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PubMed1994

Induction of hepatocyte growth factor in human skin fibroblasts by epidermal growth factor, platelet-derived growth factor and fibroblast growth factor.

Hepatocyte growth factor (HGF) is a potent mitogen for rat and human hepatocytes in primary culture and appears to be the physiological hepatotrophic factor that triggers or modulates liver regeneration. Regulation of HGF gene expression and the protein production in human skin fibroblasts was examined. Addition of epidermal growth factor (EGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF) and transforming growth factor-alpha (TGF-alpha) to confluent cultures of the cells markedly stimulated HGF secretion from the cells. The stimulating effect of EGF, PDGF and bFGF was further investigated. The effect of all three growth factors was maximal at 3-30 ng/ml and was accompanied by an increase in HGF mRNA levels. The mRNA levels were not elevated at 5 h but were at 10 h or more after addition of EGF. The levels of HGF mRNA in fibroblasts treated with the optimal doses of EGF, PDGF, bFGF, aFGF and TGF-alpha for 24 h were 6, 4, 5, 4 and 5 times that of control cultures incubated in medium only, respectively. The growth factor-induced HGF mRNA expression and HGF secretion was inhibited by addition of TGF-beta 1 or dexamethasone. Pretreatment with a high dose of phorbol 12-myristate 13-acetate (PMA), which causes down-regulation in protein kinase C (PKC) activity and PMA-induced HGF secretion, did not reduce the effects of the growth factors on HGF mRNA expression and HGF secretion, but rather enhanced them.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1993

Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits.

The epidermal growth factor (EGF) homologues encoded by vaccinia virus, myxoma virus, and malignant rabbit fibroma virus have been shown to contribute to the pathogenicity of virus infection upon inoculation of susceptible hosts. However, since the primary structures of these growth factors and the disease profiles induced by different poxvirus genera vary substantially, the degree to which the various EGF homologues perform similar roles in viral pathogenesis remains unclear. In order to determine whether different EGF-like growth factors can perform qualitatively similar functions in the induction of myxomatosis in rabbits, we created recombinant myxoma virus variants in which the native growth factor, myxoma growth factor (MGF), was disrupted and replaced with either vaccinia virus growth factor, Shope fibroma growth factor, or rat transforming growth factor alpha. Unlike the control virus containing an inactivated MGF gene, which caused marked attenuation of the disease syndrome and substantially less proliferation of the epithelial cell layers in the conjunctiva and respiratory tract, the recombinant myxoma virus strains expressing heterologous growth factors produced infections which were both clinically and histopathologically indistinguishable from wild-type myxomatosis. We conclude that these poxviral and cellular EGF-like growth factors, which are diverse with respect to primary structure and origin, have similar biological functions in the context of myxoma virus pathogenesis and are mitogenic for the same target cells.

Animals↗
PubMed1992

Effect of epidermal growth factor/transforming growth factor alpha and transforming growth factor beta 1 on growth in vitro of rat urinary bladder carcinoma cells.

The response to growth factor stimulation was evaluated in clonally derived rat bladder carcinoma cell lines, ranging from nontumorigenic to tumorigenic and metastatic, in athymic nude mice. In the nontumorigenic cell line D44c, epidermal growth factor (EGF)/transforming growth factor (TGF) alpha weakly stimulated anchorage-dependent, but not -independent, growth. In tumorigenic/nonmetastatic cells (G1-200 Cl-17), EGF/TGF-alpha stimulated markedly anchorage-independent, but marginally anchorage-dependent growth, whereas TGF-beta 1 inhibited anchorage-independent growth and DNA synthesis. In the highly tumorigenic/metastatic cell line LMC19, EGF/TGF-alpha stimulated anchorage-dependent growth weakly and anchorage-independent growth strongly. In these cells, TGF-beta 1 did not inhibit anchorage-independent growth and DNA synthesis but increased the size of colonies irrespective of the presence of EGF, and some cells were scattered around colonies in soft agar. None of the cell lines showed evidence of TGF-alpha-specific mRNA transcription. Expression of TGF-beta 1 mRNA increased in parallel to the biological aggressiveness of the cell lines. Highly tumorigenic and metastatic cells also demonstrated gelatinase activity involving 72 kilodalton and 92 kilodalton types. Our data suggest that the growth-stimulatory effect of EGF/TGF-alpha in soft agar may be limited to cells that are already tumorigenic and that EGF/TGF-alpha is not effective in making nontumorigenic cells become tumorigenic (or in making nontumorigenic cells grow in soft agar).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Insulin-like growth factor I and transforming growth factor alpha as autocrine growth factors in human pancreatic cancer cell growth.

The roles of insulin-like growth factor I (IGF-I) and transforming growth factor alpha (TGF-alpha) as autocrine factors in the proliferation of MIA-PaCa 2 cells (human pancreatic cancer cells, PC cells) were investigated. Furthermore, the mechanism(s) of inhibition of PC cell growth by a phorbol ester in relation to these two kinds of growth factor was also studied. PC cells grew autonomously when Dulbecco's modified essential medium supplemented with 4% fetal calf serum was changed to serum-free medium (0.3% bovine serum albumin-Dulbecco's modified essential medium). In addition, serum-free conditioned medium from PC cells dialyzed against fresh Dulbecco's modified essential medium had a stimulatory action on the growth of the same kind of cells when compared with that induced by nonconditioned medium. These observations suggest that a factor(s) produced and released by PC cells stimulates their own growth. Analysis of conditioned medium from PC cells revealed the presence of immunoreactive (IR)-IGF-I and IR-TGF-alpha. The molecular size of IR-IGF-I was similar to that of authentic IGF-I. On the other hand, IR-TGF-alpha was present as multiple forms when analyzed using gel chromatography. Authentic IGF-I and TGF-alpha added to culture medium stimulated PC cell growth by 1.45- and 1.5-fold above control value, respectively. A monoclonal antibody to IGF-I receptor was able to inhibit PC cell growth. PC cell proliferation was markedly inhibited by 12-O-tetradecanoyl-13-acetate (greater than 0.16 nm), whereas cell growth of human fibroblasts was stimulated by it. 12-O-Tetradecanoyl-phorbol-13-acetate also reduced the binding of 125I-TGF-alpha, but not 125I-IGF-I, to PC cells. Decrease in TGF-alpha binding was mainly due to the reduced affinity of receptors to the ligand. These results suggest that IGF-I and TGF-alpha are involved in PC cell proliferation as autocrine factors. Further, the inhibition of PC cell growth by phorbol ester could be, at least partly, due to the decreased binding of TGF-alpha to the cells.

Adult↗
PubMedDate not supplied

Growth of human gastric carcinomas and expression of epidermal growth factor, transforming growth factor-alpha, epidermal growth factor receptor and p185c-erbB-2.

We examined the expression of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR) and p185c-erbB-2 immunohistochemically and correlated the expression with growth in 66 cases of human gastric carcinoma. To evaluate growth, we used the bromodeoxyuridine (BrdU) labeling index in 51 cases and the radiographic growth rate in 15 cases. Expression of EGF was detected in 41 cases (62.1%), TGF-alpha in 42 cases (63.6%), EGFR in 34 cases (51.5%), and p185c-erbB-2 in 37 cases (56.1%). The BrdU labeling index ranged from 1.5 to 32.0%. The BrdU labeling index was higher in tumors that coexpressed EGF and EGFR or TGF-alpha and EGFR than in tumors without expression or in tumors that expressed growth factors or the receptors (p < 0.01). The BrdU labeling index was also significantly higher in tumors with the expression of EGFR and/or p185c-erbB-2. Tumors with simultaneous expression of EGF, TGF-alpha, EGFR and p185c-erbB-2 had an association with a high BrdU labeling index. Moreover, all of these growth factors and receptors were expressed simultaneously in gastric carcinomas with rapid growth. These results suggest that the expressions of EGF, TGF-alpha, EGFR and p185c-erbB-2 are closely related and then play an important role in the growth of human gastric carcinomas.

Adult↗
PubMed1988

Effects of platelet derived growth factor, epidermal growth factor and transforming growth factor-beta on the growth of human marrow fibroblasts.

The effects of three growth factors contained in platelets on human bone marrow fibroblasts as well as fibroblast colony-forming cells were investigated to clarify the pathogenesis of marrow fibrosis frequently associated with myeloproliferative disorders. Two growth factors, platelet derived growth factor (PDGF) and epidermal growth factor (EGF), cooperatively stimulated the growth of passaged fibroblasts as well as fibroblast colony-forming cells. Transforming growth factor-beta augmented the growth of fibroblasts at low concentrations in the presence of EGF and/or PDGF, but inhibited that of colony-forming cells in the presence of PDGF or EGF. These results suggest that the growth of fibroblasts causing marrow fibrosis might be finely regulated, depending on the concentrations of growth factors released or leaked from platelets or megakaryocytes into marrow environment.

Adult↗
PubMedDate not supplied

Detection of intrauterine growth retardation in twins using individualized growth assessment. II. Evaluation of third-trimester growth and prediction of growth outcome at birth.

Second- and third-trimester growth in 34 twin fetuses was evaluated with ultrasonography by measurement of five anatomic parameters. Rossavik growth models, derived from second-trimester measurements, were used to specify expected third-trimester growth curves. Actual measurements were compared to predicted measurements by calculation of the percent deviations. Growth outcome at birth [normal, intrauterine growth retardation (IUGR)] was determined from Neonatal Growth Assessment Scores. Growth in the second trimester was similar in normal and IUGR twins. In the third trimester, abnormal negative deviations were larger and more numerous in IUGR twins. However, there was considerable individual variability and normal twins also had abnormal negative deviations. In IUGR twins, the first appearance of an abnormal negative deviation was quite variable (range: 28.6 weeks to 35.1 weeks), as was the parameter to show such a deviation. Prediction of neonatal outcome was poor using individual anatomic parameters but improved considerably with use of all five parameters. However, some fetuses were misclassified when only the number of abnormal negative deviations was used. The Prenatal Growth Assessment Score (PGAS), determined by both the number and magnitude of abnormal negative deviations, predicted neonatal outcomes with a sensitivity of 100% and specificity of 100%. On average, PGAS values were abnormal 5 weeks before delivery. These results indicate that normal and IUGR twins can be separated, using third-trimester growth patterns, if multiple parameter Individualized Fetal Growth Assessment is employed.

Diseases in Twins↗
PubMed1998

The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7).

Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells.

3T3 Cells↗
PubMed2000

Quantitation of the mRNA expression of the epidermal growth factor system: selective induction of heparin-binding epidermal growth factor-like growth factor and amphiregulin expression by growth factor stimulation of prostate stromal cells.

The epidermal growth factor (EGF) system is a rapidly expanding system of growth factors involved in many aspects of normal and cancerous growth. We have developed a method for the quantitation of mRNA coding for all six growth factors activating the human EGF receptor (HER-1) and for the quantitation of mRNA for the receptors HER-1 and its preferred dimerization partner, HER-2. The method is based on the generation of specific RNA standards, which are amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) with the sample RNA and a set of calibrators. The resulting calibration curve is used to quantitate the unknown samples, which require only a single RT-PCR reaction. Our method has the advantage that quantitation is based on coamplification of an internal RNA standard, thereby controlling both the PCR and RT reactions. In addition, the RNA standards for all growth factors and receptors are combined in a single RT reaction, which minimizes variation and allows the quantitation of all eight mRNA species with only 0.1 microg RNA. This makes the method suitable for studies in which the supply of material is limited. The developed method has enabled us to demonstrate that prostate stromal cells in primary culture express EGF, heparin-binding EGF (HB-EGF), amphiregulin, betacellulin, and epiregulin as well as the HER-1 and HER-2 receptors, whereas no transforming growth factor-alpha mRNA is found. Furthermore, activation of the EGF system in these cells by stimulation with HB-EGF or EGF in mitogenic doses causes a selective increase in the expression of amphiregulin and HB-EGF mRNA (more than 15-fold and 25-fold, respectively), whereas there is no increase in the expression of mRNA for the other growth factors or receptors. In accord with the increase in amphiregulin mRNA, the amount of amphiregulin peptide released from the cells is also increased. The selective induction of amphiregulin and HB-EGF by growth factor stimulation may represent a mechanism to amplify the initial growth factor signal in prostate stromal cells.

Amphiregulin↗
PubMed1994

Modulation of epidermal growth factor and keratinocyte growth factor effects on human keratinocyte growth by protein kinase C inhibitor, GF 109203X: comparison to fibroblast growth modulation.

In this study, epidermal growth factor (EGF), 20 ng/ml, and keratinocyte growth factor (KGF), 10 ng/ml, were able to stimulate human keratinocyte growth only in presence of GF 109203X 1 microM, a selective PKC inhibitor. This suggests that PKC negatively controls keratinocyte growth in response to EGF and KGF. On the other hand, EGF and KGF have no significant effect on PKC activity. In contrast, in human fibroblasts, EGF stimulated fibroblast growth in the presence or not of GF 109203X. Thus, EGF seems to stimulate fibroblast growth in a PKC independent manner. Moreover, EGF didn't modify significantly PKC activity in fibroblasts. KGF had no effect on fibroblasts. These results show differences in the interconnections between PKC and EGF transduction pathway in the modulation of human keratinocyte and fibroblast growth. Moreover, they especially demonstrate that PKC would negatively control human keratinocyte growth in response to EGF and also to KGF.

Adult↗
PubMed1997

Factors determining pubertal growth and final height in growth hormone treatment of idiopathic growth hormone deficiency. Analysis of 195 Patients of the Kabi Pharmacia International Growth Study.

A total of 195 children (117 males and 78 females) with idiopathic growth hormone deficiency (IGHD) treated with growth hormone (GH) for at least 1 year before puberty onset and who had completed treatment to adult height, were selected from the KIGS database for study of growth during puberty. Spontaneous and induced puberty started at 13.8 and 14.9 years in boys and at 12.9 and 13.7 years in girls, respectively. Duration of GH treatment and height gained prepubertally were greater when puberty was induced; prepubertal catch up growth (expressed as a percentage of the difference between target height and height at start of GH) was greater when puberty was induced in boys (59% induced vs. 45% spontaneous, p < 0.001), and in girls (72% induced vs. 53.9% spontaneous, p < 0.01). Final height was attained at 17.8 and 19.2 years in boys and at 16.0 and 17.0 years in girls following spontaneous and induced puberty, respectively. Final heights were greater after induced puberty compared with spontaneous puberty in boys (171.3 vs. 166.0 cm, p < 0.001) and in girls (157.0 vs. 155.0 cm, n.s.). Target height was also significantly greater in boys with spontaneous puberty (172.2 cm vs. induced = 174.2 cm) as compared to girls (spontaneous = 158 cm vs. induced = 160 cm). Duration of pubertal growth was longer in boys compared to girls (3.6 vs. 3.0 years, p < 0.001) and was negatively correlated with age, height, and distance from target height at onset of puberty, but was not correlated with the dose of GH. Catch-up growth during puberty (expressed as a percentage of the difference between target height and height at puberty onset) after induced and spontaneous puberty was 87.9% and 80.5% (not significant) in boys and 66.4% and 75.5% (not significant in girls. Total pubertal growth (TPG) (cm) was inversely correlated with prepubertal growth by simple linear regression. Multiple linear regression analysis indicated 5 independent predictors of TPG accounting for 78% of the variability, namely sex (boys grew more), distance of target height from height at onset of puberty (+), dose of GH at onset of puberty (+), age at onset of puberty (-), and age at end of growth (+).

Adolescent↗
PubMed2003

Association of single nucleotide polymorphisms in the growth hormone and growth hormone receptor genes with blood serum insulin-like growth factor I concentration and growth traits in Angus cattle.

This study was conducted to identify polymorphisms in the promoter and coding regions of the bovine growth hormone and growth hormone receptor genes and to study association of polymorphisms identified in these genes with growth traits and serum insulin-like growth factor-I (IGF-I) concentration. The denaturing gradient gel electrophoresis method and sequencing were utilized to identify three new single nucleotide polymorphisms in the promoter region of the growth hormone gene in Angus cattle. Polymerase chain reaction-based restriction fragment length polymorphism procedures were developed for rapid determination of the single nucleotide polymorphism genotypes in the growth hormone and the growth hormone receptor genes among Angus calves from lines divergently selected for high or low blood serum IGF-I concentration. The IGF-I concentration and growth traits were analyzed using animal models. The single nucleotide polymorphism in the promoter region of the growth hormone receptor gene was associated with serum IGF-I concentration on d 42 of the postweaning test and with mean IGF-I concentration. The associated effects of the markers need to be verified in other populations.

Animals↗
PubMed1991

Growth response in prepubertal children with idiopathic growth hormone deficiency during the first two years of treatment with human growth hormone. Analysis of the Kabi Pharmacia International Growth Study.

From the large database of patients enrolled in the Kabi Pharmacia International Growth Study (KIGS), 289 prepubertal patients with idiopathic growth hormone deficiency (GHD), treated for 2 years with growth hormone (GH) substitution therapy, were selected. A multiple regression analysis was performed to determine both the auxological factors characterizing the patients at the beginning of the first and second years on GH therapy and the respective treatment modalities relevant to the magnitude of the growth response. It was observed that during the first year on GH therapy the magnitude of the growth response was negatively correlated with chronological age and height SDS, and positively correlated with target height SDS, GH dose (IU/kg/week) and frequency of GH injections. During the second year the growth response was negatively correlated with chronological age and the first-year GH dose (IU/kg/week), and positively correlated with height velocity during the first year, GH dose (second year), and injection frequency (second year). The data suggest that the forces of 'catch-up'--auxologically entrenched within the distance between target height SDS and height SDS--no longer prevail during the second year of GH therapy. The inverse influence of the first-year GH dose in the two yearly phases of growth suggests that optimizing GH treatment must be attempted by analysing growth in response to GH over longer periods of time and considering that the growth process is influenced by interactive factors.

Age Factors↗
PubMed2004

Vascular endothelial growth factor, fibroblast growth factor 2, platelet derived growth factor and transforming growth factor beta released in human dental pulp following orthodontic force.

OBJECTIVE: The release of four diffusible angiogenic growth factors in human dental pulp following orthodontic force was investigated by using neutralising growth factor antibodies (NAs), individually and in four different combinations to block their effects. This study investigated if increasing the number of NAs (anti h vascular endothelial growth factor (VEGF), anti h fibroblast growth factor (FGF2), anti h platelet derived growth factor (PDGF) and anti Transforming growth factor beta (TGFbeta)) in combination resulted in a progressive reduction of the angiogenic response of the pulp. MATERIALS AND METHODS: The dental pulps from two groups of 40 premolar teeth, four teeth from each of 20 patients treated with fixed appliances for 2 weeks, were divided vertically, and sections from each half pulp co-cultured with sections of rat aorta in collagen. In one group, one of each of the four NAs, and in the other group, one of the four different NA combinations were added to the media of the co-cultures from one half of the pulp from each of the four teeth of each patient; the other half pulp co-cultures were controls. Cultures were examined daily by light microscopy for growth and number of microvessels. RESULTS: NAs significantly reduced microvessel numbers in the co-cultures when added individually (P<0.004), and in each of the four combinations (P<0.002), with a trend to progressively reduced microvessel numbers with increasing number of NAs in combination. CONCLUSIONS: Results indicated that all four angiogenic growth factors examined were released following orthodontic force application and play a role in the angiogenic response of the pulp, and that these factors may be more effective in combination.

Angiogenic Proteins↗
PubMed1992

Control of protein and matrix-molecule synthesis in isolated ovine fetal growth-plate chondrocytes by the interactions of basic fibroblast growth factor, insulin-like growth factors-I and -II, insulin and transforming growth factor-beta 1.

Chondrogenesis is thought to be controlled by interactions between circulating anabolic hormones and locally produced peptide growth factors, and involves ordered changes in matrix composition which ultimately allow endochondral calcification. We have used a model of isolated ovine fetal growth-plate chondrocytes to examine the actions and interactions of basic fibroblast growth factor (basic FGF), insulin-like growth factors-I and -II (IGF-I and -II), insulin and transforming growth factor-beta 1 (TGF-beta 1) on total protein, collagen or non-collagenous protein and sulphated glycosaminoglycan synthesis. These parameters were determined by assessment of the incorporation by monolayer cultures of early passage chondrocytes of [3H]leucine, [14C]proline and [35S]sulphate respectively, followed by partial molecular characterization. Basic FGF enhanced total protein synthesis with a half-maximal effective concentration of 270 +/- 60 pmol/l (mean +/- S.E.M., four animals) and was sixfold more active on a molar basis than IGF-I or insulin, and 28-fold more active that IGF-II which is the endogenously synthesized IGF. The actions of basic FGF were additive to those of IGF-I or insulin. More detailed analysis of extracellular-matrix component synthesis showed that basic FGF, IGF-I and insulin each caused significant increases in the synthesis of collagen and sulphated glycosaminoglycans. TGF-beta 1 had no effect on total protein synthesis by chondrocytes when present alone at concentrations of 200 pmol/l or less, but was inhibitory at 400 pmol/l. However, the use of this parameter masked a stimulatory action of 50 or 100 pmol TGF-beta 1 on sulphated glycosaminoglycan synthesis and a relative shift in the ratio of collagen: non-collagenous protein synthesis in favour of the former. A synergistic interaction existed between TGF-beta 1 (20-100 pmol/l) and basic FGF which potentiated total protein and collagen synthesis, and their actions on sulphated glycosaminoglycan production were additive. The same concentrations of TGF-beta 1 inhibited the ability of IGF-I or insulin to stimulate total protein or collagen synthesis, but were additive to their stimulatory effects on sulphated glycosaminoglycan synthesis. The results suggest that matrix-molecule composition and the anabolic status of the epiphyseal growth-plate may be modulated in utero by multiple interactions between peptide growth factors produced locally, such as basic FGF, IGF-II and TGF-beta 1, and circulating hormones such as insulin and IGF-I.

Animals↗
PubMed2003

Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth.

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.

Animals↗
PubMed1975

The embryonic and postnatal growth of rat and mouse. III. growth of the whole animal in the puberty, adult, and senescence phases in two inbred mouse strains (cpb-s and kba/2). Exponential growth, sudden changes in the growth rate, and a model for the regulation of the mitotic rate.

1. The growth model forumlated for prenatal and postnatal growth up to the middle of the puberty phase seems to be valid for the later postnatal phases as well, including adulthood and senescence. 2. In this model, growth consists of phases with exponential growth (constant specific growth rate) separated by sudden changes in the rate. 3. In the period described here, 7 phases can be distinguished, beginning with puberty (phase IV) and ending with senescence (phase X). 4. In 4 of these phases the growth rate does not differ significantly between the four groups of mice used. In the other 3 phases there are no differences between three of the groups but the fourth, one of the sexes of the CPB-S strain, differs very definitely from the rest. 5. Absence of growth occurred in some phases in one of the groups. 6. Some of the phases do not occur in all individual animals; this holds especially for phase VIII, which occurred in only about 25% of the animals. 7. The 'growth constants' postulated in Part I and now studied in the individual mice, tend to have a value of about 2. A theoretical model is described for the regulation of the mitotic rate giving 'growth constants' of about the same numerical value.

Animals↗
PubMed1989

Stimulation by transforming growth factor-beta of epidermal growth factor-dependent growth of aged human fibro-blasts: recovery of high affinity EGE receptors and growth stimulation by EGF.

The stimulatory effects of transforming growth factor beta (TGF-beta) on epidermal growth factor (EGF)-dependent growth of adult and newborn human fibroblasts were investigated. EGF-stimulated growth in low serum of dermal fibroblasts from a 41 year-old adult (HSF-41) was less than half that of newborn foreskin fibroblasts (HFF). The EGF-stimulated growth of HFF after 55 population doublings (HFF-55) was similarly reduced. The decreased growth response to EGF of fibroblasts aged in vivo and in vitro appeared to result principally from a decreased sensitivity to EGF due to a decreased number and affinity of high affinity EGF receptors (H-EGFR). Pre-incubation of HSF-41 and HFF-55 with 25 pM TGF-beta enhanced the growth responses of these cells to EGF and increased the levels of high affinity EGF-binding by these cells. Thus, the stimulation by TGF-beta of EGF-dependent growth of human fibroblasts aged in vivo or in vitro is mediated by increased levels of high affinity EGF binding.

Adult↗