epidermal-growth-factor and Infant--Premature--Diseases

This review will summarize the clinical and experimental studies evaluating the role of epidermal growth factor (EGF) in prophylaxis and treatment of necrotizing enterocolitis (NEC).. Clinical studies have suggested the importance of EGF in protection of the intestine against NEC, as well as its safety for infants suffering from NEC. The recent experimental studies identified the molecular mechanisms EGF uses for intestinal protection, which involves regulation of intestinal epithelial homeostasis and barrier function. Further studies are necessary to identify the optimal dose, timing, and route of administration of EGF to NEC patients. No clinical studies are currently underway.. NEC is a devastating problem for preterm neonates, but the exact disease pathogenesis remains unclear. Growing clinical evidence supports the use of EGF as a predictive marker of NEC and its use for prevention and treatment of NEC. In addition, experimental data indicate potential mechanisms of EGF prevention against NEC. These include reduction of inflammation, improvement of barrier function, and regulation of epithelial apoptosis and autophagy.

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Enterocolitis, Necrotizing; Epidermal Growth Factor; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestinal Absorption; Intestinal Mucosa; Liver

Necrotizing enterocolitis (NEC) presents as the most common gastrointestinal emergency during the neonatal period and results in ulceration and necrosis of the distal small intestine and proximal colon. The etiology of NEC remains unknown. Based on the complexity of gut development, multiple growth factors and cytokines may be needed to synergistically support the developing gut. Epidermal growth factor (EGF) has been shown to play an important role in intestinal cell restitution, proliferation, and maturation. EGF is found in abundant quantities in many fluids, including the gastrointestinal tract, amniotic fluid, breast milk, and saliva. Preliminary clinical trials using EGF in neonates diagnosed with NEC have been shown to promote repair of intestinal epithelium. Additionally, other growth factors are also emerging as potential treatment modalities, including erythropoietin, granulocyte colony stimulating factor, and heparin-binding EGF. The role of EGF and other growth factors in the pathogenesis and prevention of NEC will be reviewed.

Topics: Enterocolitis, Necrotizing; Epidermal Growth Factor; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestinal Mucosa

Epidermal Growth Factor (EGF) reduces necrotizing enterocolitis (NEC). However, its high cost virtually prohibits clinical use. To reduce cost, soybean expressing human EGF was developed. Here we report effectiveness of soybean-derived EGF in experimental NEC.. Newborn rats were subjected to the NEC-inducing regimen of formula feeding and hypoxia. Formula was supplemented with extract from EGF-expressing or empty soybeans. NEC pathology was determined microscopically. Localization of tight junction proteins JAM-A and ZO-1 was examined by immunofluorescence and levels of mucosal COX-2 and iNOS mRNAs by real time PCR.. Soybean extract amounts corresponding to 150μg/kg/day EGF caused considerable mortality, whereas those corresponding to 75μg/kg/day EGF were well tolerated. There was no significant difference in NEC scores between animals fed plain formula and formula supplemented with empty soybean extract. Soybean-EGF-supplemented formula at 75μg/kg/day EGF significantly decreased NEC, attenuated dissociation of JAM-A and ZO-1 proteins from tight junctions, and reduced intestinal expression of COX-2 and iNOS mRNAs.. Supplementation with soybean-expressed EGF significantly decreased NEC in the rat model. Soybean-expressed EGF may provide an economical solution for EGF administration and prophylaxis of clinical NEC.

Topics: Animals; Animals, Newborn; Cyclooxygenase 2; Disease Models, Animal; Enterocolitis, Necrotizing; Epidermal Growth Factor; Glycine max; Humans; Infant Formula; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestinal Mucosa; Intestines; Junctional Adhesion Molecules; Nitric Oxide Synthase Type II; Plant Extracts; Protective Agents; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Zonula Occludens Proteins

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Topics: Administration, Intranasal; Animals; Animals, Newborn; Brain Injuries; Cell Differentiation; Cell Division; Cell Lineage; Cell Survival; Demyelinating Diseases; Disease Models, Animal; Epidermal Growth Factor; ErbB Receptors; Humans; Hypoxia; Infant, Premature, Diseases; Male; Mice; Molecular Targeted Therapy; Oligodendroglia; Regeneration; Signal Transduction; Stem Cells; Time 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

Growth factors important to lung growth and fibrosis have been poorly studied in chronic lung disease (CLD) of prematurity. Epidermal growth factor (EGF) promotes epithelial cell maturation, and vascular endothelial growth factor (VEGF) is important in angiogenesis. The concentration of these growth factors was determined in 111 bronchoalveolar lavage fluid (BALF) samples from 35 ventilated infants: 13 developed CLD (median gestation 27 weeks, birthweight 820 g), 16 developed and recovered from respiratory distress syndrome (RDS) (31 weeks, 1,415 g) and six control infants (33 weeks, 2,075 g) were ventilated for nonpulmonary reasons. At birth, EGF in BALF from the CLD and RDS infants was lower than in the control infants (control versus CLD, 7.3 versus 0.0 pg x mL(-1), p<0.01; control versus RDS, 7.3 versus 5.0, p=0.08). EGF increased in all groups with a more rapid increase in control infants. A close relationship was noted between BALF EGF and gestational age (R=0.73). VEGF was undetectable at birth but increased at a similar rate in all three groups and did not correlate with gestation. In conclusion, these data suggest that epidermal growth factor is closely correlated to gestation and that it may predispose preterm infants to develop chronic lung disease.

Topics: Bronchoalveolar Lavage Fluid; Chronic Disease; Endothelial Growth Factors; Epidermal Growth Factor; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lymphokines; Male; Protein Isoforms; Respiratory Distress Syndrome, Newborn; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The effect of glucocorticoid hormones on epidermal growth factor (EGF) concentrations has not been described in the premature infant. We examined this relationship in a group of infants treated with dexamethasone for airway edema (three to five doses) or chronic lung disease (six weeks of a tapering protocol). We collected urinary samples in 45 infants (25 for airway edema, 20 for chronic lung disease) before, during and after the use of dexamethasone. The EGF values were unchanged in infants that were given dexamethasone for airway edema. In contrast, all infants treated for chronic lung disease increased their EGF values by 1 week of therapy. At the end of the dexamethasone taper, ten of the infants had recovered successfully from ventilatory support. This group of infants had post-therapy EGF values that were significantly higher than pretherapy values. In the ten infants that were still ventilator dependent at the end of therapy, EGF values were not different from pretherapy values. We conclude that dexamethasone therapy was associated with an increase in urinary EGF values in the preterm infant treated for at least 1 week. The positive correlation of tapering from ventilatory support with increases in EGF values suggests that EGF may be a marker of dexamethasone effect or an effector of dexamethasone action.

Topics: Adrenocorticotropic Hormone; Analysis of Variance; Dexamethasone; Epidermal Growth Factor; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male