表皮生长因子及其受体与胃肠道疾病

表皮生长因子(EGF)是最重要的促细胞生长因子之一,消化道中EGF含量远远高于血循环中的浓度。近年研究表明,EGF对许多胃肠道良性疾患有治疗作用,同时也发现EGF和EGFR拮抗剂可以影响恶性肿瘤的发生、发展和消退。     

细胞因子

1.与肝脏再生相关的细胞因子:现发现在肝再生时,成纤维细胞生长因子(FGF)、表皮生长因子(EGF)、转化生长因子α(TGFα)、和肝细胞生长因子(HGF)对肝细胞的DNA合成可能起生理上的诱导因子作用。它们通过自身分泌和旁分泌机制起作用。转化生长因子β使EGF和TG     

在胆囊收缩素对肿瘤细胞的促生长效应中是否有表皮生长因子参与作用?

胆囊收缩素(CCK)和表皮生长因子(EGF)为大家熟知的促进细胞、组织生长的营养性激素和生长因子。两者能对人多种肿瘤具有促生长作用,但其作用机制未充分阐明,有待于深入研究。本文试图从一个新的方面,即CCK和EGF之间的关系来阐明CCK促生长作用的机制,包括阻断EGF作用     

体外转化生长因子-β1与表皮生长因子对人前列腺上皮细胞增殖的作用调节

目的　体外观察转化生长因子 β1(TGF β1)、表皮生长因子 (EGF)对前列腺上皮细胞增殖的调节作用。　方法　胶原酶消化组织 ,建立原代前列腺上皮细胞系 ,细胞培养于无血清培养基中。前列腺特异抗原 (PSA)、Pan Keratin等免疫组织化学染色鉴定培养细胞。绘制细胞生长曲线和运用细胞增殖ELISA染色 (BrdU)方法观察传代后细胞的生长状况及不同剂量的生长因子TGF β1、EGF对细胞增殖的作用。　结果　培养细胞具有典型的上皮细胞形态特征 ,PSA、Pan Keratin染色阳性 ,细胞传代 5～ 7次后开始衰退。不同培养基条件可明显地影响细胞生长活性。EGF促进细胞增殖活性 ,TGF β1则抑制增殖 ,其作用与剂量成正比。此外 ,EGF与TGF β1相互减弱对方的作用。　结论　体外培养的人前列腺上皮细胞增殖受生长因子TGF β1和EGF调节 ,结果提示TGF β1、EGF可能在前列腺增生 (BPH)发病中起重要作用     

体外转化生长因子—β1与表皮生长因子对人前列腺上皮细胞增作用调节

目的：体外观转化生长因子－β1(TGF-β1）、表皮生长因子（EGF）对前列腺上皮细胞增殖的调节作用。方法：胶原酶消化组织，建立原代前列腺上皮细胞系，细胞培养于无血清培养基中。前列腺特异抗原（PSA）、Pan-Keratin等免疫组织化学染色鉴定培养细胞。给制细胞生长曲线和运用细胞增殖ELISA染色（BrdU)方法观察传代后细胞的生长状况及不同剂量的生长因子TGF-β1、EGF对细胞增殖的作用。结果：培养细胞具有典型的上皮细胞形态特征，PSA、Pan-Keratin染色阳性，细胞传代5－7次开始衰退。不同培养基条件可明显地影响细胞生长活性。EGF促进细胞增殖活性，TGF-β1则抑制增殖，其作用与剂量成正比。此外，EGF与TGF-β1相经减弱对方的作用。结论：体外培养的人前列腺上皮细胞增殖受生长因子TGF-β1和EGF调节，结果提示TGF-β1、EGF可能在前列腺增生（BPH）发病中起重要作用。     

表皮生长因子与慢性萎缩性胃炎研究进展

表皮生长因子(EGF)是最早被发现的多肽类生长因子之一,它能提高葡萄糖和氨基酸的吸收,刺激蛋白质DNA和RNA的合成。近年来的研究发现,表皮生长因子家族与胃粘膜疾病关系密切。此文综述EGF的结构和生物学活性,及其在萎缩性胃炎发生发展和治疗中的作用。     

原发性肝癌患者血清表皮生长因子与甲胎蛋白的相关研究

研究表皮生长因子 (EGF)在原发性肝癌患者中的含量变化及与甲胎蛋白的相关关系 ,以探讨表皮生长因子在原发性肝癌发生、发展过程中的作用和意义。采用放射免疫方法测定 30例原发性肝癌患者和 4 8例健康体检人群的血清表皮生长因子和甲胎蛋白 (AFP)。结果发现原发性肝癌组患者EGF含量明显低于健康对照组且有显著性差异 ;经相关分析血清EGF与AFP含量间无相关性关系 (r =0 16 4 3,P >0 0 5 )。表明EGF含量变化在肝癌早期诊断方面有一定的临床价值 ,同时与AFP无相关关系 ,也说明了两者在肝癌发生机制中的不同作用     

表皮生长因子及谷氨酰胺对大鼠乙酸性结肠炎保护作用的病理学研究

目的:本文肌注表皮生长因子EGF和(或)饲喂谷氨酰胺GLN防治大鼠乙酸性结肠炎。方法:Sprague-Dawley系大鼠体重200—220g,40只分为乙酸组、EGF组、GLN组、EGF GLN组各10只,从大体.光镜、电镜(透射、扫描)观察结肠粘膜的损伤情况。结果:上述4组结肠粘膜损害的指数分别为3.11±0.93,1.78±0.97,1.30±0.48及1.10±0.32(P<0.01)。镜下观察也有明显疗效,以EGF GLN组为最佳。结论:EGF及GLN对结肠粘膜细胞形态结构具有保护作用,且优于两者单独作用,这为表皮生长因子、谷氨酰胺用于防治人类溃疡性结肠炎提供了理论依据。     

表皮生长因子与慢性萎缩性胃炎研究进展

表皮生长因子(EGF)是最早被发现的多肽类生长因子之一，它能提高葡萄糖和氨基酸的吸收，刺激蛋白质DNA和RNA的合成。近年来的研究发现，表皮生长因子家族与胃粘膜疾病关系密切。此文综述EGF的结构和生物学活性，及其在萎缩性胃炎发生发展和治疗中的作用。     

给药条件下表皮生长因子对萎缩性胃炎逆转作用研究

以往研究表明 ,表皮生长因子 (EGF)对萎缩性胃炎(CAG)具有增殖、逆转萎缩的作用。但另有研究表明 ,表皮生长因子受体 (EGFR)及癌基因C erbB2扩增表达增加 ,与高水平的EGF结合后使细胞进入致癌基因表达的最终共同通道 ,打破正常的反馈机制 ,最终形成肿瘤。因此 ,各种采用内、外源性EGF的治疗 ,存在着是否同时致癌的危险性 ,有必要进一步证实EGF的抗萎缩疗效 ,并探讨在内、外源性EGF对CAG胃黏膜的作用下 ,从EGFR及其相关的C erbB2基因蛋白表达水平变化来明确其治疗CAG的安全性 ,以权衡利弊。一、材料与方法采用健康、性成熟、…     

Minimal hydrolysis of epidermal growth factor by gastric fluid of preterm infants.

Epidermal growth factor (EGF), present in high concentrations in milk, may play a role in growth of the gastrointestinal tract. Resistance to proteolytic degradation in the stomach is necessary if ingested EGF is to function within the gastrointestinal tract. Although EGF stability to low pH and proteases predicts gastric survival, the extent of digestion in the stomach remains to be defined. Consequently, we measured gastric degradation of 125I-human recombinant EGF in preterm infants with an in vitro method in which EGF was incubated at 37 degrees C with stomach fluid at pH 1.8, 3.2, and 5.8 followed by analysis of degradation products. As maximal acid proteolytic activity is present one hour after feeding in preterm infants, fluid was obtained at that time from 18 infants with a mean gestational age at birth of 30.4 (3.0) (SD) weeks and a postnatal age of 26.3 (12.7) days at sampling. Incubations for up to 60 minutes revealed minimal loss of trichloroacetic acid precipitable radioactivity, in contrast to the substantial hydrolysis of iodinated casein which occurred under the same conditions. Chromatography of reaction mixtures on Sephadex G-25 showed a single major peak of radioactivity which coeluted with EGF. Epidermal growth factor also retained greater than 75% of its ability to bind to anti-EGF affinity columns and placental membrane receptors after incubation with gastric fluid. These data support the concept of substantial gastric survival of ingested EGF in a potentially biologically active form in preterm infants.     

Effect of gonadectomy on epidermal growth factor values in the gastrointestinal tract of male and female CD-1 mice.

The effects of gonadectomy on the epidermal growth factor (EGF) concentrations in the gastrointestinal tract of CD-1 mice were studied. The EGF concentrations in the gastrointestinal tissues were always higher in males than in females. Gonadectomy led to a decrease in the EGF concentration in males, and an increase in females. Gonadectomy with sialoadenectomy led to a decrease in the EGF concentrations in the gastrointestinal tract of both sexes; the most significant effect being observed in the stomach. Orchidectomy led to a decrease in total body weight, and to a significant decrease in the weight and the protein concentration (ng.g-1 wet weight of tissue) of the submandibular gland, but had no significant effect on the other tissues of the gastrointestinal tract of male mice. Body, tissue weights, and protein concentrations did not change with oophorectomy. This study shows that male and female gonads have a profound effect on the EGF content of the tissues of the gastrointestinal tract and suggests that the submandibular gland also influences the EGF concentration in gastrointestinal tissues in mice.     

Increased duodenal expression of transforming growth factor-alpha and epidermal growth factor during experimental colitis in rats

OBJECTIVE/BACKGROUND: Epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) protect gastrointestinal mucosa against injury. Having shown earlier, that TGFalpha but not EGF is locally increasingly expressed after mucosal injury in the colon, we now wanted to explore the pattern of expression of EGF and TGFalpha in the remaining gastrointestinal tract and to infer from the pattern of expression, to possible signals for the induction of the growth factor expression and further mechanisms for mucosal protection. DESIGN/METHODS: The trinitrobenzene sulfonic acid/ethanol-induced model of colitis in rats was used. TGFalpha-mRNA and EGF-mRNA expression was evaluated in inflamed and noninflamed colon, in the ileum, jejunum, duodenum, stomach, and in the submandibulary glands. RESULTS: A significant increase of TGFalpha-mRNA and EGF-mRNA expressions was detected in the duodenal mucosa and a significant increase in TGFalpha-mRNA expression was observed in the inflamed colonic mucosa after mucosal injury in the colon within the first hours of colitis. CONCLUSION: The increased expression of EGF and TGFalpha in the duodenum may lead to neutralization of gastric acid and proteolytic enzymes in the upper gastrointestinal tract during the course of colitis. Possible signals for the increased expression of EGF and TGFalpha presumably are fasting, parasympathetic, or adrenergic parts of the enteric nervous system or yet unknown mechanisms.     

Epidermal growth factor content of submandibular glands is increased in rats with experimentally induced gastric lesions

Occurrence and growth-promoting effect suggest that epidermal growth factor (EGF) is involved in the maintenance of the gastrointestinal mucosa. The aim of this study was to ascertain whether rats with gastric lesions, induced by cold-water stress, ethanol, or indomethacin, have altered EGF levels in their gastrointestinal tract compared with controls. For this purpose we established a solid-phase enzyme immunoassay and measured the amount of immunoreactive EGF (IR-EGF) in extracts of the submandibular gland, stomach, duodenum, jejunum, ileum, and colon. In the submandibular glands of control rats the IR-EGF content was 100-400 times higher than in the gastrointestinal tract. In animals with experimentally induced ulcer the IR-EGF content was increased in the submandibular glands (1480 versus 423 ng/g), duodenum (11.4 versus 5.8 ng/g), and colon (4.1 versus 1 ng/g), whereas no change was observed in the stomach and jejunum. When the formation of lesions was prevented by omeprazole (stress) or prostaglandin E2 (ethanol and indomethacin), the IR-EGF increase in submandibular glands and duodenum was abolished. This indicates that mechanisms regulating the synthesis and secretion of submandibular EGF might be of importance in the development of gastric and duodenal ulcers.     

The epidermal growth factor receptor (EGF-R) is present on the basolateral, but not the apical, surface of enterocytes in the human gastrointestinal tract.

BACKGROUND: While it is clear that luminal epidermal growth factor (EGF) stimulates repair of the damaged bowel, its significance in maintaining normal gut growth remains uncertain. If EGF is important in maintaining normal gut growth, the EGF receptor (EGF-R) should be present on the apical (luminal) surface in addition to the basolateral surface. AIMS/SUBJECTS/METHODS: This study examined the distribution of the EGF-R in the epithelium throughout the human gastro-intestinal tract using immunohistochemistry, electron microscopy, and western blotting of brush border preparations. RESULTS: Immunostaining of the oesophagus showed circumferential EGF-R positivity in the cells of the basal portions of the stratified squamous epithelium but surface cells were EGF-R negative. In the normal stomach, small intestine, and colon, immunostaining localised the receptor to the basolateral surface with the apical membranes being consistently negative. EGF-R positivity within the small intestine appeared to be almost entirely restricted to the proliferative (crypt) region. Western blotting demonstrated a 170 kDa protein in whole tissue homogenates but not in the brush border vesicle preparations. CONCLUSIONS: As the EGF-R is located only on the basolateral surfaces in the normal adult gastrointestinal tract, the major role of luminal EGF is probably to stimulate repair rather than to maintain normal gut growth.     

Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation.

The in vivo studies presented here demonstrate that epidermal growth factor (EGF) is an important autocrine and/or paracrine mediator of estrogen-induced growth and differentiation in mouse uterus and vagina. An antibody specific for EGF significantly inhibited estrogen-induced uterine and vaginal growth, thereby implicating EGF involvement in estrogen action. Furthermore, EGF administered via slow-release pellets in ovariectomized mice acted as a potent uterine and vaginal mitogen as well as an inducer of vaginal keratinization. Experiments with ovariectomized, adrenalectomized, hypophysectomized mice indicated that EGF mitogenesis does not require pituitary or adrenal hormones. Treatment with EGF also mimicked estrogen in the induction of uterine lactoferrin (a major estrogen-inducible secretory protein) mRNA and protein. These data suggest that EGF has estrogen-like effects in the promotion of cell growth in the reproductive tract and that EGF may serve as an important mediator of estrogen action in vivo.     

Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update

Epidermal growth factor (EGF) is a 6,000 Da polypeptide hormone produced by glands of the gastrointestinal tract, namely the salivary and Brunner's glands. It is found in a wide variety of external secretions as well as in blood and amniotic fluid. In fetal and neonatal life, EGF appears to play an important role in the development of the oral cavity, lungs, gastrointestinal tract and eyelids. Its presence in cells of the central nervous system suggests that it also plays a role in modulating the development of this system. In adult animals, the function of EGF is much less well understood. In rodents, it apparently modulates acid secretion from parietal cells in the stomach, and it undoubtedly plays an important role in wound healing, either through its localization within skin or by the licking of wounds with EGF-containing saliva. Considerable evidence now suggests that it may be one of the key factors in initiating liver regeneration after partial hepatectomy or chemical injury. The liver appears to be the principal organ which regulates the circulating level of EGF. In fact, EGF is cleared so efficiently by the liver that only the peripheral cells of the lobule (zone 1) sequester EGF, and little remains in the circulation for cells in the more distal zones (zones 2 and 3). In the liver, EGF normally binds to a plasma membrane receptor and is internalized within the liver cell, where the vast majority of EGF and its receptor are destroyed in lysosomes. A small but consistent quantity of EGF enters the bile intact. In the regenerating liver, however, the lysosomal pathway appears to be shut down, and the EGF is diverted to hepatocyte nuclei prior to the initiation of DNA synthesis. Nuclear EGF is found free as well as bound to a high-molecular-weight protein which has many characteristics identical to the plasma membrane EGF receptor. The plasma membrane receptor is a large transmembrane glycoprotein of 170,000 Da containing four domains: an extracellular EGF-binding portion, a hydrophobic membrane-spanning segment, a proximal cytoplasmic domain which binds ATP and protein substrates containing tyrosine for phosphorylation and a terminal cytoplasmic portion with 3 tyrosines which undergo autophosphorylation after EGF binding.(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of submandibular saliva and epidermal growth factor in gastric cytoprotection

The role of submandibular epidermal growth factor in protection of the gastric mucosa was investigated in rats. Removal of the submandibular glands and thereby submandibular epidermal growth factor (EGF) caused rats to develop gastric lesions (ulcerations and ulcers) after administration of the duodenal ulcerogen cysteamine. The median output of EGF in gastric juice was reduced from 45.6 pmol/12 h (total range 17.5-65.0) in unoperated controls to less than 0.06 pmol/12 h (total range less than 0.06-1.82) in rats given cysteamine after extirpation of the submandibular glands. The contents of EGF in the submandibular glands was unchanged during cysteamine treatment. Furthermore, the effects of intragastric instillation of exogenous EGF, infusion of saliva without EGF, and infusion of saliva with a high concentration of EGF on the development of cysteamine-induced gastric lesions were investigated in rats without submandibular glands. Exogenous EGF and saliva with a high but still physiological concentration of EGF significantly reduced the median area in the stomach displaying ulcers and ulcerations, whereas saliva without EGF had no effect. Although EGF is a known inhibitor of gastric acid secretion, the dose used in the present study had no effect on gastric acid secretion in chronic gastric fistula rats; removal of the submandibular glands also did not have any such effect. We conclude that exocrine secretion of submandibular EGF has a cytoprotective function in the stomach, an effect that may be physiological.     

Differential absorption and distribution of epidermal growth factor and insulin-like growth factor in diabetic NOD mice

Previous studies have shown that absorption of growth factors occurs through the gastrointestinal tract and the oral cavity. The non-obese diabetic (NOD) mouse, a model for spontaneous development of type 1 insulin-dependent diabetes (IDDM), was evaluated for the absorption and systemic distribution of growth factors. Radiolabeled epidermal growth factor (EGF) and insulin-like growth factor, type I (IGF-I), were administered by gavage into the stomach or by lozenge into the sublingual vasculature of either diabetic or nondiabetic mice. After a time-dependent uptake, the levels of absorption and distribution through the tissues were measured. A similar time course of EGF absorption following gavage administration was determined for NOD and C57BL/6 mice, with a maximum tissue distribution by 30-min post infusion. Diabetic NOD mice showed similar levels of IGF uptake and tissue distribution compared with nondiabetic NOD and normal healthy C57BL/6 mice, whether administered by gavage or sublingual lozenge. On the other hand, gavage uptake and tissue distribution of EGF was significantly higher in diabetic mice when compared to sublingual administration in nondiabetic NOD or C57BL/6 healthy control mice. These findings suggest that the overall potential uptake and distribution of saliva-derived growth factors in systemic wound-healing processes is retained with diabetes onset, and may offer a new avenue to treating this complication of diabetes.