Serum Epidermal Growth Factor Levels Research Articles

Role of epidermal growth factor, interleukin-1 and lipid peroxidation in healing of experimental gastric ulcer in rats

The aim of our study was to evaluate the role of the epidermal growth factor (EGF), interleukin-1 (IL-1) and of lipid peroxides (TBARS) in the development and healing of experimental gastric ulcer in the rat. In 66 male Sprague Dowley rats, gastric ulcer was induced by means of the serosal application of 100% acetic acid. The animals were followed up for 1 (6 cases), 3 (6) and 5 (6) hours, and 1 (6 cases), 2 (6), 3 (7), 5 (6), 10 (6) 15 (6) and 21 (6) days. Five animals were sham operated. Samples from the ulcer margin (U), from an ulcer adjacent area (UAA) and from the antrum (A) were obtained. All treated animals developed gastric ulcer, evident just after one hour; the ulcer progressively healed and after 21 days all were scarred. Mucosal U-EGF significantly increased immediately after ulcer induction; it progressively and slowly decreased paralleling ulcer scarring. UAA-EGF and A-EGF behaved likewise: they significantly increased after 1, 3 and 5 hours and returned to normal levels just 1 day after ulcer induction. Variations in mucosal IL-1 were similar to those in EGF, a correlation being found between these two parameters. The EGF serum levels of rats with ulcers of 1 and 5 hours, were significantly lower than those of controls. One day after ulcer induction, U-TBARS levels were increased, and the high levels persisted, even when the ulcers had healed. In conclusion: (1) the rapid increase in mucosal EGF occurring in the presence of gastric ulcer may be consequent to an enhanced local and/or submandibular production; (2) the parallel behaviour between EGF and IL-1 suggests that this cytokine may play a role in stimulating EGF production; (3) chronic gastric ulcer is associated with an enhancement of lipid peroxidation phenomena, which persist after healing and which may create a “loci minoris resistentiae”.

Inhibitory effect of sialoadenectomy on hepatocellular tumourigenesis in male mice induced by 3'-methyl-4-dimethylaminoazobenzene.

Male C57BL/6xDS-F1 mice that had been treated with 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) neonatally were subjected to sialoadenectomy (removal of the submandibular salivary glands) 60 days after birth. The development of adenomatous nodules and carcinomas in the livers of these mice was compared with the livers of males without sialoadenectomy. The incidence of adenomatous nodules in sialoadenectomized males at 6, 8, 10, and 12 months was significantly lower than that in sham-operated animals. Carcinomas were found in the livers of both sham-operated and sialoadenectomized males that were 10 and 12 months old and were less frequent in sialoadenectomized males although the difference was significant only at the age of 12 months. Sialoadenectomy decreased the serum concentration of epidermal growth factor (EGF) by about 40%. The present results indicate that sialoadenectomy inhibits the development of hepatocellular tumours induced by 3'-Me-DAB in male mice, an effect which may be caused by decrease in the serum level of EGF.

Effects of sialoadenectomy and exogenous EGF on molar drift and orthodontic tooth movement in rats.

Effects on bone remodeling have been attributed to epidermal growth factor (EGF). Sialoadenectomy (SX) removes the major source of EGF in rodents and decreases both salivary and serum EGF levels. EGF effects on rat alveolar bone remodeling manifested by molar drift (MD) and orthodontic tooth movement (OTM) were examined using the following two approaches: 1) EGF depletion by SX and replacement by orally administered EGF (50 micrograms.animal-1.day-1); 2) sham rats supplemented with matching amounts of EGF. MD and OTM were measured using cephalometric radiographs; bone formation was measured histomorphometrically using tetracycline labeling. Normal MD was not detected after SX, and alveolar bone formation was significantly reduced both around the tooth and in nondental sites. Replacement EGF given to SX rats and supplemental EGF administered to sham rats changed the direction and enhanced the rate of MD. A mesially directed orthodontic force applied to the molars of SX animals increased bone formation on the distal aspect of the tooth roots. Supplemental EGF did not significantly affect OTM. EGF affects alveolar bone remodeling, as manifested clinically by alterations in normal maxillary MD.

Serum and plasma epidermal growth factor in thyroid disorders

Epidermal growth factor (EGF) is an important mitogen and its secretion in neonatal animals has been shown to be affected by thyroid hormone levels. EGF in blood of humans is found in both platelets (as reflected in its serum level) and in plasma; its origin in plasma remains unclear. Serum and plasma EGF were studied in a group of patients with thyroid disorders. Twenty hyperthyroid subjects (3M, 17F) aged 37.3 +/- 14.9 years and 10 hypothyroid patients (3M, 7F) aged 58.3 +/- 18.6 years were studied before and after euthyroidism was restored. Before treatment, serum EGF in the hyperthyroid patients was elevated compared to normal controls (501 +/- 376 vs 270 +/- 154 pmol/l, p less than 0.001). After treatment of hyperthyroidism, serum EGF returned to the normal levels (232 +/- 176 pmol/l). In contrast, serum EGF was not significantly different in the hypothyroid subjects either before or after treatment (151 +/- 194 and 237 +/- 153 pmol/l respectively). A significant correlation (r = 0.461, p less than 0.001) between serum EGF and serum-free thyroxine index (FTI) was found when all samples from both untreated and treated hyper- and hypothyroid patients were examined. Multiple regression analysis revealed that both serum FTI and platelet count independently affected the serum EGF levels. Similarly, plasma EGF was also elevated in untreated hyperthyroid patients with a median of 26.4 pmol/l (range less than 16.6-88.0), whereas all normal controls and hypothyroid subjects had unmeasurable levels.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of epidermal growth factor on liver lipid peroxidation and glutathione levels in lobectomized rats.

Epidermal growth factor (EGF) is a growth-promoting polypeptide which is found in highest levels in male mice in the submaxillary gland. It may also be a key factor in regeneration of the liver. We performed experiments with 18 male Wistar rats, divided into three groups. Hepatic left lobectomy (%30) was performed on the first group of rats. This group received an intraperitoneal injection of EGF for 7 days. The second group was the control group into which normal saline was injected for 7 days. The third group was sham-operated. On days 5 and 7 tomographic studies of liver were performed. On day 7 EGF levels, lipid peroxidation, and glutathione in liver were measured in all of the rats. While serum EGF levels did not show any significant change, the levels of lipid peroxide were decreased and glutathione was increased. Tomographic measurements indicated that administration of EGF increased the amount of regeneration.

Influence of the Fetus and Estrogen on Maternal Serum Growth Hormone, Insulin-Like Growth Factor-II, and Epidermal Growth Factor Concentrations during Baboon Pregnancy*

In the present study we determined whether the fetus and estrogen affect maternal serum concentrations of GH, insulin-like growth factor-II (IGF-II), and epidermal growth factor (EGF) and placental IGF-II formation in pregnant baboons. The objective was to ascertain whether the previously reported increase in placental formation and serum concentrations of IGF-I induced by removal of the fetus and, thus, estrogen in pregnant baboons was mediated by GH and whether it was specific for IGF-I. On day 100 of gestation (term is 184 days), fetuses were removed, and placentas were left in situ, i.e. fetectomy. After fetectomy, baboons received pellets of aromatizable androstenedione (50-150 mg every 10 days, sc; n = 8), were injected with estradiol (E2) benzoate (0.50-2.5 mg/day, sc; n = 8), or were not further treated (n = 6) on days 101-159 of gestation. Placental cells obtained on day 160 were dispersed in 0.1% collagenase, isolated via 50% Percoll centrifugation, then incubated for 24 h at 37 C in medium 199. Maternal serum E2 concentrations increased with advancing gestation in intact baboons, were decreased by 79% after fetectomy and, thus, removal of adrenal C-19 steroid estrogen precursors, and restored by androstenedione or E2 treatment after fetectomy. Mean serum GH was 20.2 +/- 0.6 ng/ml on days 101-160 in untreated intact animals. Fetectomy decreased (P less than 0.001) GH levels to 12.1 +/- 0.5 ng/ml. Androstenedione or E2 treatment after fetectomy restored serum GH to 20.8 +/- 1.1 and 22.4 +/- 0.6 ng/ml, respectively. Serum IGF-II was 1406 +/- 54 ng/ml on days 101-160 in controls and decreased (P less than 0.001) rapidly after fetectomy to a value (305 +/- 16) that was 78% lower than that in untreated baboons. Androstenedione or E2 treatment after fetectomy had no effect on the fetectomy-induced decrease in IGF-II levels. In vitro secretion of IGF-II by placental trophoblasts of fetectomized baboons (10.3 +/- 0.6 ng/ml.24 h) was 88% lower (P less than 0.001) than that in controls (85.6 +/- 15.7). Despite androstenedione or E2 treatment after fetectomy, placental IGF-II production remained low (9.2 +/- 1.1 and 8.8 +/- 0.4 ng/ml.24 h, respectively). The overall mean maternal serum EGF concentration was 379 +/- 20 pg/ml in the second half of baboon pregnancy. Fetectomy or treatment with androstenedione or E2 had no effect on serum EGF levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of Thyroid Hormone on Epidermal Growth Factor-Like Immunoreactivity and Growth Velocity in Cynomolgus Monkeys

To examine the potential role of epidermal growth factor (EGF) in mediating the effects of thyroid hormone on linear growth, we measured serum EGF levels by RIA in cynomolgus monkeys before and during methimazole-induced hypothyroidism, and after 9 weeks of T4 replacement at different doses. Ten castrated prepubertal monkeys were rendered hypothyroid by methimazole (0.0125% in drinking water for 12 weeks). Methimazole was continued, and T4 was then administered for 9-week intervals. Six weeks elapsed between successive T4 doses. The sequence of different T4 doses for each animal was random. Serum EGF level was measured at baseline and at the end of each treatment period with a newly developed RIA using a polyclonal antiserum against human recombinant EGF. Serum EGF level correlated significantly with the level of serum thyroxine but not with serum triiodothyronine, over the thyroxine dosage range of 1-4 micrograms/kg/day (r = 0.41, p less than 0.005). Lower-leg growth rate correlated significantly with serum EGF level over this same thyroxine dosage range (r = 0.41, p less than 0.005). These data are consistent with the hypothesis that EGF may mediate some of the effects of thyroid hormone on skeletal growth.

Toxicity of 3,4,5,3',4',5'-hexachlorobiphenyl to mink.

Diets supplemented with 0.01 or 0.05 ppm (mg/kg) of 3,4,5,3′,4′,5′-hexachlorobiphenyl (345-HCB) were fed to mink to investigate the toxicological manifestations of this toxic polychlorinated biphenyl congener in a sensitive species. Dietary exposure of mink to 0.05 ppm 3,4,5,3′,4′,5′-hexachlorobiphenyl for 135 days resulted in 50% mortality while no deaths occurred on 0.01 ppm 345-HCB. Clinical signs of toxicity included anorexia, bloody stools, disrupted molting patterns, and thickened, elongated and deformed nails. Ascites and gastric ulcers were present in animals that died. Statistically significant increases in liver, kidney, and adrenal gland weights were found in the 345-HCB-treated mink. Decreases in total and free triiodothyronine concentrations were observed in mink fed the 345-HCB-treated diets and total thyroxine was decreased in the mink fed 0.05 ppm 345-HCB. No consistent histopathologic lesions were found in the thyroid or adrenal glands of the 345-HCB-treated mink, nor were there any statistically significant differences between the 345-HCB-treated and the control mink in serum epidermal growth factor levels, plasma 17β-estradiol and progesterone concentrations, hepatic aminopyrine N-demethylase, and benzo(α)pyrene hydroxylase activities, hypothalamic norepinephrine, dopamine, and serotonin concentrations or in the incorporation of (3H) thymidine by concanavalin-A-stimulated lymphocytes.

Epidermal growth factor measurements in mouse plasma: method, ontogeny, and sex difference.

A highly sensitive mouse plasma (serum) epidermal growth factor (EGF) radioimmunoassay was utilized to determine EGF levels in mouse plasma and submandibular gland (SMG) at different ages. Plasma and serum levels were not different. Inferior vena caval blood was used because even at the age of 12 days EGF levels were markedly higher in neck blood. At 2 wk serum EGF levels were 60% of adult female levels. After a temporary decrease, mean EGF concentrations reached adult values at 31 and 60 days in the female but not yet in the male. In adults male serum EGF levels were twofold higher than female levels. This difference is parallel to but much smaller than the sex difference in SMG-EGF. SMG-EGF showed a very different ontogeny. Moreover, no correlation was present in the adults between the SMG and serum EGF concentrations. Testosterone treatment of adult females doubled their serum EGF levels, but the stimulated values were still below the mean of the male levels. The present observed plasma (serum) EGF levels in the mouse are 20-40% of previously reported values, probably because of the absence of EGF contamination from hair (urine) and milk.

Epidermal Growth Factor in the Submandibular Gland and Serum of Mice with Muscular Dystrophy: Chemical Properties in Dilute Gland Extracts*

Epidermal growth factor (EGF) has been measured in extracts of submandibular glands from mice with hereditary muscular dystrophy. RIA results show that adult male and female dystrophic mice have significantly less submandibular gland EGF than do unafflicted controls. Despite the differences in gland content of the protein, serum levels of EGF are similar in both dystrophic and control animals. Furthermore, submandibular gland concentrations of amylase are normal in the dystrophic mice, indicating that not all proteins synthesized by the glands are affected. Gel filtration studied reveal that the elution properties of EGF in extracts of glands from dystrophic and control animals are indistinguishable. Unexpectedly, the chromatographic profiles indicate that most of the EGF in gland extracts elutes as a low molecular weight protein when the molecule is studied at low, biologically active concentrations; only a small portion of the protein is associated with a high molecular weight complex. Under the same experimental conditions, submandibular gland nerve growth factor maintains its association with other components in a high molecular weight form.

Renal Hypertension

Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor–derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node–negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis.