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 circulating levels of IGF and IGF-binding proteins in adult Goettingen minipigs.

It has recently been demonstrated that epidermal growth factor (EGF) administration to neonatal rodents causes growth retardation with concomitant reductions in circulation levels of IGF-I. We describe the effects of systemic EGF administration for 4 weeks on circulating levels of IGF-I and IGF-binding proteins (IGFBPs) and on thyroid hormones (tri-iodothyronine, T3; thyroxine, T4) in sexually mature pigs. Goettingen minipigs of either sex were treated with placebo (n = 5) or EGF (30 micrograms/kg per day, n = 6) s.c. for 4 weeks (in relation to an oesophageal sclerotherapy regimen). Blood samples were taken under anaesthesia before and after 1, 2, 3 and 4 weeks of treatment. Circulating levels of IGF-I, insulin, glucose, T3 and T4 were analysed every week and IGFBPs every second week. IGF-I was not reduced significantly after 1 week but significantly reduced after 2 and 3 weeks of EGF treatment. A similar decline was observed for the major IGFBP, IGFBP-3, which was reduced after 2 and 4 weeks. IGFBP-1, IGFBP-2 and IGFBP-4 increased throughout the treatment period (all significantly at week 4). EGF treatment induced increased circulating T3 after 2, 3 and 4 weeks of EGF treatment. In conclusion, we report that EGF treatment for 4 weeks in Goettingen minipigs reduces circulating IGF-I and IGFBP-3, increases circulating IGFBP-1, IGFBP-2 and IGFBP-4, and induces a slight hyperthyroidism as judged from increased circulating levels of T3.

Tissue distribution of 131I-labelled epidermal growth factor in the pig visualized by dynamic scintigraphy.

We visualized the metabolism of intravenously injected 131I-labelled epidermal growth factor in the pig using dynamic scintigraphy combined with repetitive samplings of blood, urine and bile. The labelled peptide was recognized in the samples by means of immunoprecipitation and high pressure liquid chromatography. The plasma elimination was extremely rapid, and it was described with a triexponential equation, C(t) = A*e -alpha*t+B*e-beta*t+C*e-gamma*t. The first two exponentials denoted the distribution phase, and the third the elimination phase. T1/2 alpha ranged from 0.4-0.7 min, T1/2 beta from 2.0-2.2 min and T1/2 gamma from 53.3-97.6 min. Concomitant with the rapidly declining plasma concentration, the gamma camera visualized the uptake by the liver and the kidneys. The liver was the principal organ for clearance and degradation of the labelled peptide, but only 0.12-0.30% of the injected dose was excreted into the bile. The renal uptake and the urinary excretion accounted for 6.6-13.0 and 2.5-4.9% of the given dose, respectively.

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.

A double-blind placebo-controlled trial of omeprazole on characteristics of the migrating motor complex in healthy volunteers.

The aim of the study was to investigate a possible effect of omeprazole on the characteristics of the migrating motor complex. The study was performed as a double-blind crossover study and the pressure recordings were performed after 3 days of treatment with placebo or omeprazole 40 mg o.m. The calculations were based on 5 h of recording in each subject and in both investigations. There were two characteristics in the omeprazole group which were significantly different from placebo. Firstly, duodenal phase III was more often accompanied by an antral phase III and secondly, the duration of duodenal phase III was increased. The results suggest that the rapid cleaning mechanism, represented by phase III activity, is more pronounced after omeprazole treatment, possibly arising from its antisecretory effect.

Antroduodenal motility and gastric emptying. Gastroduodenal motility and pH following ingestion of paracetamol.

The influence of paracetamol on antroduodenal motility and gastric pH was studied in 11 healthy subjects and the relationship between gastroduodenal motility and gastric emptying rate time, tmax, to peak concentration of serum paracetamol, Cmax, was evaluated. The incidence of antral phase III activity and the duration of phase III was diminished with paracetamol (P less than 0.05). The other motility parameters assessed were unchanged. Three patterns of motility and absorption were observed. One group (n = 5) were fast absorbers with a tmax of 1 h and a motility pattern characterized by antral activity, a high motility index and a short duration of phase II (33-60 min); the phase IIIs were complete except in one case. The second group (n = 4) had tmax at 1.5 h and their phase II motility was characterized by a longer duration (80-133 min) (P less than 0.05), by antral activity, and by a high motility index; their phase IIIs were all incomplete. The last group (n = 2) were slow absorbers: Cmax was not reached in the investigation period, no antral contractions were seen, and the motility index was low. The area under the serum-concentration curve of paracetamol differed between the groups at 90 and 180 min (P less than 0.01).

Systemic treatment in the rat with epidermal growth factor causes polycystic growth of the ovaries.

BACKGROUND: It has previously been suggested that epidermal growth factor (EGF) plays a role in the function of the ovary. We administered systemic EGF to assess the influence of EGF receptor stimulation on the morphology of the ovaries. METHODS: Forty-eight female Wistar rats were allocated to five groups receiving EGF treatment (150 microgram/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks. All rats were exactly 8 weeks at the start of the experiment and 12 weeks at sacrifice. The EGF was administered in the weeks prior to sacrifice. At sacrifice, the perfusion-fixed ovaries were removed and weighed, and the volumes of tissue components were quantified using stereology. RESULTS: EGF administration increased the total weight of the ovaries from 129 +/- 18 mg in the controls to 158 +/- 29 mg (p<0.05) after one week. In subsequent weeks the total weight increased to 230 +/- 73 mg (p<0.001). The weight gain after one week of treatment was exclusively due to a fourfold increase in follicular cyst volume (p<0.01). In subsequent weeks the cyst volume was increased up to eightfold. After 2, 3 and 4 weeks of treatment the quantity of luteinizing cells was likewise increased by 70% (p<0.01). CONCLUSION: EGF administration causes the follicular cells to produce cysts and increases the quantity of luteinizing cells.

Chronic systemic treatment with epidermal growth factor in the rat increases the mucosal surface of the small intestine.

We examined the effects of treatment with human recombinant epidermal growth factor (EGF) on the functioning small intestine in the rat. Male Wistar rats, 7-8 weeks old, were treated with EGF administered subcutaneously in doses of 0 (n = 7) or 150 micrograms/kg/day (n = 8) for 4 weeks. The histological composition and mucosal surface area of the perfusion-fixed small intestine was quantified with stereological principles. The length of the gut remained unchanged. The amount of tissue and surface area per length of gut (median (ranges)) were increased from 117 (101-131) mg/cm and 2.6 (2.1-3.5) cm2/cm in the controls to 146 (138-152) mg/cm and 3.5 (2.5-3.8) cm2/cm for the complete small intestine (both comparisons P < 0.02). The weight increase was due to mucosal growth in all parts of the intestine, whereas the surface area was only increased in proximal and middle parts. It is concluded that EGF treatment in rats increases the mucosal weight and surface area of the functioning small intestine.

The effects of chronic administration of epidermal growth factor (EGF) to rats on the levels of endogenous EGF in the submandibular glands and kidneys.

Epidermal growth factor (EGF) is mainly produced in the submandibular glands (SMG) and in the kidneys. It has recently been reported that EGF-related ligands may induce their own biosynthesis (autoinduction) in vitro. In the present paper, we investigated whether chronic systemic treatment with EGF influenced the amount of endogenous EGF in the SMG and kidneys. Eight-week-old female Wistar rats were treated with subcutaneous injections of placebo (n = 16) or human recombinant EGF (150 micrograms/kg per day, n = 8) for 4 weeks. Urine was sampled the last 24 h of the study period. At the time of killing, the SMG and the kidneys were removed. The SMG was larger in the EGF-treated animals, 229.8 +/- 35.5 (mean +/- SD) mg than in the control animals, 181.7 +/- 18.1 mg (P < 0.01). The total EGF content was smaller (0.51 +/- 0.15 vs. 1.12 +/- 0.40 nmol EGF/SMG, P < 0.001). The kidneys were larger in the EGF-treated animals (1.38 +/- 0.08 vs. 1.28 +/- 0.08 g, P < 0.05), but the EGF content and urinary excretions were not changed. In conclusion, chronic systemic treatment with EGF causes growth of the SMG with concomitantly reduced contents of EGF, and growth of the kidneys with unchanged content and excretion of EGF. These findings suggest that EGF may play a part in the regulation of the growth of the SMG and in EGF biosynthesis.

Systemic treatment with epidermal growth factor in the rat. Biomechanical properties of the growing small intestine.

Prolonged treatment with epidermal growth factor (EGF) in the rat provides an experimental model to growth of the gastrointestinal tract. We treated female Wistar rats for 0 (n = 15), 1 (n = 8), 2 (n = 8), and 4 (n = 8) weeks with subcutaneous EGF (i50 micrograms.kg-1.day-1). Segments were taken from locations at 10, 50 and 90% along the length of the small intestine, weighed, the wall thickness was measured and the luminal cross-sectional area and passive biomechanical properties were assessed using impedance planimetry. In addition, the wall composition was evaluated on histological sections. The weight of the total small intestine and of the three segments (measured in mg.cm-1) increased with the duration of the EGF treatment due to mucosal and muscular growth. After 1 week of treatment the wall thickness increased. After 2 weeks of treatment the cross-sectional area began to increase. The circumferential stress-strain distributions revealed translation of the curves to the right in the graphs implying reduced wall stiffness during EGF treatment. In conclusion EGF treatment for 1 to 4 weeks caused a time-dependent increase in intestinal weight. The growth was characterized by increased wall thickness, increased cross-sectional area and reduced wall stiffness.

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.

Preventive effects of recombinant human epidermal growth factor on the oesophageal epithelium in pigs subjected to sclerotherapy.

OBJECTIVE: To investigate the role of epidermal growth factor (EGF), a small (relative molecular mass 6000) polypeptide with mitogenic properties in the protection of gastrointestinal mucosal integrity. DESIGN: A prospective, randomized and blinded study. METHODS: Twenty-four minipigs with surgically induced portal hypertension underwent four consecutive weekly sessions of oesophageal sclerotherapy with 5 ml 1% polidocanol and were concomitantly treated with either a placebo or human recombinant EGF administered subcutaneously. Mucosal damage was evaluated on a weekly basis by endoscopic estimation of the size of the ulcerated area and by post-mortem morphometry. The EGF-induced morphological changes in the oesophageal epithelium were also evaluated histologically. RESULTS: In sclerosed and non-sclerosed parts of the oesophagus EGF significantly increased the thickness of the oesophageal epithelium (P < 0.03), but failed to reduce significantly the degree of oesophageal damage associated with sclerotherapy (P = 0.11). CONCLUSIONS: Systemic EGF treatment induces proliferation of the oesophageal mucosa, and EGF may therefore have the potential to reduce sclerotherapy-induced oesophageal damage.

Impedance planimetric characterization of the distal oesophagus in the Goettingen minipig.

Regional differences in biomechanical properties of the oesophagus were studied in 15 healthy Goettingen minipigs by means of impedance planimetry. The investigation was performed during anaesthesia by stepwise pressure-induced balloon distensions with concomitant measurement of pressure and luminal cross-sectional area (CSA) in the oesophagus 5 and 10 cm above the gastro-oesophageal junction. The circumferential wall tension, circumferential strain and incremental elastic modulus were computed from the measurements of pressure and CSA at steady-state conditions. Probably due to the anaesthesia, only scant peristalsis was recorded and the CSA always reached steady state during the balloon distensions. The CSAs were highest in the distal oesophagus (P < 0.001). At the highest induced pressure, the CSAs were 605 +/- 32 and 453 +/- 29 mm2 (mean +/- SEM) for the locations 5 and 10 cm from the gastro-oesophageal junction. The tension-strain distributions were non-linear and the curve obtained 5 cm above the gastro-oesophageal junction was shifted to the right when compared with the curve obtained from 10 cm above this junction. Fitting of the function tension = exp(a+b strain) to the data gave determination coefficients higher than 0.97 and P values lower than 0.001 for both measuring points. The constant a differed between the two locations in the oesophagus (P < 0.05). In conclusion, the pressure-CSA and the tension-strain distributions differed between the two measuring points suggesting that the elastic properties are different.

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.

The relation between antral contractile activity and the duodenal component of the migrating motility complex.

The aim of the study was to investigate the relationship between antral and duodenal fasting motor activity in 19 healthy volunteers using a perfused tube assembly with side-holes placed in the distal antrum, second part of the duodenum and in the duodenum near the ligament of Treitz. Registrations were performed until the end of the second duodenal phase III. Eighty-two per cent of the duodenal phases III were preceded by antral activity. The duration of duodenal phase III showed a positive correlation to the preceding number of antral contractions (p less than 0.001) as well as to antral phase III (p less than 0.05), but no correlation to the duration of antral phase III was found. The duration of the migrating motility complex (MMC) showed a positive correlation to the duration of duodenal phase III (p less than 0.05), but no correlation to the preceding number of antral contractions were found. It may be concluded that the level of duodenal activity is very dependent on the preceding antral activity.

Ureteric growth in a Goettingen minipig induced by epidermal growth factor. A case report.

We have recently discovered that prolonged systemic administration of epidermal growth factor (EGF) induces a remarkable growth of all wall layers of the urinary tract in minipigs. In the present paper, we report the most pronounced changes induced by 4 weeks of systemic EGF challenge in two pigs treated for four weeks with either solvent or EGF (30 micrograms/kg/day), respectively. The EGF treated ureter was longer and thicker with an approximately four fold increase in diameter. All wall layers were enlarged. The urothelium was increased from 5 to 10 cellular rows with basal hyperplasia and an increased number of goblet cells and cells with intracytoplasmic lumina in the luminal half. In the muscular coat, the bundles of hypertrophied cells and intervening connective tissue were enlarged. The present paper suggests a possible in vivo approach to increase the amount of tissue needed in reconstructive surgery of the urinary tract.

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)

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.