HB-EGF与坏死性小肠结肠炎的研究进展

坏死性小肠结肠炎（necrotizing enterocolitis,NEC）是一种常见且严重的胃肠道疾病,主要发生在早产儿.尽管采取了诸多措施,NEC的病死率仍然很高.近年来,诸多研究显示肝素结合表皮生长因子样生长因子（heparin-binding epidermal growth factor-like growth factor,HB-EGF）可以保护肠道上皮细胞免受多种伤害.并且,在成年大鼠肠道缺血再灌注损伤模型和新生NEC模型鼠进行的实验显示,HB-EGF可以保护肠道免受损伤.这些研究为NEC的治疗和预防提供了一个新的研究方向.     

血小板活化因子与新生儿坏死性小肠结肠炎

新生儿坏死性小肠结肠炎(necrotizing enterccolitis,NEC)是新生儿(特别是早产儿)最常见和最严重的疾病之一。由于肺表面活性物质的应用及医务人员综合素质的提高,许多小早产儿得以存活,然而近30年来NEC的发病率并未下降,主要原因是NEC的发病机制尚不十分清楚。     

Epidermal growth factor reduces hepatic sequelae in experimental necrotizing enterocolitis

BACKGROUND AND AIM: Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. We recently demonstrated that the gut/liver axis plays an important role in the pathophysiology of NEC through the release of inflammatory mediators into the intestinal lumen. We have also shown that supplementation of formula with epidermal growth factor (EGF) dramatically decreases ileal pathology associated with experimental NEC. In this study, we examined the effects of EGF on the liver portion of the gut/liver axis in the neonatal rat model of NEC. METHODS: Newborn rats were divided into three experimental groups, NEC, hand-fed with growth-factor free formula; NEC + EGF, hand-fed with formula supplemented with 500 ng/ml rat EGF; or DF, dam fed. All animals were exposed to asphyxia and cold stress twice daily for 4 days to develop NEC. RESULTS: EGF receptor expression was significantly (p 相似文献   

Effect of necrotizing enterocolitis on urinary epidermal growth factor levels

The pattern of urinary epidermal growth factor/creatinine levels in necrotizing enterocolitis was examined in 75 infants (in 28 infants the diagnosis of necrotizing enterocolitis was considered; 47 infants were studied for effect of surgery or nutrition on epidermal growth factor levels). There was a consistent and significant increase in epidermal growth factor/creatinine values at the time of diagnosis of necrotizing enterocolitis compared with baseline values. Epidermal growth factor levels in infants without necrotizing enterocolitis and in early nutrition remained unchanged. These results suggested that urinary epidermal growth factor/creatinine levels may differentiate stage II and III necrotizing enterocolitis from stage I disease. The increased epidermal growth factor/creatinine levels may be related to the absorption into the circulation of preexisting gastrointestinal tract epidermal growth factor through damaged tissue or to increased synthesis by the gastrointestinal tract in response to the injury caused by necrotizing enterocolitis.     

Intestinal microcirculation and necrotizing enterocolitis: The vascular endothelial growth factor system

Necrotizing enterocolitis (NEC), a leading cause of morbidity and mortality in preterm neonates, is a devastating disease characterized by intestinal tissue inflammation and necrosis. NEC pathogenesis is multifactorial but remains unclear. Translocation of bacteria and/or bacterial products across a weak intestinal barrier in the setting of impaired mucosal immunity leads to an exaggerated inflammatory response and secondary mucosal epithelial injury. In addition to prematurity, other risk factors for NEC include congenital heart disease, maternal pre-eclampsia with placental vascular insufficiency, severe anemia and blood transfusion – all conditions that predispose the intestine to ischemia. We recently found that maldevelopment of the intestinal microvasculature plays an important role in NEC pathogenesis. Here we review the evidence supporting a role for defective development of the intestinal mucosal microvasculature and perturbations of intestinal blood flow in NEC, emphasizing the importance of vascular endothelial growth factor (VEGF) and the VEGF receptor-2 signaling pathway.     

The effect of vascular endothelial growth factor overexpression in experimental necrotizing enterocolitis

Purpose

Necrotizing enterocolitis (NEC) is a serious condition, predominantly observed in premature infants. We used an experimental NEC model to investigate the effects of vascular endothelial growth factor (VEGF) cloned into a plasmid.

Materials and methods

Twenty-four newborn Wistar albino rats were randomized equally into three groups as follows: control, NEC and NEC+VEGF. NEC was induced by hyperosmolar enteral formula feeding, exposure to hypoxia/reoxygenation and cold stress. In the NEC+VEGF group, VEGF (1 μg) incorporated into plasmid (2 μg) was administered subcutaneously once daily for a total of 3 days starting on the first day of the NEC procedure. All rats were sacrificed on the 4th day of life, and the specimens were harvested for histopathological and biochemical examinations [including tissue oxidative stress (malondialdehyde and nitric oxide), inflammation (myeloperoxidase, interleukin-6 and tumor necrosis factor alpha) and apoptosis (caspase-3 activity) parameters].

Results

In the NEC+VEGF group, tissue malondialdehyde, nitric oxide, interleukin-6, tumor necrosis factor alpha levels and caspase-3 activity were significantly decreased. In addition, the myeloperoxidase level was increased compared to that of the NEC group (p < 0.05). Histopathologically, VEGF overexpression enhanced angiogenesis, alleviated villous atrophy and tissue edema (p < 0.05).

Conclusion

VEGF overexpression with plasmids seems to be a promising approach in the management of NEC.     

Role of epidermal growth factor in the pathogenesis of neonatal necrotizing enterocolitis

Neonatal necrotizing enterocolitis (NEC) is an increasingly frequent condition encountered in premature infants for which the etiology is not well understood. Epidermal growth factor (EGF) is abundant in many fluids bathing the fetal and neonatal gastrointestinal tract, including amniotic fluid, saliva, and breast milk. EGF is acknowledged to be important for normal intestinal development as well as repair following injury to the gastrointestinal mucosa. There appears to be mounting evidence to support a possible link between deficient EGF production and the development of NEC. The relevant evidence for the role of EGF in intestinal development and mucosal repair, as well as its potential involvement in the genesis of NEC will be reviewed.     

Platelet-activating factor, tumor necrosis factor, hypoxia and necrotizing enterocolitis

The pathogenesis of necrotizing enterocolitis (NEC) is poorly understood. We have established several animal models of NEC by using a combination of various stimuli and stress, including endotoxin, PAF, TNF, and hypoxia. We discuss the mechanism of their actions and the possible roles of these factors in the pathogenesis of human NEC.     

Intestinal obstruction following necrotizing enterocolitis (author's transl)

The increase in survival from necrotizing enterocolitis results in an increased rate of late sequelae. We would like to take the opportunity to emphasize these new complications by a review of our patient material. 11 (23.9%) patients from a total number of 46 showed signs and symptoms of intestinal obstruction at different points in the course of the disease. In two surviving patients out of this group of 11, a resection of postinflammatory gut stenosis had to be performed within the first year. In the 9 children who died, particular emphasis is being paid in the autopsy reports to obstructive lesions in the gastrointestinal tract. Due to this rather frequent event (23.9%) of postinflammatory formation of strictures and stenoses in the recovery from NEC a functional radiographic study of the intestinal patency seems mandatory before discharge of any patient with NEC with operative or conservative treatment.     

Heparin-binding angiogenic factors (basic fibroblast growth factor and vascular endothelial growth factor) in early neonatal life.

This study investigated whether serum levels of the potent angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are abundantly produced in utero by the placenta and fetal tissues, change after birth at term, consequent to diminished angiogenic but increased adaptational demands in extrauterine life. Moreover, whether serum levels of the above factors correlate with sex, birth weight, or mode of delivery was also evaluated. One milliliter of blood was drawn from 30 healthy, appropriate for gestational age, full-term infants on d 1 (N1) and 4 (N4) postnatally. In 10 of the above cases maternal and umbilical cord blood samples were also drawn. Serum was analyzed by enzyme immunoassays, using commercial kits. Levels of bFGF and VEGF were significantly lower in maternal serum than in umbilical cord (p = 0.02 and 0.036, respectively) or N1 (p = 0.009 and 0.006, respectively) and N4 serum (p = 0.009 and 0.006, respectively). Levels of bFGF in umbilical cord serum did not differ significantly from those in N1 and N4. In contrast, levels of VEGF rose in N1, differing significantly from levels in umbilical cord serum (p = 0.008). Both factors did not change from N1 to N4. Neither bFGF nor VEGF serum levels depended on sex, mode of delivery, or birth weight. In conclusion, bFGF levels in neonates do not differ from levels in fetuses, possibly reflecting diminished angiogenesis in extrauterine life, which already has started in utero. On the contrary, neonatal levels of VEGF rise significantly after birth, possibly signifying adaptation demands, in addition to angiogenesis, as VEGF is also considered a regulator of normal function.     

Heparin-binding epidermal growth factor-like growth factor and intestinal ischemia-reperfusion injury

Intestinal ischemia/reperfusion (I/R) injury affects patients of different ages, especially premature babies and the elderly. The outcome after intestinal I/R is often dismal, which may be attributed to loss of the barrier and immune functions of the intestines, as well as development of secondary injury in remote organs. The available treatment for advanced gut ischemia mandates extensive resection, which may cause growth retardation in infants and nutritional problems in the elderly. Throughout the past decade we have been investigating the potential therapeutic role of heparin-binding epidermal growth factor-like factor (HB-EGF) in intestinal I/R. The mitogenic and chemoattractant functions of HB-EGF formed the initial rationale for our investigations. In addition, HB-EGF is a potent antiapoptotic protein that enables cells and tissues exposed to different apoptotic stimuli to survive hypoxic, oxidative, and nutritional stresses. HB-EGF is known to have a vital role in wound healing and postischemic regeneration in different organs. In the current review, we summarize the results of our findings of the beneficial effects of HB-EGF in intestinal I/R, supported by additional evidence from the literature and an explanation of different possible mechanisms of its actions. Collectively, the data strongly suggest a potential therapeutic role for the use of HB-EGF to treat intestinal ischemic diseases such as I/R and necrotizing enterocolitis.