The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis

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Abstract

Necrotizing enterocolitis (NEC) is a devastating intestinal disease resulting in major neonatal morbidity and mortality. The pathology is poorly understood, and the means of preventing and treating NEC are limited. Several endogenous growth factors have been identified as having important roles in intestinal growth as well as aiding intestinal repair from injury or inflammation. In this review, we will discuss several growth factors as mediators of intestinal regeneration and repair as well as potential therapeutic agents for NEC.

Introduction

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency encountered in the neonatal period.1 The exact pathogenesis of NEC is unknown and likely multifactorial. Prematurity, aberrant bacterial colonization, hypoxia, and intestinal ischemia have all been implicated.2 Localized intestinal mucosal injury is thought to result in an amplified cycle of bacterial invasion, immune activation, uncontrolled inflammation, and gut barrier failure, leading to necrosis, perforation, sepsis, and shock.2., 3., 4.

In the dynamic milieu of the developing gut, growth factors play a critical role in intestinal development. Growth factors have also been established to be important mediators of gastrointestinal repair, with roles in cellular proliferation, differentiation, migration, and survival.5., 6., 7., 8. It is logical to consider that absent or reduced levels of specific factors that are normally expressed during later periods of gestation may contribute to the development of NEC. As such, exogenous replacement of these key factor(s) may be of clinical value in the prevention and treatment of NEC.9 Epidermal growth factor (EGF), heparin-binding epidermal-like growth factor (HB-EGF), growth hormone (GH), insulin-like growth factor (IGF), glucagon-like peptide 2 (GLP-2), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), erythropoietin (Epo), and intestinal trefoil factor (ITF) have all been implicated in the pathogenesis and prevention of NEC, and will be the focus of the present review (the effects of these growth factors are summarized in Table 1).

Section snippets

EGF and normal intestinal development

EGF is a 53-amino acid peptide, established as a major trophic factor for the developing intestine.10., 11., 12., 13. EGF is normally found in fluids that bathe the developing intestine, including amniotic fluid, fetal urine, breast milk, bile, and saliva.14 As gestation progresses, the concentration of EGF in the amniotic fluid increases.13., 15. In rabbits, exogenous in utero infusion of EGF stimulates intestinal growth and accelerates maturation of intestinal enzyme activity.16

Maternal

Heparin-binding epidermal-like growth factor

HB-EGF is a 22-kDa glycoprotein that is a member of the EGF family and signals via the EGFR pathway to stimulate cellular growth and differentiation.100 Unlike other members of the EGF family, HB-EGF is unique in its ability to bind strongly to heparin.101 Like EGF, HB-EGF is found in biologically significant quantities in amniotic fluid and human milk.102 HB-EGF expression has been demonstrated to be elevated in response to tissue damage, hypoxia, and stress, and during wound healing and

Glucagon-like peptide 2

GLP-2 is a 33-amino acid peptide that regulates a wide range of actions on the intestine including growth, motility, nutrients, and blood flow. It is secreted from the enteroendocrine L cells of the distal small intestine and colon in response to enteral nutrients, particularly fatty acids and glucose.122., 123.

The full mechanism of GLP2 is not well understood. The GLP-2 receptor is a G-protein-coupled receptor that is expressed in greatest concentration in the proximal bowel and decreases

Growth hormone

Growth Hormone (GH) is a 22 kDA anabolic protein that is synthesized in the anterior pituitary and released into the systemic circulation with multiple tissue targets. GH has a significant role in postnatal growth as well as lipid and carbohydrate metabolism.167., 168.

The GH receptor is a type 1 cytokine receptor that signals the tyrosine kinase JAK2 pathways. GH receptors are expressed throughout the small and large intestine in the muscularis propria, submucosa, muscularis mucosa, lamina

Insulin-like growth factor-1

IGF-1 is a small 70-amino acid polypeptide synthesized primarily in the liver but also in the gastrointestinal tract. IGF-1 is found in the fetal intestine and in human milk, suggesting a role in intestinal development.186., 187., 188. The IGF-1 Receptor (IGF-1R) is a transmembrane tyrosine kinase receptor with structural homology to insulin receptors. Activation of IGF-1R leads to autophosphorylation and activation of signaling cascades such as IRS-1/PI3K/AKT and GRB2/Ras/ERK pathways.189

Granulocyte colony-stimulating factor

G-CSF is an 18.8-kDa glycoprotein involved in the regulation of neutrophil production. Neutrophils are key players in the human inflammatory and immune response, dysregulation of which has been implicated in the pathogenesis on NEC. G-CSF is found in the amniotic fluid and human milk in physiologically significant concentrations.209., 210., 211. Consistent with the increased risk of NEC in premature infants, the concentration of G-CSF in cord blood of term infants is higher than that of preterm

Erythropoietin

Epo is a 30.4-kDa glycoprotein, secreted by the fetal liver and adult kidney in response to anemia.219 In addition to stimulating erythropoiesis, Epo has been implicated in immunologic modulation, anti-inflammatory effects, improved wound healing, and reduction in hypoxia-induced apoptosis.220 Epo is present in the amniotic fluid and breast milk.221., 222., 223., 224., 225., 226. Functional Epo receptors are present in the fetal and postnatal small bowel.227., 228. Fetal human enterocytes have

Intestinal trefoil factor

The trefoil factor family (TFF) is a group of 7- to 14-kd polypeptides that are secreted by mucus-producing epithelial cells, predominantly in the gastrointestinal tract. Three mammalian TFF members have been identified; TTF1 expressed by the surface and pit mucus cells in the stomach, TTF2 expressed by the mucus neck and glandular mucus cells of the stomach and Brunner's glands of the proximal duodenum, and TTF3 (also known as ITF) expressed by goblet cells of the intestine and colon.233

Keratinocyte growth factor

KGF is a member of the fibroblast growth factor family and stimulates growth and differentiation of epithelial cells.246 Exogenous KGF supplementation in rats results in epithelial cell proliferation and induction of mucin-producing goblet cells.247 KGF and its receptor are present in the human fetal gastrointestinal tract and in vitro stimulation of human fetal enterocytes with KGF results in cellular proliferation.248 Expression of KGF is increased in surgical patients with inflammatory bowel

Hepatocyte growth factor

HGF is a 94-kDa glycoprotein that regulates cellular proliferation, survival, and angiogenesis in many different cells through MET receptor tyrosine kinase.257., 258. It is present in breast milk as well as in fetal intestinal tissue.259., 260. HGF is secreted by mesenchymal cells in an inactive form and is subsequently activated by HGF activator (HGFA), which is synthesized primarily in the liver and to a lesser extent in the intestine.261., 262.

HGF plays an active role in the repair of

Conclusion

Growth factors play an important role in both the development of the gastrointestinal tract and the response to injury. These factors play important roles as mediators of cellular proliferation, migration, differentiation, and survival. In both the fetal and postnatal environment, the developing intestine is exposed to EGF, HB-EGF, GH, IGF, GLP-2, G-CSF, Epo, ITF, KGF, and HGF through luminal exposure to amniotic fluid and human milk. While the exact pathogenesis of NEC is unknown, the trophic

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