Absence of colon as the predominant risk factor for liver fibrosis in adults requiring home parenteral nutrition.

BACKGROUND: Liver fibrosis is a well-known complication of long-term use of parenteral nutrition in patients with intestinal failure associated to the nutrient composition in parenteral nutrition. This study investigates the prevalence of significant liver fibrosis and identifies risk factors for liver fibrosis. METHODS: This was a retrospective study of 35 parenteral nutrition-dependent patients with intestinal failure and 54 patients with intestinal insufficiency and oral nutrition only with a valid liver stiffness measurement obtained with transient elastography from November 2016 to August 2018. Clinical and demographic parameters including age, fat mass index and fat-free mass index, intact colon or colectomy, and nutritional management were analyzed for their association with liver stiffness. RESULTS: A prevalence for liver fibrosis (liver stiffness >7.0 kPa) was established at 37.1% in parenteral nutrition-dependent patients and at 22.2% in patients on oral nutrition. Several factors were significantly and independently associated with liver fibrosis including lipids in home parenteral nutrition (OR 10.66, p = 0.010) and colectomies (OR 3.24, p = 0.036). CONCLUSION: More than a third of patients receiving home parenteral nutrition have liver fibrosis. Several risk factors were demonstrated such as the amount of lipids and performed colectomies despite current international guidelines for lipids are followed. Our findings emphasize suggest a new perspective to prevent significant hepatic complications: colectomies.

Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

The effect of epidermal growth factor on the incremental Young's moduli in the rat small intestine.

Biomechanical remodelling of the rat small intestine after treatment with epidermal growth factor (EGF) subcutaneously for 2 days (n=6), 4 days (n=6), 7 days (n=6), and 14 days (n=4) was studied. The incremental circumferential, longitudinal and cross moduli close to the in vivo state were computed from bi-axial test data (combined inflation and axial stretching) by a least square method. The moduli in the circumferential direction and the longitudinal direction differed in all groups, i.e. the mechanical properties were anisotropic in both normal and EGF-treated rats. Time-dependent variation existed for the Young's moduli in all directions during EGF treatment (P<0.05). The circumferential modulus decreased during the first 7 days of EGF treatment and it almost remodelled back to that of the control group after 14 days treatment. The incremental modulus in the circumferential direction ranged between 17.4 and 24.2 kPa. The modulus in the longitudinal direction ranged between 22.9 and 32.4 kPa. The longitudinal modulus after 4 days EGF treatment was significantly larger than that of control group (P<0.02). The cross modulus decreased during the first 4 days of EGF treatment thereafter it increased to a maximum at 7 days. The values for the cross moduli were between 4.7 and 6.6 kPa. In conclusion, the mechanical properties in the intestinal wall are anisotropic and remodel during treatment with EGF.

Inverted Meckel's diverticulum masquerading Crohn disease in the small intestine.

We describe a case of Meckel's diverticulum containing ectopic gastric epithelium being the leading point in an ileoileal intussusception. This is usually an acute or subacute condition, but in this case the course was protracted and the case was misdiagnosed and treated as Crohn disease.

Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats.

Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P < 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.

Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver.

BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth factor I for either 3 or 7 days. The amount of epidermal growth factor receptor, transforming growth factor-alpha, and epidermal growth factor mRNA was quantitated by a calibrated user-friendly RT-PCR assay (CURT-PCR), and the expression of transforming growth factor-alpha and epidermal growth factor peptides was quantitated by ELISA. RESULTS: Control liver (n=16) contained a mean (+/-SD) value of 12.7+/-7.4x10(-18) mol epidermal growth factor receptor mRNA, 3.8+/-2.0x10(-18) mol transforming growth factor-alpha mRNA and 0.8+/-0.4x10(-18) mol epidermal growth factor mRNA per microg total RNA and 9.8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein transforming growth factor-alpha. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-alpha and epidermal growth factor receptor, as well as the expression of transforming growth factor-alpha peptide. The level of epidermal growth factor receptor and transforming growth factor-alpha mRNA expression was found to correlate both in control and growth factor-treated animals, whereas the expression of epidermal growth factor receptor and epidermal growth factor showed no correlation. Marked differences were seen upon activation of the two growth factor systems, as epidermal growth factor, but not insulin-like growth factor I treatment, increased the plasma concentration of urea and decreased the concentration of insulin-like growth factor I and the liver enzymes, alanine aminotransferase and alkaline phosphatase. CONCLUSION: Our results show that epidermal growth factor and insulin-like growth factor I, which belong to two different growth factor systems, both induce a correlated upregulation of transforming growth factor-alpha and epidermal growth factor receptor mRNA in rat liver. Although marked differences were observed after treatment with either epidermal growth factor or insulin-like growth factor I on the liver as reflected in the plasma concentrations of e.g. liver enzymes, a common motif in their action involves an upregulation of the expression of the epidermal growth factor system.

The effect of epidermal growth factor and IGF-I infusion on hepatic and renal expression of the IGF-system in adult female rats.

Systemic administration of epidermal growth factor (EGF) in neonatal rats results in reduced body weight gain and decreased circulating levels of IGF-I, suggesting its involvement in EGF-induced growth retardation. We investigated the effect of EGF and/or IGF-I administration for 7 days on circulating IGF-I and IGFBP levels and hepatic and renal IGF-system mRNA expression profiles in adult female rats. EGF administration (30 microg/rat/day) did not influence body weight, liver or kidney weight. In contrast, IGF-I (400 microg/rat/day) and EGF/IGF-I administration increased both body weight and kidney weight. Also, serum IGF-I and the 30 kDa IGFBPs (IGFBP-1 and -2) were significantly increased in these groups. Serum IGFBP-3 levels increased in the IGF-I group along with increased hepatic IGFBP-1 and -3 mRNA levels. In contrast, in the EGF administration group serum IGFBP-3 levels were significantly decreased; however, the mRNA levels remained unchanged. In the EGF/IGF-I administration group, serum IGF-I and IGFBP-3 levels were significantly lowered when compared with the IGF-I administration group. This was in contrast to the effect on kidney weight increase that was identical for the IGF-I and EGF/IGF-I groups. The decrease in serum IGFBP-3 was not reflected at the hepatic IGFBP-3 mRNA level. IGFBP-3 expression might be regulated at a post-transcriptional level although EGF induced IGFBP-3 proteolysis could not be demonstrated in vitro. We conclude that EGF administration reduced serum IGFBP-3 whereas IGF-I administration increased the level of IGFBP-3 and IGF-I and resulted in an increased body and kidney weight in adult female rats.

Time-dependent changes in the luminal surface and mass of the rat colon during prolonged systemic treatment with epidermal growth factor.

BACKGROUND: Systemic treatment with epidermal growth factor (EGF) for 4 weeks increases the colonic mucosal weight and surface area. The present study was initiated to describe the time-dependent colonic changes during prolonged treatment with EGF. METHODS: Forty-eight female Wistar rats were allocated into five groups receiving subcutaneous EGF treatment (150 microg/kg/day) for 0 (controls), 1, 2, 3, or 4 weeks. EGF was administered in the weeks before they were killed. By means of modern stereologic techniques (point counting and vertical sections), the weights of the colonic wall layers and the luminal surface area were measured on histologic sections. The colon was subdivided into proximal and distal parts. RESULTS: The weight of the total colon increased relatively more than the total body weight. After 1 week of treatment with EGF the surface area and wet weight of the total colon increased by 47% and 10%, and after 4 weeks by 62% and 37%, respectively. After 4 weeks the weight increase was mainly due to increased mucosal weight (by 65%, P < 0.01) and less prominently the submucosa (by 45%, P < 0.01) and the muscularis propria (by 32%, P < 0.01). On the basis of the wet weight increase, the proximal colon was more responsive to EGF treatment than the distal colon. CONCLUSIONS: Systemic treatment with EGF for 1 week increased the luminal surface area relatively more than the mass of the colon. Treatment with EGF for more than 1 week caused only a minor further surface area increase, whereas the colonic mass continued to increase in a time-dependent manner.

Systemic administration of epidermal growth factor increases UCP3 mRNA levels in skeletal muscle and adipose tissue in rats.

We have previously reported that systemic epidermal growth factor (EGF) treatment in rats reduces the amount of adipose tissue despite an unaltered food intake. The mitochondrial uncoupling proteins (UCP2 and UCP3) are thought to uncouple the respiratory chain and thus to increase energy expenditure. In order to find out whether the UCP system was involved in the EGF-induced weight loss, the effects of EGF on UCP2 and UCP3 in adipose tissue and skeletal muscle were investigated in the present study. Eight rats were treated with placebo or EGF (150 microg/kg/day) for seven days via mini-osmotic pumps. The EGF-treated rats gained significantly less body weight during the study period than the placebo-treated animals and had significantly less adipose tissue despite a similar food intake. The placebo group and the EGF group had similar UCP2 mRNA expression (in both adipose tissue and skeletal muscle), whereas the EGF-treated group compared to the placebo group had significantly higher UCP3 mRNA expression in both skeletal muscle (3.76 +/- 0.90 vs 8.41 +/- 0.87, P < 0.05) and in adipose tissue (6.38 +/- 0.71 vs 12.48 +/- 1.79, P < 0.05). In vitro studies with adipose tissue fragments indicated that the EGF effect probably is mediated indirectly as incubations with EGF (10 microM) were unable to affect adipose tissue UCP expression, whereas incubations with bromopalmitate stimulated both UCP2 and UCP3 mRNA expression twofold. Thus, EGF treatment in vivo was found to enhance UCP3 mRNA expression in both adipose tissue and skeletal muscle, which may indicate that the EGF effect on body composition might involve up-regulation of UCP3 in skeletal muscle and adipose tissue.

Pharmacological effects of epidermal growth factor (EGF) with focus on the urinary and gastrointestinal tracts.

Epidermal growth factor (EGF) belongs to a family of growth factor ligands and receptors. At present, five ligands have been recognized which as EGF exert their effects via binding to the same EGF receptor. The family has three other receptors erbB2, erbB3, and erbB4, which have their own ligands (the heregulins). The system is ubiquitously distributed in mammals, and has important roles in normal development, and in regenerative and neoplastic growth. Mouse and human EGF were discovered in 1962 and 1975 by Stanley Cohen and Harry Gregory, respectively, due to EGFs potent systemic effects. EGF accelerated eyelid opening in newborn mice and inhibited gastric acid secretion in humans. Already in the late thirties, a factor in human urine was recognized which prevented or accelerated healing of experimental damage in the gastrointestinal tract. This factor appeared to be EGF. Around 1980, an effect of commercial interest was described-EGF caused shedding of the fleece in sheep. In line with the original observations, several studies have examined effects of EGF on developmental processes. Amongst other effects, EGF accelerates lung and intestinal maturation before birth and in newborn mammals. Due to the possible use of EGF in the wool industry, it was mandatory to know more about EGF. Amongst other effects in mature sheep and other animals are haemodynamic changes, changes in electrolyte homeostasis, and endocrinological changes. In relation to experimental damage, the therapeutic potential of systemic EGF has been demonstrated in all parts of the gastrointestinal tract, in the kidneys, in the liver and in the trachea. EGF has even been tried in humans in gastric ulcer healing and in necrotising enterocolitis. Studies on prolonged treatment with EGF have first recently appeared. We described effects of 4-5 weeks of treatment in Goettingen minipigs and in rats, and two other groups described effects in monkeys and in rats. In summary, species differences were observed. The species of higher order were most sensitive to treatment with EGF. EGF did not consistently change the total body weight despite EGF consistently reduced circulating levels of insulin-like growth factor I (IGF-I) in Goettingen minipigs as well as in rats. Low circulating levels of IGF-I are usually associated with retarded growth. This review mostly focuses on the organs which appeared to be most sensitive to EGF, the urinary and gastrointestinal tracts including the liver and the pancreas. The histopathological changes consisted mainly of epithelial proliferations in the gastrointestinal, urinary and respiratory tracts. These findings match the knowledge obtained from animals overexpressing the EGF agonist, transforming growth factor alpha (TGF alpha), and the mice with a knock out of the gene encoding for the EGF receptor. EGF receptor hyperstimulation (TGF alpha overexpression) in the context of the whole animal leads to epithelial proliferations whereas hypostimulation (EGF receptor knock out) leads to epithelial immaturities. In the minipigs, the epithelia of the oesophagus, ducts of the pancreas, and the urothelium were hyperplastic, the latter two epithelia with accumulation of glycoconjugates. In the rats, the epithelial hyperplasias in these tissues and in the small and large intestines were without glycoconjugate accumulations. In rats, the mucosal proliferations in the intestines resulted in increased mucosal surface area. Mesenchymal growth effects were also noted. In the ureters of the minipigs, smooth muscle cell hyperplasia and hypertrophia were found. The heart of the minipigs was also enlarged, an interesting finding regarding interactions between the different parts of the EGF system, as knock out mice of the receptors erbB2 and erbB4 die due to maldevelopments in the heart. Measurements in blood and serum also revealed consistent changes. (ABSTRACT TRUNCATED)

Glycoproteins in the urothelium and in the urine of the epidermal growth factor induced growing urinary tract in rats.

Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. We have previously described that the EGF stimulated urothelium in Goettingen minipigs accumulates glycoproteins. The aim of the present study was to examine and partly characterize glycoproteins in the urothelium and in the urine from rats treated with EGF. Seventy-two female Wistar rats were allocated into five groups receiving EGF treatment (150 microg/kg per day) for 0 (controls), 1, 2, 3 and 4 weeks before being killed. Glycoconjugates were characterized by means of lectins on tissue sections, and using Western blotting, in bladder extracts and in urine. The characterization mostly focused on the expression of the mucin-type core structures T and Tn using the lectins peanut agglutinin (PNA) and Vicia villosa (VVA) and specific monoclonal antibodies. The thickened EGF-stimulated urothelium retained the normal differentiation pattern as judged from the appearance on electron microscopy and from the expression of carbohydrate structures. Within the urothelium and in the urine there was increased expression of mucin-type glycoproteins suggesting increased urothelial production and excretion of mucin-type glycoproteins. In conclusion, the EGF stimulated hyperplastic urothelium most probably excretes increased amounts of mucin-type glycoproteins to the urine but it retains the normal pattern of differentiation as assessed by lectin characterization.

The effects of exogenous epidermal growth factor on the developing urinary tract in rats: a stereological description.

Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. In this study, we describe the time-dependent growth of the ureter and bladder. Forty-eight female Wistar rats were allocated into five groups receiving EGF treatment (150 microg/kg per day) for 0 (controls), 1, 2, 3 or 4 weeks before being killed. The 24-h urine excretion was increased only in the group treated for 4 weeks with EGF. Measured by a simple infusion device, EGF significantly increased the bladder capacity by more than 50% in all the EGF-treated groups. The volumes of the wall layers of the ureter and bladder were quantified using stereology. After 4 weeks of treatment with EGF, the total volumes of the ureter and bladder were 1.8- and 2.1-fold larger than in the control group (the urothelium was 2.8- and 3.5-fold larger and the muscular coat 1.6- and 1.6-fold larger in the ureter and bladder, respectively). In conclusion, the EGF-induced growth of the urinary tract is characterized by increased bladder capacity, and increased volume of all wall layers --most prominently the urothelium.

Endoscopic sclerotherapy in porcine esophagus changes luminal cross-sectional area and wall distensibility dose- and time-dependently.

The dose- and time-dependent effects of endoscopic sclerotherapy on luminal cross-sectional area and wall distensibility were studied in pigs at 5 and 12 cm proximal to the gastroesophageal junction by means of impedance planimetry. Sixteen healthy animals underwent two sessions of endoscopic sclerotherapy two weeks apart with injections of either 5 or 10 ml of 1% Polidocanol in the distal 7 cm of the esophagus each time. The animals were investigated before sclerotherapy, two weeks after each session, and finally six weeks after the last session. Six healthy animals were studied as controls. Endoscopic sclerotherapy caused luminal narrowing in the sclerosed zone followed by normalization six weeks after the last treatment (P < 0.05 in both groups). Wall distensibility decreased in the sclerosed zone after treatment with 10 ml sclerosant (P < 0.05) followed by partial normalization, while no effect was found after 5 ml sclerosant (P > 0.2). Progressive dilations were observed in the proximal esophagus in both groups and were most pronounced in the 10 ml group (P < 0.05). Wall distensibility did not change proximal to the site of sclerotherapy in either group (P > 0.1).

Systemic administration of epidermal growth factor reduces fat mass in rats: effects on the hormone-sensitive-lipase, lipoprotein lipase and leptin.

We examined whether the reduction in fat mass induced by EGF treatment in mature animals was via activation of hormone-sensitive lipase (HSL) and thereby the induction of lipolysis, or through inhibition of lipoprotein lipase activity thus reducing fat uptake in adipose tissue. Sixteen male rats were treated with placebo or EGF 150 microg/kg/day for 7 days via mini-osmotic pumps. The results demonstrate that systemic EGF treatment reduces the amount of adipose tissue, most likely due to increased lipolysis as HSL activity as well as HSL mRNA were increased. The circulating levels of free fatty acids were slightly increased and leptin levels reflected the decrease in adipose tissue mass.

Time-dependent changes of levels of endogenous epidermal growth factor in submandibular glands, in kidneys, and in urine in rats during systemic treatment with EGF.

BACKGROUND: Exogenous EGF influences the levels of endogenous EGF differently in the submandibular glands (SMG) and the kidneys. The aim of the present study was to examine the time-dependent changes in levels of endogenous EGF during 1-4 weeks of EGF treatment. METHODS: Female rats were allocated into five groups receiving EGF subcutaneously (150 microg/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks prior to sacrifice at an age of 12 weeks. At the end of the study period, 24-h urine samples were collected. RESULTS: The weight of the SMG increased during EGF treatment (303+/-33 (controls), 359+/-37 (1 week EGF, P < 0.01), 390+/-30 (4 weeks EGF, P < 0.001) (mg mean+/-S.D.)). The EGF content of the SMG was unchanged after 1 week but threefold decreased after 4 weeks of treatment, respectively. The expression of EGF mRNA was decreased after 1 and 4 weeks as assessed with in situ hybridization. The weight of the kidneys was unchanged after 1 week and increased after 4 weeks of treatment (828+/-105 mg (controls) vs. 935+/-44 mg (4 weeks EGF, P < 0.005)). The renal content and the urinary excretion of EGF were significantly increased by 20-30% only in the group treated for 4 weeks. CONCLUSION: EGF treatment induces a time-dependent decrease in the EGF content in the SMG most likely by reducing the biosynthesis of endogenous EGF. In contrast, the EGF content in kidneys and in urine was unchanged after 1 week and increased after prolonged treatment.

Systemic treatment with epidermal growth factor causes organ growth concomitant with reduced circulating levels of IGF-I and IGFBP-3: time-dependent changes in female rats.

Systemic treatment with epidermal growth factor (EGF) in neonatal rats reduces circulating levels of insulin-like growth factor I (IGF-I) and causes somatic growth retardation. In this study, we investigated the effects of EGF treatment on the IGF system and on visceral organ growth and longitudinal growth in mature rats. We treated female Wistar rats for 0 (n = 16), 1 (n = 8), 2 (n = 8), 3 (n = 8), or 4 (n = 8) weeks with subcutaneous EGF (150 microg/kg/day). The animals were weighed once a week. At sacrifice, various viscera were removed and weighed. Blood and serum samples obtained at sacrifice were analysed for growth hormone (GH), IGF-I, IGF binding proteins (IGFBPs) and various routine parameters. EGF treatment increased the total body weight. All parts of the gastrointestinal tract, the liver, the pancreas, the spleen, the bladder, the suprarenal glands and the ovaries increased proportionately more in weight than the increase in total body weight; the heart and the kidneys increased proportionately in weight whereas the weight of the perirenal fat was reduced. There were no changes in tail length but the mean length of the tibia was slightly increased in the group treated for 4 weeks with EGF. Circulating GH was unchanged but IGF-I and IGFBP-3 were reduced approximately 25 and 45%, respectively, in all EGF treated groups. There were no changes in the hepatic content of IGF-I and IGFBPs. In conclusion, systemic EGF treatment causes visceral growth concomitant with reduced circulating levels of IGF-I and IGFBP-3 in mature female rats.

Systemic treatment with epidermal growth factor in pigs induces ductal proliferations in the pancreas.

BACKGROUND & AIMS: Epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and the EGF receptor are often overexpressed in chronic pancreatitis and in malignant pancreatic growth. Transgenic mice overexpressing TGF-alpha develop tissue changes in the pancrease resembling changes found in chronic pancreatitis. The effects of systemic treatment with EGF on the porcine pancrease were investigated in this study. METHODS: Mature Goettingen minipigs were treated with solvent (n = 5), EGF (30 micrograms.kg-1.day-1; n = 6) for 4 weeks, or EGF (30 micrograms.kg-1.day-1; n = 5) for 5 weeks followed by 3 weeks of recovery. Pancreata were studied by routine histological examination and electron microscopy and were immunostained for proliferating cell nuclear antigen (PCNA). RESULTS: In the EGF-treated animals, mainly larger interlobular ducts of the pancreas appeared to be considerably hyperplastic, with an increased number of nuclei that stained for PCNA. The epithelia of these ducts were increased in height, with accumulations of glycoconjugates in the columnar cells and in an increased number of goblet cells. CONCLUSIONS: A new approach to experimentally induced hyperplastic changes of the excretory ducts of the pancreas is presented. Because ductal changes with glycoconjugate accumulations are common features of chronic pancreatitis and pancreatic cancer, the findings may be relevant to the pathogeneses of these conditions.

Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate.

PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate. MATERIALS AND METHODS: Eight week old Wistar rats were allocated into groups of eight, receiving systemic treatment for 3 and 7 days with either IGF-I (400 micrograms/rat/day) or EGF (30 micrograms/rat/day) alone or in combination with DFMO. RESULTS: Systemic treatment with IGF-I for 7 days resulted in a 29% (p < 0.01) increase in the mean wet weight of the ventral prostate. The mean weight of the dorsolateral lobe of the prostate increased by 39% (p < 0.05), and the seminal vesicle and coagulating gland increased 69% (p < 0.05) compared to controls. The ODC-activity in the prostate was significantly increased by IGF-I after 3 days of treatment, and administration of IGF-I concomitantly with DFMO significantly inhibited ODC activity and the weight increase of the prostate. Stereological examination of the prostate in the IGF-I-treated animals showed growth of the epithelial component of the gland. Systemic treatment with EGF did not affect the mean weight of the prostate or the seminal vesicle compared to controls. CONCLUSION: The results demonstrate that treatment with IGF-I but not EGF for 7 days induces profound growth of the rat prostate and the seminal vesicle, and that the growth is dependent on an intact ODC-activity.

Acute contractile effects of epidermal growth factor on bladder smooth muscles. An in vivo and in vitro study in rats.

Chronic treatment with epidermal growth factor (EGF) stimulates growth of all wall layers of the urinary tract in pigs and rats. Herein, we investigated the acute effects of EGF on detrusor smooth muscle activity. For in vivo examination, awake rats received EGF (75 micrograms/kg) intravenously and detrusor smooth muscle activity was monitored cystometrically. The EGF bolus caused no alteration in diuresis but a doubling of the micturition frequency, a 25% increase in micturition pressures, and increased irregular baseline contractile activity. For in vitro examination detrusor smooth muscle strips were exposed to EGF (1 microgram/ml). EGF caused contraction and increase in the spontaneous activity. In conclusion, EGF increases rat detrusor smooth muscle contractile activity in vivo and in vitro. The finding suggests that a direct effect of EGF on bladder smooth muscles is part of the genesis to the growth of the detrusor smooth muscle observed after chronic EGF treatment.

Chronic systemic treatment with epidermal growth factor induces smooth muscle cell hyperplasia and hypertrophy in the urinary tract of mature Goettingen minipigs.

OBJECTIVE: To determine the effect of systemic treatment with epidermal growth factor (EGF) on the induction of growth in the urinary tract. MATERIALS AND METHODS: Mature Goettingen minipigs were treated daily with vehicle (Tris-HCl; n = 5) or EGF (30 micrograms/kg) (n = 6) for 4 weeks. The total number of smooth muscle cells was counted using an optical disector in a 20 microns thick cross-section of the ureter and the mean smooth muscle cell volume estimated. Cell proliferation was detected by immunostaining for the marker Ki67. RESULTS: The ureters of the animals treated with EGF were longer and thicker than those of the controls and the median cross-sectional area of the ureter was 3.3-fold larger; the growth involved all wall layers. The median (range) number of smooth muscle cells in a 20 microns thick cross-section of the ureter was 11 (9-12) x 10(3) in the pigs treated with placebo and 55 (19-80) x 10(3) in those treated with EGF, and the median (range) volume of the smooth muscle cells was 2.3 (2.2-2.4) x 10(3) and 4.0 (3.0-4.5) x 10(3) mm3, respectively. CONCLUSIONS: There were two likely mechanisms contributing to smooth muscle cell hyperplasia, the division of fully differentiated smooth muscle cells and division of fibroblasts in the borderline between the submucosal layer and muscular coat, with ensuing differentiation into smooth muscle cells. Treatment with EGF induces the growth of all wall layers in the urinary tract with remarkable hyperplastic and hypertrophic changes of the smooth muscle cells in the muscular coat.