further studies. In this review, we summarize the current evidence on the management of neonatal anemia and compare the various international guidelines. In addition, we discuss the various strategies to prevent neonatal anemia and reduce the need for RBC transfusions and discuss important trials currently enrolling patients to improve the management in neonatal anemia.

Topics: Anemia, Neonatal; Cord Blood Stem Cell Transplantation; Databases, Factual; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Guidelines as Topic; Humans; Infant, Newborn; Risk Factors

Red blood cell (RBC) transfusions convey benefits but they also carry risks. Among NICU patients, some transfusion risks are well defined and their occurrence odds can be estimated and weighed against benefits. However other risks are poorly defined and it is not currently possible to estimate their occurrence adds or weigh these against benefits.. We reviewed publications in the past 15 years, listed in PubMed, dealing with risks and benefits of RBC transfusions to newborn infants.. Risks of RBC transfusion to adult patients decreased significantly with the advent of nucleic acid testing for viral pathogens. However, new or previously unknown risks of transfusions have been suggested for neonatal recipients. These include developmental delay, intraventricular hemorrhage, and necrotizing enterocolitis. These potential transfusion risks are all currently in the form of statistical associations, and cause-and-effect relationships have not been proven. Mean of reducing transfusions, tested during the past 15 years, include adopting transfusions guidelines, erythropoietic stimulating agents, delayed cord clamping, cord stripping, drawing all NICU admission blood tests from the placenta, and limiting phlebotomy losses for blood testing.. We advocate always attempt to weigh benefits and risks when ordering a transfusion for a neonatal patient. Certainly some such are life-saving or otherwise clearly beneficial. Perhaps others carry risks unbalanced by meager benefit. Efforts to improve NICU transfusion practice have been proposed and appear to be working to diminish costs and improve outcomes.

Topics: Adult; Anemia; Blood Transfusion, Autologous; Cerebral Hemorrhage; Developmental Disabilities; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Risk Assessment; Risk Factors; Umbilical Cord

Erythropoientin (Epo), a glycoprotein hormone, plays an important role in erythropoiesis and neuroprotection. Recently,Epo is also considered to have protective effects against hyperoxic lung injury, retinopathy of prematurity and neonatal necrotizing enterocolitis. Recombinant human erythropietin (rhEpo) as Epo gene cloning drug has been widely used in neonatal clinical practice.

Topics: Enterocolitis, Necrotizing; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Recombinant Proteins; Retinopathy of Prematurity

To evaluate the effects of enteral administration of recombinant human erythropoietin (rhEPO) on feeding-related complications in preterm infants.. This double-blind, randomized controlled pilot study enrolled 120 preterm infants born ≤ 32 weeks' gestation who were admitted to the neonatal intensive care unit in a tertiary hospital; 60 patients randomly received recombinant human erythropoietin while the other 60 received placebo. Newborns who underwent cardiopulmonary resuscitation, infants with genetic syndromes, infants with inborn errors of metabolism, infants with major congenital or acquired gastrointestinal tract malformations, infants with previous use of parenteral growth factors such as recombinant human erythropoietin and granulocyte-macrophage colony-stimuating factor (GM-CSF) and infants previously treated with intravenous immunoglobulin were excluded. Overall, 48 patients withdrew from the study because of intravenous haematopoietic growth factor intake or death before treatment was completed. A total of 72 preterm infants remained in the study: 36 preterm infants in the erythropoietin (EPO) group, and 36 preterm infants in the placebo group. The day that enteral feeding was successfully started, the time to establishing one-half, two-thirds, and full enteral feedings (reaching at least 150 mL/kg/day), the number of episodes of feeding intolerance, the time to regain birth weight and the incidence of necrotizing enterocolitis (NEC) were recorded.. Both groups showed no significant difference in the time to achieve one-half, two-thirds, or full enteral feeding, no signs of feeding intolerance, and no cases of NEC were recorded.. Enteral erythropoietin does not appear to affect feeding intolerance or NEC incidence.

Topics: Double-Blind Method; Enteral Nutrition; Enterocolitis, Necrotizing; Erythropoietin; Female; Food Intolerance; Humans; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Pilot Projects; Recombinant Proteins; Survival Rate

Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants.. The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age ≤ 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age.. A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 ± 0.4 vs. 2.7 ± 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age < 28 weeks (p = 0.019), and the incidence of all stages NEC in preterm infants with hemoglobin < 90 g/l (p = 0.000) and 5 min Apgar score > 5 (p = 0.028).. Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial registration The protocol was registered retrospectively at ClinicalTrials.gov (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500.

Topics: Enterocolitis, Necrotizing; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Prospective Studies; Retrospective Studies

To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants.. Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth.. There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group.. Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events.. ClinicalTrials.gov: NCT00413946.

Topics: Bronchopulmonary Dysplasia; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Enterocolitis, Necrotizing; Erythropoietin; Europe; Hematocrit; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Leukocyte Count; Leukomalacia, Periventricular; Neuroprotective Agents; Platelet Count; Recombinant Proteins; Reticulocyte Count; Retinopathy of Prematurity; Sepsis

To evaluate the efficacy and safety of enteral recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEPO) in preventing feeding intolerance.. An interventional randomized control trial was conducted in 90 preterm infants born at ≤33 weeks gestational age. The neonates were assigned to 4 groups; 20 received rhG-CSF, 20 received rhEPO, 20 received both, and 30 received distilled water (placebo control). The test solution was given at the beginning of enteral feeding and was discontinued when enteral intake reached 100 mL/kg/day or after a maximum of 7 days, whichever came first. Feeding tolerance and adverse effects of treatment were assessed. Serum granulocyte colony-stimulating factor and erythropoietin levels were measured on days 0 and 7 of treatment.. All neonates tolerated the treatment without side effects. Neonates who received rhG-CSF and/or rhEPO had better feeding tolerance, as reflected by earlier achievement of 75 mL/kg/day, 100 mL/kg/day, and full enteral feeding of 150 mL/kg/day with earlier weight gain and a shorter hospital stay (P < .05). The risk of necrotizing enterocolitis was reduced from 10% to 0% in all treatment groups (P < .05). There was a shorter duration of withholding of feeding secondary to feeding intolerance among neonates receiving both rhG-CSF and rhEPO compared with those receiving placebo (P < .05). Serum levels of granulocyte colony-stimulating factor and erythropoietin at 0 and 7 days did not differ across the treatment groups.. Enteral administration of rhG-CSF and/or rhEPO improves feeding outcome and decreases the risk of necrotizing enterocolitis in preterm neonates. The mechanism may involve the prevention of villous atrophy.

Topics: Enterocolitis, Necrotizing; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Recombinant Proteins

Apoptosis that occurs after hypoxia/reoxygenation (H/R) has an important role in the pathogenesis of necrotizing enterocolitis (NEC). Telomerase activity, showing the regeneration capacity, may also be important in the recovery process. Therefore, we aimed to investigate the effects of insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO) on apoptosis and telomerase activity in an H/R model.. Young mice were divided into four groups each containing ten Balb/c mice. Group 1 (H/R) were exposed to H/R; group 2 and group 3 were pretreated with IGF-1 and EPO, respectively, for 7 days before H/R. Group 4 served as control. Intestinal injury was evaluated by histological scoring and assessment of apoptosis was performed by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) test. Proapoptotic and antiapoptotic gene expressions and telomerase activity were analyzed by real-time PCR.. IGF-1- and EPO-treated animals had decreased histological damage and apoptosis, confirmed by TUNEL test and caspase activity. Telomerase activity was increased in these animals in addition to increased expression of antiapoptotic genes. However, proapoptotic gene expressions were not statistically different.. The protective effects of IGF-1 and EPO in H/R damage may be through increased expression of antiapoptotic genes and increased telomerase activity, especially for IGF-1.. This is a comprehensive study measuring various variables, namely IGF-1, EPO, apoptosis, apoptotic and antiapoptotic genes, and telomerase activity in the NEC model. The intestinal protective effects of IGF-1 and EPO in H/R damage may occur through increased expression of antiapoptotic genes and increased telomerase activity. To the best of our knowledge, telomerase activity has not been investigated in the NEC model before. Regarding our results, novel strategies may be implemented for the early definitive diagnosis, robust preventive measures, and effective treatment modalities for NEC.

Topics: Animals; Apoptosis; Disease Models, Animal; Enterocolitis, Necrotizing; Erythropoietin; Insulin-Like Growth Factor I; Mice; Mice, Inbred BALB C; Telomerase

Necrotizing enterocolitis is a common but serious complication among premature babies. Currently, there are limited treatment options. These include intensive supportive care and surgical intervention. In this study, we hypothesize that erythropoietin (Epo) could be protective against cell necrosis by increasing the levels of glutathione. This can be regulated by increasing the activity of system xC

Topics: Amino Acid Transport System y+; Animals; Cell Line; Cell Survival; Enterocolitis, Necrotizing; Erythropoietin; Glutathione; Humans; Infant; Intestinal Mucosa; Rats; Sulfasalazine

To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs).. Prospective cohort study.. Neonatal care units at 14 participating hospitals in the USA.. 867 children born before the 28th week of gestation from the ELGAN study cohort.. EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day.. Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance.. EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gestational Age; Humans; Infant, Extremely Premature; Infant, Premature, Diseases; Prospective Studies; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Risk Factors; Time Factors

Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of preterm infants. Increased intestinal epithelium permeability is an early event in NEC pathogenesis. Autophagy and apoptosis are induced by multiple stress pathways which may impact the intestinal barrier, and they have been associated with pathogenesis of diverse gastrointestinal diseases including inflammatory bowel disease. Using both in vitro and in vivo models, this study investigates autophagy and apoptosis under experimental NEC stresses. Furthermore this study evaluates the effect of erythropoietin (Epo), a component of breast milk previously shown to decrease the incidence of NEC and to preserve intestinal barrier function, on intestinal autophagy and apoptosis. It was found that autophagy and apoptosis are both rapidly up regulated in NEC in vivo as indicated by increased expression of the autophagy markers Beclin 1 and LC3II, and by evidence of apoptosis by TUNEL and cleaved caspase-3 staining. In the rat NEC experimental model, autophagy preceded the onset of apoptosis in intestine. In vitro studies suggested that Epo supplementation significantly decreased both autophagy and apoptosis via the Akt/mTOR signaling pathway and the MAPK/ERK pathway respectively. These results suggest that Epo protects intestinal epithelium from excessive autophagy and apoptosis in experimental NEC.

Topics: Animals; Animals, Newborn; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Caspase 3; Disease Models, Animal; Enterocolitis, Necrotizing; Epithelial Cells; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Humans; Infant, Newborn; Intestinal Mucosa; Intestines; Membrane Proteins; Microtubule-Associated Proteins; Milk, Human; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; TOR Serine-Threonine Kinases

The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases.

Topics: Animals; Animals, Newborn; Cell Line, Tumor; Disease Models, Animal; Electric Impedance; Enterocolitis, Necrotizing; Enterocytes; Erythropoietin; Fluorescent Antibody Technique; Humans; Immunoblotting; Intestinal Mucosa; Intestines; Membrane Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; RNA Interference; Tight Junctions; Zonula Occludens-1 Protein

Necrotizing enterocolitis (NEC) sometimes occurs after a transfusion, but it is unclear whether this is a chance association or cause and effect.. We compared features of neonates that developed surgical NEC within 48 hours after transfusion with others that developed NEC not preceded by transfusion. We assessed the blood used for transfusion and feeding practices among NEC cases and controls.. Forty neonates developed surgical NEC after a transfusion and 72 developed NEC unrelated to a transfusion. Those with NEC after transfusion were born at earlier gestation (mean 27 weeks, 90% confidence interval [CI] 26-28 years vs. mean 30, 90% CI 29-31; p < 0.001) and were of lower birth weight (mean 981 g, 90% CI 835-1128 g vs. mean 1371 g, 90% CI 1245-1496; p < 0.001) and developed NEC later during their neonatal intensive care unit course (day of life: mean 23, 90% CI 20-27 vs. mean 16, 90% CI 13-19; p < 0.001). Transfusions were more prevalent among those that developed NEC (p < 0.001). The blood transfused to those that developed NEC was not older, but those who developed NEC had been fed larger volumes of milk in the 24 hours before and during transfusion (p = 0.04) and were more likely to have been fed a bovine product during that period (p = 0.004).. Approximately one-third of surgical NEC cases in our system occurred after a transfusion. We speculate that a target area for reducing the prevalence of posttransfusion NEC involves feeding practices immediately before and during RBC transfusion.

Topics: Case-Control Studies; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Recombinant Proteins; Risk Factors

Holder pasteurization renders donor human milk safe for consumption. Because human milk reduces the risk of necrotizing enterocolitis in preterm infants, we tested whether Holder pasteurization affects certain factors in human milk that protect the intestines: epidermal growth factor (EGF), transforming growth factor (TGF)-beta1, erythropoietin (EPO), and interleukin (IL)-10. Donor human milk from a milk bank was examined.. The aqueous phase of 17 samples of donor term human milk (mean duration of lactation, 8 +/- 3.5 months) was examined before and after Holder pasteurization. In the case of IL-10, lesser degrees of pasteurization were also evaluated. The agents were quantified using enzyme immunoassays. The function of IL-10 was also tested.. Concentrations of EGF and IL-10 were markedly lower than previously reported values in human milk from earlier phases of lactation. Holder pasteurization significantly reduced the concentrations of EPO and IL-10, whereas lesser degrees of heating increased the detection of IL-10. The immunosuppression of T-cell proliferation by human milk, thought to be attributed to IL-10 alone, persisted after Holder pasteurization.. Holder pasteurization greatly decreased concentrations of EPO and IL-10 in human milk. These decreases may impact the ability of human milk to protect against necrotizing enterocolitis. Evidence of possible binding of IL-10 to other proteins in human milk was also found. Experiments to test whether Holder pasteurization affects the function of IL-10 in human milk produced evidence for an agent in human milk other than IL-10 that inhibits T-cell proliferation and resists Holder pasteurization.

Topics: Adult; Enterocolitis, Necrotizing; Epidermal Growth Factor; Erythropoietin; Female; Food Preservation; Hot Temperature; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-10; Lactation; Milk, Human; Transforming Growth Factor beta1

Necrotizing enterocolitis (NEC) seems to result from the inflammatory response of an immature intestine. Human milk is protective against NEC via an unknown mechanism. We hypothesized that specific factors found in human milk would decrease stimulated IL-8 secretion in intestinal epithelial cells. HT29-cl19A and Caco2 cells were compared with the fetal human primary intestinal epithelial cell line H4 and temperature-sensitive conditionally immortalized fetal human intestinal (tsFHI) cells. Cells were pretreated with transforming growth factor-beta (TGF-beta), erythropoietin (Epo), IL-10, or epidermal growth factor (EGF) at physiologic concentrations before stimulation with tumor necrosis factor-alpha (TNF-alpha) or IL-1beta, and then IL-8 was measured by ELISA. The fetal cells produced significantly more IL-8 when stimulated by TNF-alpha or IL-1beta. There were also differences in the pattern of alteration of IL-8 secretion by human milk factors. In HT29-cl19A cells, IL-10 inhibited TNF-alpha-stimulated IL-8 secretion by 52%, and EGF increased secretion by 144%. In H4 cells, TGF-beta1 and Epo inhibited TNF-alpha-stimulated IL-8 secretion to control levels, and EGF increased secretion by 29%. IL-1beta-stimulated IL-8 secretion was inhibited 25% by TGF-beta1 in Caco2 cells and in H4 cells was inhibited by TGF-beta1, Epo, and TGF-beta2. TsFHI cells confirmed H4 cell results. Fetal human enterocytes have an exaggerated IL-8 secretion in response to TNF-alpha and IL-1beta. TGF-beta and Epo decrease this stimulated IL-8 secretion, which may partially explain the protective effect of human milk in NEC.

Topics: Age Factors; Caco-2 Cells; Enterocolitis, Necrotizing; Epidermal Growth Factor; Epithelial Cells; Erythropoietin; Fetus; HT29 Cells; Humans; In Vitro Techniques; Interleukin-1; Interleukin-10; Interleukin-8; Intestinal Mucosa; Milk, Human; Transforming Growth Factor beta

Necrotizing enterocolitis (NEC) is an important neonatal disease with a high mortality rate; erythropoietin (Epo) is a hematopoietic growth factor. Functional Epo receptors are in the fetal and postnatal small bowel and their ligands are available for binding. Excessive nitric oxide (NO) production by an isoform of NO synthase inducible by inflammatory stimuli leads to changes in vascular permeability and tissue injury. The aim of this study was to investigate NO formation in an experimental model of NEC and the possible role of NO in the protection Epo provides against NEC.. Twenty-four Wistar albino rat pups were divided into three groups: group 1 = control; group 2 = hypoxia-reoxygenation and saline; group 3 = hypoxia-reoxygenation and recombinant human EPO (rhEpo) pretreatment. rhEpo was given 750 U/kg/week by intraperitoneal injection 3 times a week for 2 weeks. On the 15th day, hypoxia was induced by placing the pups in a 100% CO(2) chamber for 5 min. After the hypoxia period the pups were reoxygenated for 10 min with 100% O(2) and returned to their mothers. All pups were killed 4 h after the hypoxia-reoxygenation period was over. The abdomen was opened and representative samples of injured areas were taken for histopathologic examination. Then nitrite levels were determined in the intestine by Griess Reagent.. On histopathological examination, injury scores in group-2 animals were found to be significantly higher than in group-3 animals (p = 0.001). Significantly increased intestinal nitrite levels were found in group-2 rats compared to the rats of groups 1 and 3 (p = 0.001 and p = 0.001, respectively). There was a positive correlation between the histological findings and the intestinal nitrite levels in group-2 and -3 animals (r = 0.94, p = 0.001; r = 0.99, p = 0.001, respectively).. The present study demonstrates that the Epo-pretreated group had decreased levels of NO and limited mucosal necrosis in intestinal tissue samples. We believe that these results deserve further experimental studies in order to elucidate the possible effector mechanisms involved in the inhibitory relationship between Epo, NO and NEC.

Topics: Animals; Enterocolitis, Necrotizing; Erythropoietin; Humans; Hypoxia; Intestinal Mucosa; Intestines; Nitrites; Rats; Rats, Wistar; Recombinant Proteins

In the present study we examined the effect of recombinant human erythropoietin (rhEPO) on intestinal malondialdehyde (MDA) as an index of lipid peroxidation, related to iron-catalysed free radical reaction and platelet-activating factor (PAF) synthesis in the experimental model of necrotizing enterocolitis (NEC). Three groups, each consisting of eight 1-day-old Wistar albino rat pups, were studied; Group 1, hypoxia-reoxygenation; Group 2, hypoxia-reoxygenation and rhEPO pretreatment; Group 3, control. rhEPO was given 750 U/kg/week by intraperitoneal injection three times a week for 2 weeks. On day 15th of life, hypoxia was induced by placing rat pups in a 100% CO2 chamber for 5 min. After hypoxia, the rat pups were reoxygenated for 10 min with 100% oxygen and returned to their mothers. All pups were killed at 4h following hypoxia-reoxygenation. The abdomen was opened and representative samples of injured areas were taken for histopathologic examination. MDA and PAF levels were determined in the intestine. Significantly increased intestinal MDA content was found in Group 1 rat pups compared to Group 2 and Group 3 pups (p < 0.001 and p < 0.001, respectively). However, PAF concentrations were highly elevated in the intestine of Group 1 and Group 2 pups (p>0.05) when compared to the intestine of Group 3 pups (p < 0.001 and p < 0.001, respectively). Histopathologic findings did not differ between Groups 1 and 2. The present study demonstrates that oxygen-derived free radicals and PAF are involved in the pathophysiological mechanism of the development of NEC. This study also shows that administration of rhEPO significantly decreases lipid peroxidation; however, PAF generation was not inhibited in hypoxia-induced bowel necrosis.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Enterocolitis, Necrotizing; Erythropoietin; Female; Injections, Intraperitoneal; Lipid Peroxidation; Male; Malondialdehyde; Platelet Activating Factor; Probability; Rats; Rats, Wistar; Recombinant Proteins; Reference Values; Sensitivity and Specificity; Statistics, Nonparametric

The presence of erythropoietin (Epo) in human milk and the expression of Epo receptors on intestinal villous enterocytes of neonates suggest that Epo has a role in growth and development of the gastrointestinal tract. On this basis, the authors hypothesized that recombinant Epo (rEpo) given for prevention or treatment of the anemia of prematurity would protect against necrotizing enterocolitis (NEC).. A retrospective cohort study was conducted from a university neonatal intensive care unit of 483 very low birth weight (500 to 1,250 g) neonates born from July 1, 1993 to January 1, 1998.. A total of 260 neonates received rEpo, and 223 did not (control group). The rEpo and control groups were similar in gender distribution (52% v. 48% boys), gestational age (26.8+/-2.1 v. 27.6+/-2.9 weeks; mean +/- SD), birth weight (895+/-198 v. 911+/-208 g), 1 and 5 minute Apgar scores (4.2 and 6.1 v4.7 and 6.7), and incidence of severe intraventricular hemorrhage (8.9% v. 10.3%). The rEpo group had a lower incidence of NEC (12 of 260, 4.6% v. 24 of 223, 10.8%; P = .028, 95% confidence interval for difference: -0.108 to -0.015).. In very low birth weight infants, the incidence of NEC is lower in those who received rEpo.

Topics: Enterocolitis, Necrotizing; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Male; Recombinant Proteins; Retrospective Studies