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Growth factors in the gastrointestinal tract
Abstract
This paper reviews areas of interest in gut mucosal growth factor physiology. Several epidermal growth factor (EGF)-like peptides (EGF, transforming growth factor [TGF]-alpha, heparin-binding EGF-like peptide, amphiregulin, and betacellulin) have been identified in the gut, EGF is produced by the salivary glands and is present in milk. It may act on the mucosa from the lumen as a surveillance peptide promoting mucosal repair. A stem-cell-derived "ulcer-associated cell lineage" develops adjacent to ulcers and produces EGF, which may play a role in ulcer healing. TGF-alpha is expressed by villus enterocytes and may have an important role in mucosal healing. The Trefoil peptides (pS2, spasmolytic polypeptide, intestinal trefoil factor) are protease resistant molecules secreted by mucin cells throughout the gut, with a role in mucosal healing. The TGF-beta family inhibit cell proliferation, and promote cell differentiation. TGF-beta has a gradient of expression along the crypt villus axis, with maximum production at the villus tip. It is suspected that it may prevent cell proliferation and support differentiation of villus enterocytes. Hepatocyte growth factor is a multifunctional growth factor expressed in many tissues, including the gastrointestinal tract. It has a role in organogenesis. Intestinal adaptation is highly dependent on enteral nutrition, and it is likely that growth factors are involved in adaptation. Little is known, however, about interactions between nutrients and growth factors. Milk contains a range of potentially important growth factors. Their biological significance is uncertain, and this is an area of active research.
... Growth factors and their receptors play important roles in cell proliferation, migration, tissue injury repair and ulcer healing. Several EGF-like peptides have been identified in the gut [125] including EGF, TGFa, heparin-binding EGFlike peptide, amphiregulin and betacellulin. TGFa is expressed by villous enterocytes and may have an important role in mucosal healing. ...
... The TGFf3 family inhibits cell proliferation and promotes cell differentiation. HGF is a multifunctional growth factor expressed in many tissues, including the gastrointestinal tract [125]. Intestinal adaptation is highly dependent on enteral nutrition, and it is likely that growth factors are involved in the adaptive process. ...
... Little is known, however, about interactions between nutrients and growth factors [125]. ...
... In addition to the components having a role in immune response that, as result of their dual activity, have been discussed above, a number of other chemokines/growth factors have been detected in human milk. [41][42][43][44][45][48][49][50][51]53,54,119,120 Some of these polypeptides promote development of a wide number of cell types (CSF1, CSF3, EGF, FGF4, FGF6, FGF7, FSTL1, GHI, GHRH, GM-CSF, GRO, HGF, IGF1, IGF2, IL3, IL6, LHRH, OSM, PDGFB, PIGF, PPIA, SCGB3A1, SCF, SPP1, THPO, TGFA, TGFB1, TGFB2, TGFB3, TNF), while others are more selective in modulating outgrowth of adipocyte (AZGP1, LPT), osteoblast (OPG, PTHR, SORT1), neuronal (ATRN, BDNF, FGF9, GDNF, LHRH and LIF) and erythrocyte/vascular (EPO, TIMP1 and TIMP2) cell types. These molecules have also been described as modulator of cell differentiation (BDNF, CSF1, CSF3, EGF, FSTL1, GDNF, GM-CSF, GRO, IGF1, IGF2, IL3, IL6, PDGFB, PTHR, SST, TGFA, TGFB1, THPO, TIMP1, TIMP2 and TNF). ...
... A paradigmatical example is EGF, a 53-amino acid peptide present in human colostrum (200 µg/ L) and milk (30-50 µg/L), which has been proposed to stimulate growth and development of epithelial cells in the gastrointestinal tract. 119,120 In vitro experiments using gastric juice from preterm infants indicate that milk-borne EGF is only partially deactivated under typical gastric proteolytic conditions. 121,122 Once EGF enters the small intestine, it is susceptible to proteolytic digestion under fasting conditions but is preserved by the presence of other ingested food proteins. ...
... 123 Functional studies examining the distribution of EGF receptor in the normal adult human gastrointestinal tract suggest that EGF may act as a "luminal surveillance peptide" in the adult gut, readily available to stimulate the repair process at sites of injury. 120 It is important to note, however, that luminal EGF might gain access to basolateral receptors in the immature neonatal gut 124 because of its increased permeability. The EGF in colostrum and milk may therefore play a role in preventing bacterial translocation and stimulating gut growth in suckling neonates. ...
Although human milk has been studied for decades, big strides have been made in very recent years, owing to the introduction of innovative qualitative and quantitative approaches in proteomics. Since our recent report on the human milk proteome, where 285 unique proteins were listed, almost two years of research in this field have generated an UPDATED inventory consisting of 761 entries. This huge increment might further boost improvements in the field of novel nutritional formulas. By performining bioinformatic analysis on this updated dataset, we here substantiate that, despite the significant increase in the overall entries, human milk proteins are mainly devoted to three main biological functions, which include nutrient transport/lipid metabolism, concretization of the immune system response and mediation of cellular proliferation processes. Of note, human milk proteins seem also to promote maturing of the immune and central nervous system, through a series of biological mediators, including hormones, cytokines and other signaling molecules. Furthermore, the introduction of novel technological approaches has also helped furthering our understanding of the quantitative fluctuations of human milk proteins; this issue may represent a key aspect in the design of novel infant formulas as much as close to the actual breast milk.
... As, Hdh-MLGF is a secreted protein and highly expressed in digestive gland tissue it may be the secretion of submucosal gland of Pacific abalone. Digestive gland secreted growth factors are mainly involved in gastrointestinal adaptation [35]. In situ hybridization localization of MLGF in the submucosa layer of the digestive tubules of Pacific abalone may be related to the gastrointestinal adaptation of adult abalone, as the interaction of nutrition and growth factors is poorly understood [35]. ...
... Digestive gland secreted growth factors are mainly involved in gastrointestinal adaptation [35]. In situ hybridization localization of MLGF in the submucosa layer of the digestive tubules of Pacific abalone may be related to the gastrointestinal adaptation of adult abalone, as the interaction of nutrition and growth factors is poorly understood [35]. Different proteins, enzymes, and hormones have been reported to secrete from the digestive gland and digestive system. ...
Growth factors are mostly secreted proteins that play key roles in an organism’s biophysical processes through binding to specific receptors on the cell surface. The mollusk-like growth factor (MLGF) is a novel cell signaling protein in the adenosine deaminase-related growth factor (ADGF) subfamily. In this study, the MLGF gene was cloned and characterized from the digestive gland tissue of Pacific abalone and designated as Hdh-MLGF. The transcribed full-length sequence of Hdh-MLGF was 1829 bp long with a 1566 bp open reading frame (ORF) encoding 521 amino acids. The deduced amino acid sequence contained a putative signal peptide and two conserved adenosine deaminase domains responsible for regulating molecular function. Fluorescence in situ hybridization localized Hdh-MLGF in the submucosa layer of digestive tubules in the digestive gland. The mRNA expression analysis indicated that Hdh-MLGF expression was restricted to the digestive gland in the adult Pacific abalone. However, Hdh-MLGF mRNA expressions were observed in all stages of embryonic and larval development, suggesting Hdh-MLGF might be involved in the Pacific abalone embryonic and larval development. This is the first study describing Hdh-MLGF and its involvement in the Pacific abalone embryonic and larval development.
... Jugular or femoral blood samples were collected at weeks 0, 4,8,12,16,20,24,28,32,36,40,42, and 44 (using BD Vacutainers with sodium citrate as the anticoagulant, Becton & Dickenson). To obtain plasma, blood samples were centrifuged at 10,000 RCF for 10 min at 6 • C and plasma stored at −80 • C until assayed for immune markers. ...
... This targeted immune response occurred without an overall change in plasma IgA and IgM (37). Growth factors present in BC such as EGF, TGF-α, TGF-β (38), IGF (39), PDGF, vascular endothelial growth factor (VEGF) and growth hormone (GH) also play an important role in maintaining a healthy gut wall (40). ...
In its early life a kitten faces many significant events including separation from its mother, re-homing and vaccination. The kitten is also slowly adapting to their post-weaning diet. Recent advances in companion animal nutrition have indicated that functional ingredients such as colostrum can help support the immune system and gastrointestinal health. Here we report for the first time the effect of feeding a diet containing 0.1% spray dried bovine colostrum (BC) to growing kittens on gut-associated lymphoid (GALT) tissue responses, systemic immune responses, and on intestinal microbiota stability. BC supplementation induced increased faecal IgA expression, and a faster and stronger antibody response to a rabies vaccine booster, indicative of better localised and systemic immune function, respectively. BC supplementation also helped to maintain kittens' intestinal microbiota stability in the face of a mildly challenging life event. These results show that BC supplementation can help strengthen the immune system and enhance the gut microbiota stability of growing kittens.
... Growth factors are also found co-localized with mucins, especially in the gut 166,167 . EGF has been of particular interest, since it was shown to upregulate the expression of MUC2 and MU5AC at the transcriptional and protein level 168,169 and is involved in mucosal regeneration 170 . ...
... Although our knowledge on how EGF affects the expression of mucins and cell proliferation is well-established, details regarding the potential interactions between mucins and EGF are scarce. EGF and mucins are co-localized in saliva 171 , milk, and in the digestive system 166 . In the gut, EGF is thought to act as a surveillance peptide, stimulating mucosal repair, only when the altered epithelial barrier allows access to the basolateral side where the receptors have been localized 172 . ...
Mucins are large glycoproteins that are ubiquitous in the animal kingdom. Mucins coat the surfaces of many cell types and can be secreted to form mucus gels that assume important physiological roles in many animals. Our growing understanding of the structure and function of mucins molecules and their functionalities has sparked interest in investigating the use of mucins as building blocks for innovative functional biomaterials. These pioneering studies have explored how new biomaterials can benefit from the barrier properties, hydration and lubrication properties, unique chemical diversity, and bioactivities of mucins. Owing to their multifunctionality, mucins have been used in a wide variety of applications, including as antifouling coatings, as selective filters, and artificial tears and saliva, as basis for cosmetics, as drug delivery materials, and as natural detergents. In this review, we summarize the current knowledge regarding key mucin properties and survey how they have been put to use. We offer a vision for how mucins could be used in the near future and what challenges await the field before biomaterials made of mucins and mucin-mimics can be translated into commercial products.
... In patients with IBD the goal of nutritional treatment is not only to improve nutritional status, but also to modify the inflammatory immunological response in order to decrease disease activity and induce clinical remission. 2 Several epidermal growth factor-like peptides (EGF, transforming growth factor [TGF]-α, heparin-binding EGFlike peptide, amphiregulin, and betacellulin) are present in the gut 3 . Among them TGF-β, a multifunctional polypeptide (cytokine) present in human and bovine milk, plays a critical role in the development of tolerance, the prevention of autoimmunity, and in anti-inflammatory responses. ...
... TGF-β has a gradient of expression along the crypt villus axis, with maximum production at the villus tip. 3 are involved in this adaptation. Data referring to experimental colitis in rats suggest that IL-10-/-mice fed a TGF-β containing diet, gained more weight, did not develop diarrhoea, and had lower pathological scores, 4,5 thus supporting the use of TGF-β containing enteral diets as a possible therapeutic modality for CD patients. ...
Rationale: Dietetic intervention with polymeric diet rich in transforming growth factor-β2 (TGF-β2) represents a relatively satisfactory therapeutic modality in adult patients with mild to moderately active Crohn's disease. however, there is no information concerning long-term results of this special diet. The aim of this study was to compare the results of the administration of a special diet (Modulen IBD) rich in TGF-β2 with those of the administration of mesalamine, in maintaining remission in patients with Crohn's disease. Methods: Of the 83 patients initially included in the study, 76 (91.5%) [36 in the Modulen and 30 in the mesalamine arm] completed the trial. Patients were randomly assigned to receive either two meals (2X50g) of Modulen IBD plus two regular meals per day (43 patients) or mesalamine (800mg three times a day) (40 patients) for six months. Patients were assessed at sixth months after initiation of the trial. Relapse was defined as a Crohn's Disease Activity Index of greater than 150 points or at least 60 points over baseline. Various anthropometric parameters and serum estimations including eSR, CRP, platelets, albumin, vitamin B12 and folic acid were carried out at the beginning of the trial and after six months. Results: Twenty-five patients in the Modulen arm (69%) continued to be in remission after six months compared with 18(60%) re-ceiving mesalamine (no significant differences). Among patients with relapse the mean time to relapse was 103 days for those treated with mesalamine and 123 days for those treated with Modulen (no significant differences). Conclusion: Modulen-IBD treatment reduced relapse rate to a bet ter degree compared with mesalamine treatment, although statistical significance was not achieved.
... In patients with severe fluid losses refractory to combination antimotility agents and intravenous PPI, the somatostatin analogue octreotide may be used [25]. This can effectively reduce massive enteral fluid losses; however, its use should be reserved for the most refractory cases, as its inhibition of multiple gut hormones may impair intestinal adaptation [26]. Antibiotics are used in patients with suspected SIBO, typically in cyclical fashion [8]. ...
Severe short bowel syndrome (SBS) is a major cause of chronic (Type 3) intestinal failure (IF) where structural and functional changes contribute to malabsorption and risk of micronutrient deficiencies. Chronic IF may be reversible, depending on anatomy and intestinal adaptation, but most patients require long-term nutritional support, generally in the form of parenteral nutrition (PN). SBS management begins with dietary changes and pharmacologic therapies taking into account individual anatomy and physiology, but these are rarely sufficient to avoid PN. New hormonal therapies targeting intestinal adaptation hold promise. Surgical options for SBS including intestinal transplant are available, but have significant limitations. Home PN (HPN) is therefore the mainstay of treatment for severe SBS. HPN involves chronic administration of macronutrients, micronutrients, fluid, and electrolytes via central venous access in the patient’s home. HPN requires careful clinical and biochemical monitoring. Main complications of HPN are related to venous access (infection, thrombosis) and metabolic complications including intestinal failure associated liver disease (IFALD). Although HPN significantly impacts quality of life, outcomes are generally good and survival is mostly determined by the underlying disease. As chronic intestinal failure is a rare disease, registries are a promising strategy for studying HPN patients to improve outcomes.
... EGF might play a role in the healing of ulcer. (Blum and Hammon, 1999;Koldovsky, 1995;Murphy, 1998;Murray et al., 1992;Schams, 1994). ...
Until recently, the biological role of milk has been viewed mostly as a source of nutrients for the newborn mammal, covering energy, protein and lipid demands as well as the supply of essential nutrients such as vitamins and minerals. However, in addition to the established nutritional value many different factors are present in milk, which exhibit specific physiological activities essential to growth and development of the neonate and to protect against diseases and infections. Milk thus represents a very valuable weapon for enhancing the immature immunologic system of the newborn and for strengthening its deficient host defense mechanisms against infective or other foreign agents and might modulate many physiological functions such as the maturation of gastrointestinal tract and the endocrine system of the neonate.
... In this study, we thus used a ME dosage form of TGF-a, as previously described [5,19], to minimize the enzymatic degradation of TGF-a in gastrointestinal tract (GIT). Immunohistochemical studies have shown that, TGF-a immunoreactivity is found in duodenum, especially duodenal epithelium, Brunner's gland [20], villus enterocytes and may have an important role in mucosal healing [21]. ...
Objective: This study was designed to investigate the effects of aqueous or Microemulsion solution containing Transforming Growth factors-alpha (TGF-a) and/or administration of aprotinin on healing rate of duodenal ulcer induced by acetylsalicylic acid, and to examine the relationships between oxidative processes and TGF-a formulation during duodenal ulcer healing by measuring malondialdehyde, glutathione and total nitric oxide levels. Methods: Male Wistar albino rats were divided into nine groups 1. Control, 2. Acute Ulcer, 3. Chronic Ulcer (untreated), 4. Physiological saline (PS) 5. PS containing TGF-α (10μg/kg), 6. Microemulsion (ME), 7. Microemulsion containing TGF-α (T-ME), 8. Microemulsion containing aprotinin (AME) 9. Microemulsion containing TGF-α and aprotinin (T-AME). Acute duodenal lesions were induced by intragastric administration of acidified acetylsalicylic acid (150 mg/kg dissolved in 0.2 N HCl) to rats Ulcer areas were detected planimetrically. Tissue malondialdehyde, glutathione and total nitric oxide levels were measured by spectrophotometric methods The ultrastructural changes in duodenum observed by Transmission Electron Microscopy (TEM). Results: T-ME and/or aprotinin application decreased the duodenal ulcer areas and malondialdehyde levels and increased glutathione and total nitric oxide levels. Histological evaluation indicated that the best regeneration was observed in T-ME and T-AME groups. Conclusions: TGF-α in microemulsion dosage form accelerates the healing rate of duodenal ulcer and reduces oxidative stress.
... As an example, Epidermal Growth Factor (EGF) is secreted into the gastrointestinal lumen while its receptors are mainly expressed on the basolateral membrane of epithelial cells . In a physiological setting, this pool of EGF is only though to come in contact with its receptors upon mechanical or infectious damage to the epithelium, and the ensuing proliferating effect of EGF is thought to facilitate wound healing (Murphy 1998;. However, in premalignant tissue, constant proliferative effect of EGF is made possible by chronic TJ disruption, thus contributing to the onset of adenomas and/or carcinomas (Mullin 1997(Mullin , 2004. ...
The intestine plays a major role in the absorption of nutrients, water, and electrolytes during digestion and protects the inner organs from the external environment. One of the major characteristics of this organ is that, while maintaining its function, it undergoes constant renewal at a very high rate, with the entire intestine renewed every 5–7 days in humans. This process occurs without disrupting the epithelial barrier, thus guaranteeing that the separation between external (lumen) and internal compartments is maintained, and that cell polarity is preserved. Tight junctions (TJ) are among the multi-protein complexes that play an essential role in the maintenance of this epithelial barrier. A number of observations have been made that the structure of tight junctions can be disrupted from early stages of neoplastic development in the intestine, and alterations of tight junction protein expression and/or localization have been reported in epithelial cancers, which significantly impacts on early tumorigenesis as well as tumor progression. In the present review, we summarize the current knowledge concerning alterations of tight junction protein expression in colorectal tumors, before discussing some of the likely consequences of these disruptions for tumorigenesis and the potential clinical use of tight junction proteins as prognostic markers or as targets for therapy in this type of tumors.
... 1 It is well known that several epidermal growth factor (EGF)-like peptides (EGF, transforming growth factor [TGF]-á, heparin-binding EGF-like peptide, amphiregulin, and betacellulin) are present in the gut. 2 Among them TGF-â, a multifunctional polypeptide (cytokine) present in human and bovine milk, plays a critical role in the development of tolerance, the prevention of autoimmunity, and in anti-inflammatory responses. It is a potent inhibitor of intestinal epithelial cell growth and stimulates intestinal epithelial cell differentiation. ...
So far, nutritional support with a polymeric diet rich in TGF-â has been studied only in children with Crohns disease and produced satisfactory results. There are no data concerning the effect of this kind of diet in adult patients with Crohns disease. The aim of this pilot study was to present our initial experience on the use of a pol-ymeric diet rich in TGF-â in patients with mild or mod-erately active Crohns disease. Patients and Methods: Twenty nine patients with active Crohns disease received Modulen IBD as an exclusive diet for 4 weeks (50gx5/d). Patients continued to be on their regular conservative treatment (if so). Activity of the disease was assessed at the beginning of the therapeutic trial and after 4 weeks by the use of CDAI. Var-ious anthropometric parameters and serum estimations, including ESR, CRP, platelets, albumin, vitamin B12 and folic acid were carried out at the beginning and after 4 weeks of application of the special diet. Results: Clinical improvement was noticed in 69% (20 out of 29 patients). No change of the situation or worsening was noticed in 9 patients (31%). The main alterations on anthropometric, hematological and biochemical parame-ters estimated before and after the application of the spe-cial diet are shown in the table. Conclusion: Dietetic intervention with polymeric diet rich in TGF-â2 represents a quite satisfactory therapeutic mo-dality in adult patients with mild to moderately active Crohns disease. However, these results must be confirmed in larger, randomized, placebo controlled clinical trials.
... The EGF act on its target cells after binding to specific tyrosine kinase membrane receptors that been identified in the epithelial cells of the mucosa of the stomach and small intestine (Murphy, 1998). The expression of EGF mRNA was detected using reverse transcriptase polymerase chain reaction in gastric mucosa of the ulcerated group that received treatment with medicinal plants (Toma et al., 2004;Paula et al., 2008). ...
Ipomoea imperati (Vahl) Griseb., Convolvulaceae, is used in traditional medicine for the treatment of inflammation, swelling and wounds, as well as to treat pains and stomach problems. This work evaluates the anti-oxidative activity by ESR (Electron Spin Resonance spectroscopy) and the preventive and curative actions of I. imperati in gastric ulcer animal model. Ipomoea imperati (200 mg/kg, p.o.) prevented the formation of gastric lesions in 78% (p<0.05) when compared with the negative control tween 80. Lanzoprazole, prevented in 85% the gastric lesions formation induced by ethanol (p<0.05). Therefore, the oral administration of I. imperati one hour before the ulcerogenic agent prevented the ulcer formation, conserving the citoprotection characteristics of the gastric mucosa and assuring the integrity of gastric glands and gastric fossets. The healing activity of I. imperati (200 mg/kg, p.o.) evaluated in chronic ulcer experiments induced by the acetic acid, was 72% (p<0.05). The positive control, ranitidine, healed 78% of the gastric lesions (p<0.05). The histological analysis confirmed the recovery of the mucosal layer and the muscle mucosal layer harmed by the acetic acid. Experiments in vitro with DPPH (2.2-diphenyl-1-picrylhydrazyl) of anti-oxidative activity demonstrated that I. imperati presents an IC50 of 0.73 +/- 0.01 mg/mL.
... A number of studies indicate that BC can contribute to GI tract maintenance by recruiting healthy cells and by stimulating the growth of epithelial cells, which line the entire length of the GI tract (30,37). To assess the efficacy of BC supplementation on maintaining GI permeability during heat stress, Prosser and colleagues (39) supplemented rats with BC for seven days and assessed the transfer of chromium-labelled ethylenediaminetetraacetic acid (Cr-EDTA) from the gut to circulation while increasing their core temperature to 41.5°C. ...
Colostrum is the first milk produced by mammalian mothers and is essential for the health and survival of the newborn. Bovine colostrum (BC) has greater concentrations of the bioactive components (i.e. immune and growth factors) than those found in human colostrum. As a result, BC supplementation has been recently adopted by many sport competitors as a means of enhancing immune function as well as improving performance. Improvements in physical performance associated with BC supplementation may stem from the ability of BC to maintain gastrointestinal (GI) integrity by decreasing GI permeability. During exercise in the heat, blood flow to the GI tract is reduced that leads to endotoxin leakage into circulation. Endotoxins, such as lipopolysaccharide, can trigger an inflammatory cascade leading to physiological strain that, in turn, increases heat storage and decreases time to exhaustion. GI permeability is lessened during passive heat stress following BC supplementation, but the influence of BC supplementation on GI function during exercise heat stress remains to be determined. The implications of endotoxemia during exercise in the heat is a matter of growing importance and warrants further study given the global increase in ambient temperatures during sport competitions.
... In this study we showed that EGFR/IL15R-a cooperation is crucial for gliadin-induced crypt enterocyte proliferation and activation of the innate immune response in CD. Previous reports from our laboratory and others have indicated that EGF and IL15 induce enterocyte proliferation and that both EGFR and IL15 activity contribute to the gliadin-induced epithelial cell proliferation in CD biopsy samples (11,13,29,30). In this study, we used CaCo-2 cells, a colon carcinoma-derived intestinal epithelial cell line and a well-known responder to gliadin and gliadin peptides (11,31)-to demonstrate that IL15 and EGF cooperate to induce enterocyte proliferation. ...
On ingestion of gliadin, the major protein component of wheat and other cereals, the celiac intestine is characterized by the proliferation of crypt enterocytes with an inversion of the differentiation/proliferation program. Gliadins and A-gliadin peptide P31-43, in particular, act as growth factors for crypt enterocytes in patients with celiac disease (CD). The effects of gliadin on crypt enterocyte proliferation and activation of innate immunity are mediated by epidermal growth factors (EGFs) and innate immunity mediators [interleukin 15 (IL15)].
The aim of this study was to determine the molecular basis of proliferation and innate immune response to gliadin peptides in enterocytes.
The CaCo-2 cell line was used to study EGF-, IL15-, and P31-43-induced proliferation. Silencing messenger RNAs and blocking EGF receptor and IL15 antibodies have been used to study proliferation in CaCo-2 cells and intestinal biopsy samples from patients with CD and control subjects.
In the CaCo-2 cell model, IL15 and EGF cooperated to induce proliferation in intestinal epithelial cells at both the transcriptional and posttranscriptional levels, and the respective receptors interacted to activate each other's signaling. In addition, the effects of the P31-43 peptide on CaCo-2 cell proliferation and downstream signaling were mediated by cooperation between EGF and IL15. The increased crypt enterocyte proliferation in intestinal biopsy samples from patients with CD was reduced by EGF receptor and IL15 blocking antibodies, only when used in combination.
EGFR/IL15R-α cooperation regulates intestinal epithelial cell proliferation induced by EGF, IL15, and the gliadin peptide P31-43. Increased proliferation of crypt enterocytes in the intestine of CD patients is mediated by EGF/IL15 cooperation.
... Otra vía por la que las citocinas podrían verse indirectamente implicadas en los cambios observados en el intestino es a través de sus efectos en la producción de factores de crecimiento epitelial, como el KGF 22 , por las células de la estroma, que actúa específicamente sobre las células del epitelio intestinal 25 . Las células epiteliales producen sus propios mitógenos, como TGFα y factor de crecimiento epitelial (epithelial growth factor, EGF), y su liberación aumenta tras el daño tisular 26 . Es muy probable que la producción de esas moléculas y sus receptores pueda ser modulada por citocinas, aunque aún se necesitan más estudios para confirmar su importancia en el daño intestinal inducido por los linfocitos T 27 . ...
Celiac disease is manifested by an enteropathy caused by intolerance to gluten, a family of proteins found in wheat and other cereals. Following intestinal T-cell activation in predisposed individuals, different inflammatory mechanisms are triggered under the control of the cytokine balance including those with a pro-inflammatory Th1 pattern such as IFNγ, TNFα, IL-15 and IL-18; and regulatory cytokines such as TGFβ and IL-10. These cytokines, besides increasing the intensity of the activation and the number of immune cells within the intestinal mucosa, regulate the activity of epithelial growth factors and metalloproteinases, a group of molecules involved in the maintenance and turnover of the intestinal mucosa structure; in inflammatory conditions, they also induce the intestinal lesion responsible for malabsorption syndrome.
... Cow milk contains not only essential nutrients but also a number of natural bioactive substances that have many beneficial effects on human health (7)(8)(9)(10). Raw cow milk contains a large amount of TGFb, with a predominance of TGFb2 over TGFb1 (10,11); some of the beneficial effects of cow milk or cow milkderived whey proteins on human health, particularly on inflammatory activity, have been suggested to be associated with this immunoregulatory molecule (10). ...
Cow milk contains a large amount of an immunoregulatory cytokine, transforming growth factor-b (TGFb). The present study investigated whether commercially available pasteurized cow milk retains TGFb activity both in vitro and in vivo. Some commercial cow milk increased TGFb/Smad-responsive reporter activity and induced Smad2 phosphorylation and the transcription of the TGFb/Smad target genes TGFb itself and Smad7 in vitro. Mice treated orally with 500 mL of cow milk containing TGFb (3 mg/L) daily for 2 wk had increased phosphorylation of Smad2 and TGFb and Smad7 mRNA expression in the intestine. These mice also had significantly greater serum TGFb concentrations than the mice treated orally with PBS. Furthermore, oral administration of 500 mL of cow milk containing TGFb (3 mg/L) daily for 2 wk before the induction of dextran sodium sulfate colitis and lipopolysaccharide-induced endotoxemia ameliorated tissue damage and mortality, respectively, in mice. These in vivo effects of cow milk were abrogated by the simultaneous administration of TGFb type I receptor kinase inhibitor with the cow milk, and they were not observed after the oral administration of cow's milk containing little TGFb. In humans, 1 oral challenge of 10 mL/kg cow milk containing TGFb (3 mg/L) increased the plasma TGFb concentrations at 4 h after the challenge. Thus, some commercially available pasteurized cow milk retains TGFb activity, which may be able to provide protection against experimental colitis and endotoxemia associated with increased intestinal and circulating TGFb levels. J. Nutr. 139: 69-75, 2009.
... The authors of these studies hypothesised that colostrum acted by firstly stimulating the movement of healthy cells into the site of damage and secondly by actually stimulating the growth of new cells. In support of this hypothesis, bovine colostrum contains several factors that can stimulate growth of epithelial cells, at least in culture (17,20,25). Colostrum also contains antimicrobial and antiviral agents that reduce the impact of bacterial or viral pathogens on intestinal epithelium (9). ...
... Breast milk contains a number of different growth factors, including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and transforming growth factor-β1 and β2 (TGF-β1/β2), among others [60,61]. These factors activate PI3 kinase and mitogenactivated protein (MAP) kinase signaling pathways to achieve their growth-promoting effects, which are associated with increased metabolic activity and its attendant increase in ROS production. ...
Although autism is first and foremost a disorder of the central nervous system, comorbid dysfunction of the gastrointestinal (GI) and immune systems is common, suggesting that all three systems may be affected by common molecular mechanisms. Substantial systemic deficits in the antioxidant glutathione and its precursor, cysteine, have been documented in autism in association with oxidative stress and impaired methylation. DNA and histone methylation provide epigenetic regulation of gene expression during prenatal and postnatal development. Prenatal epigenetic programming (PrEP) can be affected by the maternal metabolic and nutritional environment, whereas postnatal epigenetic programming (PEP) importantly depends upon nutritional support provided through the GI tract. Cysteine absorption from the GI tract is a crucial determinant of antioxidant capacity, and systemic deficits of glutathione and cysteine in autism are likely to reflect impaired cysteine absorption. Excitatory amino acid transporter 3 (EAAT3) provides cysteine uptake for GI epithelial, neuronal, and immune cells, and its activity is decreased during oxidative stress. Based upon these observations, we propose that neurodevelopmental, GI, and immune aspects of autism each reflect manifestations of inadequate antioxidant capacity, secondary to impaired cysteine uptake by the GI tract. Genetic and environmental factors that adversely affect antioxidant capacity can disrupt PrEP and/or PEP, increasing vulnerability to autism.
... Breast milk contains a number of different growth factors, including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and transforming growth factor-β1 and β2 (TGF-β1/β2), among others [60,61]. These factors activate PI3 kinase and mitogenactivated protein (MAP) kinase signaling pathways to achieve their growth-promoting effects, which are associated with increased metabolic activity and its attendant increase in ROS production. ...
Although autism is first and foremost a disorder of the central nervous system, comorbid dysfunction of the gastrointestinal (GI) and immune systems is common, suggesting that all three systems may be affected by common molecular mechanisms. Substantial systemic deficits in the antioxidant glutathione and its precursor, cysteine, have been documented in autism in association with oxidative stress and impaired methylation. DNA and histone methylation provide epigenetic regulation of gene expression during prenatal and postnatal development. Prenatal epigenetic programming (PrEP) can be affected by the maternal metabolic and nutritional environment, whereas postnatal epigenetic programming (PEP) importantly depends upon nutritional support provided through the GI tract. Cysteine absorption from the GI tract is a crucial determinant of antioxidant capacity, and systemic deficits of glutathione and cysteine in autism are likely to reflect impaired cysteine absorption. Excitatory amino acid transporter 3 (EAAT3) provides cysteine uptake for GI epithelial, neuronal, and immune cells, and its activity is decreased during oxidative stress. Based upon these observations, we propose that neurodevelopmental, GI, and immune aspects of autism each reflect manifestations of inadequate antioxidant capacity, secondary to impaired cysteine uptake by the GI tract. Genetic and environmental factors that adversely affect antioxidant capacity can disrupt PrEP and/or PEP, increasing vulnerability to autism.
... At this point, it is worth mentioning that these polypeptides are constantly present in the gastrointestinal lumen, either secreted by glands or ingested via foodstuffs such as milk and colostrum. Their contribution to the maintenance of mucosal mass and integrity is of special interest in the neonatal bowel or in the adult damaged gut where permeability of the bowel may be increased (Murphy, 1998;Playford, MacDonald, & Johnson, 2000). Furthermore, the gastrointestinal tract of neonates may enhance the survival of milk borne growth factors due to relatively low levels of gastric acidity and luminal proteolytic digestion (Burrin, 1997). ...
In recent years, intense scientific interest has been focused on the identification of factors within bovine milk that may be relevant to improving human health. This paper provides an overview of current areas of research with regard to a number of minor bioactive milk components (growth factors, vitamins and nucleotides), and focuses on aspects that are directly relevant to nutritional and technological matters.
... Growth factors secreted by the enterocyte, including hepatocyte growth factor (HGF), transforming growth factor, and epidermal growth factor, 8,9 promote regeneration and healing of the skin and other tissues. We hypothesize that in severe portal hypertension the local concentration of these growth factors or their receptors may be insufficient to support the regenerative function of dermatocytes. ...
The occurrence of leg ulcers in patients with cirrhosis is not well documented in the literature. In this case series, we describe 4 patients with cirrhosis complicated by leg ulceration that failed all conventional therapy, yet healed completely following the placement of transjugular intrahepatic portosystemic shunt. The course of disease and the possibility of a hepatodermal syndrome underlying this observation are discussed.
... As reported for some proteins mentioned above, these chemokines/hormones may not only be involved in the development, but also in the repair and metabolism of specific suckling's organs. [164][165][166] Targeted tissues include: (i) thyroid (TSHB); (ii) gastrointestinal tract (EGF, FGF1, FGF2, PDGFB and TGFA); (iii) bones (PTHLH, SPP1, STC1 and TGFB); (iv) brain (LHRH); (v) adipose tissues (AZGP1, LEP and PPARG). Conversely, GH, GHRH, INS, IGF1, IGF2 and SST have been described acting on the whole body. ...
Bovine milk represents an essential source of nutrients for lactating calves and a key raw material for human food preparations. A wealth of data are present in the literature dealing with massive proteomic analyses of milk fractions and independent targeted studies on specific groups of proteins, such as caseins, globulins, hormones and cytokines. In this study, we merged data from previous investigations to compile an exhaustive list of 573 non-redundant annotated protein entries. This inventory was exploited for integrated in silico studies, including functional GO term enrichment (FatiGO/Babelomics), multiple pathway and network analyses. As expected, most of the milk proteins were grouped under pathways/networks/ontologies referring to nutrient transport, lipid metabolism and objectification of the immune system response. Notably enough, another functional family was observed as the most statistically significant one, which included proteins involved in the induction of cellular proliferation processes as well as in anatomical and haematological system development. Although the latter function for bovine milk proteins has long been postulated, studies reported so far mainly focused on a handful of molecules and missed the whole overview resulting from an integrated holistic analysis. A preliminary map of the bovine milk proteins interactome was also built up, which will be refined in future as result of the widespread use of quantitative methods in protein interaction studies and consequent reduction of false-positives within associated databases.
Mucin, a family of glycoproteins, is widespread in the inner linings of various lumen organs and plays key roles in protecting epithelial cells from invasion by foreign species and communicating with the external environment. Here, we demonstrated that Mucin could be engineered as a promising building block in biomaterials with unexpected multifunctionalities by codepositing with procyanidin (PC, a kind of flavanol polyphenol) through a layer-by-layer technique. The process of generating PC/Mucin multilayers was well characterized and monitored, which was controllable by the assembly conditions. The behaviors of bone marrow mesenchymal stem cells (BMSCs), including proliferation, antioxidant ability, and expression of vinculin, were investigated to reveal the role of PC/Mucin multilayers on the osteogenic differentiation of BMSCs. Our data showed that PC/Mucin multilayers promoted osteogenesis-related genes (Col1, ON, OCN and RUNX2) in BMSCs in vitro and bone generation in vivo by activating the Wnt/β-catenin pathway. These findings demonstrate that engineering Mucin might be a new route in the future to implant materials or coatings for bone regeneration.
Hydrogels made of crosslinked macromolecules used in regenerative medicine technologies can be designed to affect the fate of surrounding cells and tissues in defined ways. Their function typically depends on the type and number of bioactive moieties such as receptor ligands present in the hydrogel. However, the detail in how such moieties are presented to cells can also be instrumental. In this work, how the crosslinking architecture of a hydrogel can affect its bioactivity is explored. It is shown that bovine submaxillary mucins, a highly glycosylated and immune-modulating protein, exhibit strikingly different bioactivities whether they are crosslinked through their glycans or their protein domains. Both the susceptibility to enzymatic degradation and macrophage response are affected, while rheological properties and barrier to diffusion are mostly unaffected. The results suggest that crosslinking architecture affects the accessibility of the substrate to pro-teases and the pattern of sialic acid residues exposed to the macrophages. Thus, modulating the accessibility of binding sites through the choice of the crosslinking strategy appears as a useful parameter to tune the bioactivity of hydrogel-based systems.
This chapter reviews the characteristics of inflammatory bowel disease, the nature of the inflammatory process, and the potential role for nutrition interactions Also, nutrition and short bowel syndrome, one of the potential complications of Crohn's disease and other gastrointestinal maladies, are addresses in the chapter.The two primary forms of idiopathic inflammatory bowel disease, Crohn's disease and ulcerative colitis, are characterized as chronic, inflammatory diseases of varying severity. The cause is unknown but the disease appears to involve significant interaction of the intestinal wall with intestinal microbes, ingested foods and beverages, gastrointestinal secretions, local and systemic immune components, and genetic factors. The disease may result in malabsorption of nutrients, obstruction of the gastrointestinal tract, decreased oral intake, increased nutrient requirements, and adverse response to ingested foods. Malnutrition is common. Medications and other therapies employed in treating inflammatory bowel disease can further compromise nutritional status. Specific dietary factors may enhance or attenuate the underlying inflammatory processes involved in the disease, and certain dietary habits can worsen or reduce the severity of symptoms of inflammatory bowel disease. Surgery is common in the life of patients with inflammatory bowel disease and, in some cases, may significantly affect the ability of the patient to maintain adequate nutritional status without specialized nutrition care. Consequently, dietary interventions have a significant role in the management of inflammatory bowel disease, its symptoms, and its consequences.are reviewed.
Trefoil factor family (TFF) peptides are produced rapidly at sites of injury, stimulating epithelial migration, a process involving rapid changes in cell shape and volume, requiring rapid flow of water into and out of the cell. We examined the effect of TFFs on fluidity of cells by measuring their sensitivity to osmotic challenges and cell migration, and determined whether those results were mediated through altering the levels of aquaporins (AQPs), a family of transmembrane water channels involved in cellular water homeostasis. Gastric (AGS) and colonic (Caco-2) cell lines had intrinsic TFF levels determined and the predominant TFF peptide knocked down (RNA interference). Knockdown caused lessened responsiveness to changes in external osmotic challenge (by 51 and 69% in AGS and Caco-2 cells, respectively) and reduced cell migration and transepithelial permeability but did not influence proliferation. Exogenous TFF increased several AQPs, particularly AQP3, and those were reciprocally reduced in knockdown cells. TFF-induced, but not fetal calf serum-induced, cell migration was inhibited by the presence of AQP3 blocker (CuSO4). We summarize that TFF peptides promptly produced at sites of injury increase AQP levels, most notably AQP3, thereby enhancing the cells' ability to rapidly change their shape as part of the restitutive process. TFF peptides also require functioning AQP3 channels to induce cell migration.-Marchbank, T., Playford, R. J. Trefoil factor family peptides enhance cell migration by increasing cellular osmotic permeability and aquaporin 3 levels.
Neural Stem Cells have the cardinal properties of stem cells-the ability to self-renew and to generate differentiated progeny. They are found broadly throughout the vertebrate central and peripheral neural germinal tissues and are responsible for generating millions of neurons and glia. The nervous system is a unique tissue composed of different cell types produced on a precise time course, so that each new wave of cells in a particular region migrates into position in an orchestrated manner to generate the final intricate cytoarchitecture essential for neural function. Over the past decade, substantial strides have been made in understanding the characteristics of neural stem cells, the markers defining the overall class, and the molecular mechanisms that subdivide them into the various subtypes. Substantial challenges remain in understanding the cellintrinsic programming responsible for their various cellular outputs, and the important environmental regulation by molecules in stem cell niches. Solving these questions will bring us closer to the monumental challenge of understanding how the brain forms, and how we can use this knowledge to combat nervous system afflictions. © Springer Science+Business Media New York 2001. All rights are reserved.
Cytokines and growth factors play diverse roles in the uninflamed fetal/neonatal intestinal mucosa and in the development of inflammatory bowel injury during necrotizing enterocolitis (NEC). During gestational development and the early neonatal period, the fetal/premature intestine is exposed to high levels of many “inflammatory” cytokines and growth factors, first via swallowed amniotic fluid in utero and then, after birth, in colostrum and mother’s milk. This article reviews the dual, seemingly counter-intuitive roles of cytokines, where these agents play a “trophic” role and promote maturation of the uninflamed mucosa, but can also cause inflammation and promote intestinal injury during NEC.
Chronische Anastomosenfisteln repräsentieren ein klinisch komplexes Problem nach verschiedenen gastrointestinalen Eingriffen. Die Ätiologie der Fistelentstehung ist multifaktoriell. Risikofaktoren für chronische Anastomosenfisteln können in drei Kategorien eingeteilt werden: 1. patientenabhängige Risikofaktoren, 2. chirurgisch bedingte Risikofaktoren, 3. durch die prä- und perioperative Begleittherapie bedingte Risikofaktoren. Die therapeutischen Strategien bei chronischen Anastomosenfisteln beinhalten einerseits eine Optimierung des Risikoprofils, medikamentöse Strategien zur Wundheilungsoptimie-rung, interventionell endoskopische Strategien und chirurgische Maßnahmen.
Wachstumsfaktoren gehören zu den wichtigsten Modulatoren von Wachstum, Differenzierung und Regeneration im Intestinaltrakt. Mit dem Begriff Wachstumsfaktor im engeren Sinne wird eine heterogene Gruppe regulatorischer Peptide mit verschiedenartigen strukturellen und funktionellen Eigenschaften zusammengefasst, deren Molekulargewicht in der Regel unter 25.000 liegt. Die Nomenklatur der regulatorischen Peptide ist überlappend und wird in der Literatur z.T. uneinheitlich benutzt [19, 23, 32, 33]. So werden die Begriffe Wachstumsfaktoren, Zytokine, Interleukine, Interferone und Stammzellfaktoren mitunter synonym gebraucht(_
Abb. 18-1).
Although medical therapies are widely accepted by health practitioners, sometimes without adequate testing. nutritional therapy is frequently looked upon uniformly as without merit. There are many reasons for this attitude. However, a substantial body of literature has accumulated that objectively demonstrates the value of adding nutritional therapy to the prevention or treatment of some diseases or specific risk factors for diseases. Examples of successful nutrition therapy that can be combined with medical management include treatment of hypertension, hyperlipidemia. intermittent claudication, osteoporosis, respiratory distress syndrome, and arthritis.
Objective To test the hypotheses that transforming growth factor alpha (TGF alpha) is present in cord blood and that TGF alpha concentration is associated with gestational age. Methods Umbilical venous cord blood samples (n=79) were processed immediately after delivery. Each cord serum sample was analyzed for TGF alpha concentration (pg/ml) by radioimmunoassay. Obstetric and neonatal clinical characteristics were also collected. Prematurity was defined as a gestational age of <37 weeks. The relationship of TGF concentration with clinical characteristics of the cohort was determined. Results TGF alpha was present in all cord blood samples tested. The TGF alpha concentration in the samples varied significantly as a function of gestational age (p=0.0001). The mean ( SID) cord serum TGF alpha concentration was 16.4 +/-5.9 pg/ml in infants of <37 weeks' gestation and 27.0<plus/minus>9.7 pg/ml in infants of greater than or equal to 37 weeks' gestation. A lower mean TGF alpha concentration was associated with low birth weight (p=0.002), respiratory distress syndrome (p=0.004) and with infants whose mothers had received betamethasone for fetal lung maturity (p=0.004) and tocolytic therapy (p=0.03); however, these differences were no longer significant after controlling for gestational age. Conclusions Cord blood TGF alpha concentration and gestational age were strongly associated, independently of birth weight and ethnicity: infants of greater than or equal to 37 weeks' gestation had significantly higher TGF alpha concentrations than those of <37 weeks.
Ipomoea asarifolia (Desr.) Roem. & Schult., Convolvulaceae, is a weed that infests agricultural areas and is toxic to cattle. In spite of its toxicity, the leaves of this plant are used in traditional remedies in the state of Bahia, Brazil. The present work describes the leaf anatomy of I. asarifolia and characterizes the exudates of its secretory structures. The leaves have a unistratified epidermis composed of ordinary cells with straight to slightly sinuous anticlinal walls and thin cuticles. Paracytic stomata are found on both surfaces of the leaves at the same level as the ordinary epidermal cells. Trichomes producing polysaccharide secretions occur on the petiole and leaf blade and are considered colleters. The mesophyll is dorsiventral and the vascular bundle of the central vein is bicollateral. Two opposed nectaries occur on the petiole near the leaf blade. Each nectary is composed of a small canal with internal ramifications and numerous secretory trichomes. The laticiferous glands are articulated, not anastomosed, and are composed of large diameter cells with thin cell walls. The secretions of the laticiferous glands are lipidic.
Purpose of review:
To illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.
Recent findings:
Some studies link exposure to infectious agents to development of brain disorders; others have identified autoantibodies in individuals with these conditions without finding evidence of pathogens. Neither line of work demonstrates consistent associations between a specific neuropsychiatric disease and a particular environmental trigger or immune marker. Growing evidence suggests that the microbiome conditions host immunity to microbes and xenobiotics, and regulates autoimmune responses that can affect the central nervous system (CNS). The presence of CNS receptors for cytokines and other immune molecules underscores the importance of brain-immune crosstalk in maintaining normal function. An increased prevalence of familial autoimmunity, exposure to pathogens prenatally and postnatally, and findings of antibrain antibodies is common in disorders as diverse as schizophrenia, obsessive-compulsive disorder and autism, and suggests that differences in exposure timing and genetic vulnerability toward autoimmunity are important determinants of neuropsychiatric outcomes.
Summary:
Microbes, both pathogenic and commensal, can induce autoantibodies that bind to brain and affect behavior in susceptible hosts. Interventions that correct the microbial balance or diminish autoantibody binding may be effective in diverse neuropsychiatric conditions mediated by autoimmunity.
Peptic ulcer disease is one of the most common chronic infections in human population. Despite centuries of study, it still troubles a lot of people, especially in the third world countries, and it can lead to other more serious complications such as cancers or even to death sometimes.
This book is a snapshot of the current view of peptic ulcer disease. It includes 5 sections and 27 chapters contributed by researchers from 15 countries spread out in Africa, Asia, Europe, North America and South America. It covers the causes of the disease, epidemiology, pathophysiology, molecular-cellular mechanisms, clinical care, and alternative medicine. Each chapter provides a unique view. The book is not only for professionals, but also suitable for regular readers at all levels.
Multilayer films of biopolymers are attractive tools to exploit the extraordinary properties of certain biomacromolecules and introduce new functionalities to surfaces. Mucins, the gel-forming constituents of mucus, are versatile glycoproteins that have potential as new building blocks for biomaterial surface coatings. Multilayer films have mostly been assembled through the electrostatic pairing of polyelectrolytes, which results in limited pH and salt stability and screens charges otherwise available for useful payload binding. Here, we aim at assembling mucin multilayer films that differ from conventional paired polyelectrolyte assemblies to obtain highly stable and functional surface modifications. Using the lectin wheat germ agglutinin (WGA) to cross-link mucin-bound sugar residues, we show that (Mucin/WGA) films can grow into hydrated films and sustain exceptional resistance to extreme salt conditions and a large range of pH. Furthermore, we show that the addition of soluble N-acetyl-d-glucosamine can induce the controlled release of WGA from (Mucin/WGA) films. Last, we show that (Mucin/WGA) films can repeatedly incorporate and release a positively charged model cargo. The lubricating, hydration, barrier, and antimicrobial properties of mucins open multiple applicative perspectives for these highly stable mucin-based multilayer films.
Acute pancreatitis is a disease of variable severity and outcome: mild disease may be treated at home, while severe disease
often leads to several weeks in the ICU with mortality rates approaching 50%. Cell and molecular biological studies have increased
our knowledge of the pathophysiology of the disease dramatically over the past decade, but have not, as yet, led to a specific
treatment. All of the improvement in outcome can be attributed to supportive measures, such as nutrition. Clinical investigations
have shown that acute pancreatitis is a highly catabolic illness, and protein deficiency could occur before the 2nd week of
illness if no feeding is given. Parenteral nutrition (PN) is effective in preventing protein catabolism, and also ‘rests’
the pancreas, but increases the already high risk of septic and metabolic side-effects, and worsens outcome in mild illness.
Enteral feeding is superior to PN in the management of acute pancreatitis, even if it is polymeric or infused directly into
the stomach. Unfortunately, however, enteral feeding stimulates pancreatic trypsin production and may exacerbate the disease
process unless delivered well down the jejunum. The most likely reason for the superiority of enteral over parenteral feeding
is its capacity to maintain intestinal function and suppress the cytokine-mediated systemic inflammatory response and consequent
multiple organ failure.
The small intestine is a remarkably complex organ that is capable of digestion, vectorial transport (absorption and secretion),
and endocrine function. In addition, the small intestine protects the internal environment against noxious ingested substances
and against luminal bacteria and their toxins. It is increasingly appreciated that the mucosal immune system plays a critical
role in mucosal defense, and that dysregulation of this function underlies the pathogenesis of a number of clinical disorders.
The potential surface area available for digestion and absorption is amplified 600-fold by the presence of circular mucosal
folds, villus mucosal architecture, and the microvillus surface of the small intestinal epithelium. Although specific properties
(e.g., bile acid absorption) are confined to specific segments of the small bowel, a sizable fraction of the length of the
small bowel can be removed without excessive morbidity. In fact, substantial compensatory adaptation of the remaining bowel
can occur after massive resection.
Neural stem cells are multipotent stem cells that have an unlimited capacity to proliferate and self-renew but whose progeny
are restricted to the neural lineages. Neural stem cells can generate large numbers of mature neuronal and glial progeny,
often through transient amplification of intermediate progenitor pools, similar to the pattern observed in other organ systems
(1). Although self-renewal can occur through symmetric cell divisions that generate two identical daughter cells, asymmetric
cell divisions that generate a renewable stem cell and a more lineage-restricted daughter cell are a hallmark of stem cells.
Cells that do not self-renew indefinitely but that nevertheless proliferate and have the capacity to generate multiple phenotypes
are often referred to as multipotential progenitor cells, but they will be included in a broad definition of stem cells for
the purposes of this review. Other stem cell-derived precursor populations that are able to proliferate but that have more
restricted lineage potential (e.g., glial restricted or neuronal restricted cells) are discussed elsewhere in this volume.
In the nervous system, neural stem cells follow a sequential process of development. More differentiated cells have a more
limited repertoire of fate choices while fully differentiated cells do not have any alternative fates and may not be able
to reenter the cell cycle at all (reviewed in refs. 1 and 2). This progressive restriction of developmental potential is a normal aspect of development, and phenotypic plasticity appears
uncommon. To a large part, analysis with gene specific promoters, culture of isolated populations of cells, clonal analysis,
and challenge perturbation experiments (3) have confirmed this lack of plasticity and suggested that cells acquire an identity prior to terminal mitosis and this positional
and phenotypic identity is difficult to alter (4,5). Overall the idea that there is a cell intrinsic change that restricts the potential of initially pluripotent cells is appealing,
as it helps explain how the same regulatory molecules can be reiteratively used at multiple stages and in different tissues
to direct differentiation and different fates in multiple distinct lineages (2,6).
The vertebrate retina is a well-characterized central nervous system (CNS) structure, consisting of seven major cell types,
which in adult are arranged in a stereotypical laminar organization. These cell types are born in an evolutionarily conserved
temporal sequence: the majority of retinal ganglion cells (RGCs), horizontal cells, amacrine cells, and cone photoreceptors
are born during early histogenesis, whereas the majority of rod photoreceptors, bipolar cells, and the Müller glia are generated
during late histogenesis (1). Thus, as elsewhere in the CNS (2), neurogenesis in the retina precedes gliogenesis. Underlying cellular diversity in the retina is population of neural progenitors
that generate stage-specific neurons and glia (3). Evidence from a variety of experimental approaches including cell ablation studies and in vivo lineage analyses demonstrated
that neural progenitors in the developing retina were multipotential, possessing capacity to generate all seven retinal cell
types, including the Müller glia (4–8). Although retinal progenitors have not been demonstrated to possess the potential of self-renewal (9,10), a hallmark of stem cells, they are included within the broad description of stem cells, with the assumption that they possess
the potential of self-renewal. Potentially this is not demonstrable in vitro because of a lack of a conducive environment
(3). In mammals and other warm-blooded vertebrates, neural stem cells are found only in the embryonic retina (11–13). Recently a quiescent population of neural stem cells with retinal potential has been identified in the ciliary epithelium
of warm-blooded vertebrates (13–15). These cells are regarded as analogous to those found in the ciliary marginal zone (CMZ) of adult fish and frog retina (11,16,17). In adult fish, neural stem cells are not confined to CMZ but are also located in the inner retina and are regardedto generate
rod photoreceptors during regeneration and in response to injury (16).
The convergence of genomic technologies, high-throughput screening techniques, the availability of pluripotent embryonic stem
(ES) cell lines provides an unprecedented opportunity to identify the molecular mechanisms guiding mammalian development,
the pathogenesis of disease, and spontaneous regeneration and repair. The isolation and characterization of human ES cells
for use in drug discovery programs and as therapeutic agents in degenerative diseases has revitalized interest in the development
of methods for stable, perhaps indefinite, culture of ES cells, and methods for predictably driving ES cells to differentiate
into specific precursor populations and definitive cell types (Table 1).
Nervous system development is a complex process that begins with a small number of cells and ends with a highly organized
and specialized organ. Neural stem cells play a critical role in this process. These cells have the capacity to self-renew,
proliferate, and give rise to lineage-restricted neuronal and/or glial progenitor cells and postmitotic specialized daughter
cells. The number of neural stem cells contributing to neural development depends on the balance between proliferation, self-renewal,
differentiation, and cell death. Studies of apoptosis-associated molecules have indicated significant cell death in neural
precursor cells, defined as neural stem cells and lineage restricted progenitors, and immature neurons prior to the generation
of synaptic contacts. These studies complement the extensive body of work dedicated to cell death regulation in mature neurons,
where competition for limited amounts of target-derived neurotrophic factors plays a direct role in activating cell death
pathways during neuronal histogenesis and cell injury. The striking neurodevelopmental abnormalities observed in mice with
targeted disruptions in genes regulating cell death emphasizes the importance of programmed cell death during development.
Studies of these animals further reveal that cell death regulation is remarkably specific to cell type and stage of neural
differentiation.
Approximately two decades ago, it became evident that the developing and adult mammalian central nervous system (CNS) contained
a population of neural stem cells (NSCs). These immature, undifferentiated, multipotent cells could be isolated, expanded,
and used as cellular vectors for the treatment of neurodegenerative and demyelinating diseases. Their potential as therapeutic
agents in a wide range of CNS and peripheral nervous system (PNS) disorders is beginning to be understood. NSCs may give rise
to more committed progenitors, such as oligodendrocyte progenitor cells (OPCs), that may also be used as reparative cells.
As the “repair” mechanisms by which NSCs act begin to be better elucidated, new therapies may emerge.
Over the past two decades, studies of cell genesis in the adult vertebrate brain have revealed the persistence of neural progenitor
cells in both the neuroepithelial lining of the cerebral ventricles and the developmentally contiguous hippocampal dentate
gyrus. Competent neural progenitor cells have been identified in adult fish, reptiles, birds, rodents, monkeys, and humans
(1,2). Across phylogeny, both multipotential and phenotypically restricted progenitors populate the ventricular lining (3–7), within which they appear to be largely subependymal in origin (8,9). These subependymal neural progenitor cells extend throughout the adult ventricular system (10–12), persist throughout adult life (13,14), and may include or derive from multipotential founders (15–17). Although ependymal cells have also been reported to include multipotential progenitors (18), this observation remains controversial and as yet unverified. Rather, most studies have pointed to the existence in adults
of a subependymal progenitor cell population, which remains neurogenic in selected regions, such as the avian neostriatum
and rodent olfactory bulb, but that more typically is quiescent unless activated (17,19), then yielding either glia or short-lived neuronal progeny (18,20).
The broad clinical heterogeneity of Menetrier's disease (MD) has been recently described by Rich et al .1 There are few reports on MD patients with a history of ulcerative colitis (UC). Overexpression of the transforming growth factor α (TGFα) leads to gastric epithelium abnormalities similar to those of MD.2 A significant increase in TGFα levels has been observed in inactive UC compared with healthy controls. TGFα could be the link between both inactive UC and the development of MD.
TGFα stimulates gastric cell proliferation as well as mucin biosynthesis. Normal gastric mucosa expresses MUC1 and MUC5Ac in foveolar epithelium and MUC6 in the glands, while MUC2 and MUC3 are predominantly expressed in goblet cells and enterocytes, respectively, of the small intestine.
We investigated mucin expression in a …
The aim of this study was to examine whether liquid glutamine given to rabbits after resection is as effective as intravenous (i.v.) glutamine and to study the positive effects of glutamine on mucosal atrophy that occurs after bowel resection.
Thirty rabbits with an average weight of 2500 g were used. On the third day, 30 rabbits were divided into three groups as follows: Group I (controls): bowel resection + oral total parenteral nutrition, Group II (oral liquid L-glutamine): Bowel resection + oral total parenteral nutrition + oral liquid L-glutamine, and Group III (i.v. L-glutamine): bowel resection + oral total parenteral nutrition + i.v. L-glutamine. On the postoperative 7th day, all subjects were sacrificed to examine intestinal adaptation indicators.
There was an increase in average villus height and crypt depth in Group III compared to the other groups (p=0.0001). In Group II, the villus height and crypt depth increased more than in Group I, but the difference was less significant (p=0.038). There was no significant difference between groups in terms of average goblet cell proliferation.
In our experimental study, it was observed that the orally given L-glutamine liquid in the rabbit intestinal adaptation model prevented mucosal atrophy after 50% bowel resection and even increased mucosa mass. However, i.v. glutamine led to similar and even better results. Neither route of glutamine administration was determined to have an effect on goblet cell proliferation.
The aim of the study was to investigate the effect of angiogenesis inhibition by bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF) antibody, on the healing process of colonic anastomoses in rats, assessing some specific involved factors. This new agent is used mainly in metastatic colorectal cancer. The angiogenesis plays an important role in both wound healing and metastatic invasion and spread of malignant cells. There has not been any evidence assessing the optimal time for its safe use in operated patients.
Forty Wistar rats were randomly allocated into four equal groups. A colonic anastomosis was performed in all rats. Half of them received intraoperatively a single dose of bevacizumab 5 mg/body weight and the rest received placebo. The animals were sacrificed on the 7th (Avastin 7th, placebo 7th) and 14th (Avastin 14th, placebo 14th) postoperative day. The anastomosis was resected and sent for histological study and for tissue biochemical assays (VEGF, endothelin-1 (ET-1), C-reactive protein (CRP), pro-oxidant-antioxidant balance (PAB), carbonylated proteins, hydroxyproline) using specific enzyme-linked immunosorbent assay kits. For statistical analysis, the Mann-Whitney U test was used (of statistical significance when P < 0.05).
No complication or anastomotic dehiscence was observed. Histology did not reveal statistically significant differences between groups concerning degree of inflammation, fibroblasts, collagen, and fibrosis. Likewise, hydroxyproline levels did not differ. However, some statistically significant differences were found in VEGF, CRP and carbonyl proteins (Avastin 7th vs placebo 7th, placebo 14th vs placebo 7th), ET-1, and PAB (Avastin 14th vs Avastin 7th), which did not finally affect the collagen synthesis marker hydroxyproline, nor did the anastomotic strength.
Bevacizumab, when administered intraoperatively, has no significant effect on colon anastomotic healing in rats despite a transient mild ischemia.
The jury is still out on the role of luminal EGF in the normal gastrointestinal tract. Recent evidence, however, suggests that its major function is to act as a 'luminal surveillance' peptide, which is available to stimulate repair and that it is not of major importance in maintaining normal gut growth. Recombinant EGF administered via the gut lumen could still prove a valuable tool for the treatment of gastrointestinal ulceration. Perhaps the old term for EGF, 'epidermal healing factor' or EHF, was more appropriate after all!
pS2 is a member of the trefoil peptide family, all of which are overexpressed at sites of gastrointestinal injury. We hypothesized that they are important in stimulating mucosal repair. To test this idea, we have produced a transgenic mice strain that expresses human pS2 (hpS2) specifically within the jejunum and examined the effect of this overexpression on proliferation and susceptibility to indomethacin-induced damage. A transgenic mouse was produced by microinjecting fertilized oocytes with a 1.7-kb construct consisting of rat intestinal fatty acid binding protein promoter (positions -1178 to +28) linked to full-length (490 bp) hpS2 cDNA. Screening for positive animals was by Southern blot analysis. Distribution of hpS2 expression was determined by using Northern and Western blot analyses and immunohistochemical staining. Proliferation of the intestinal mucosa was determined by assessing the crypt cell production rate. Differences in susceptibility to intestinal damage were analyzed in animals that had received indomethacin (85 mg/kg s.c.) 0-30 h previously. Expression of hpS2 was limited to the enterocytes of the villi within the jejunum. In the nondamaged intestine, villus height and crypt cell production rate were similar in transgenic and negative (control) litter mates. However, there was a marked difference in the amount of damage caused by indomethacin in control and transgenic animals in the jejunum (30% reduction in villus height in controls vs. 12% reduction in transgenic animals, P < 0.01) but the damage sustained in the non-hpS2-expressing ileal region was similar in control and transgenic animals. These studies support the hypothesis that trefoil peptides are important in stimulating gastrointestinal repair.
Reduction of postnatal morbidity and mortality of mammalian neonates poses a significant challenge to agricultural and medical sciences. Because nutritional insufficiency and diarrhea represent major stressors, an understanding of factors mediating postnatal growth and development of the gastrointestinal tract is essential. This review explores the role that milkborne growth factors may play in stimulating functional development of the neonatal intestine, with emphasis on the porcine, bovine, and ovine species. Studies reporting milk concentrations and intestinal effects are reviewed, with emphasis on epidermal growth factor, insulin, and the insulin-like growth factors. Collectively, these studies suggest that milkborne growth factors may provide important regulatory signals to the neonatal intestine under both normal and pathophysiological states.
Short bowel patients with a jejunostomy have large volume stomal outputs, which may in part be due to rapid gastric emptying of liquid. Short bowel patients with a preserved colon do not have such a high stool output and gastric emptying of liquid is normal.
To determine if differences in the gastric emptying rate between short bowel patients with and without a colon can be related to gastrointestinal hormone changes after a meal.
Seven short bowel patients with no remaining colon (jejunal length 30-160 cm) and six with jejunum in continuity with a colon (jejunal length 25-75 cm), and 12 normal subjects.
The subjects all consumed a 640 kcal meal; blood samples were taken for 180 minutes for measurement of gastrointestinal hormones.
Patients with a colon had high fasting peptide YY values (median 71 pmol/l with a colon; 11 pmol/l normal subjects, p < 0.005) with a normal postprandial rise, but those without a colon had a low fasting (median 7 pmol/l, p = 0.076) and a reduced postprandial peptide YY response (p < 0.050). Motilin values were high in some patients without a colon. In both patient groups fasting and postprandial gastrin and cholecystokinin values were high while neurotensin values were low. There were no differences between patient groups and normal subjects in enteroglucagon, pancreatic polypeptide, or somatostatin values.
Low peptide YY values in short bowel patients without a colon may cause rapid gastric emptying of liquid. High values of peptide YY in short bowel patients with a retained colon may slow gastric emptying of liquid and contribute to the "colonic brake'.
The two papers in this issue of HEPATOLOGY (1, 2) dealing with hepatocyte growth factor (HGF) underscore the increasing importance of this novel growth factor in relation to hepatic growth biology. The emerging literature has already established HGF as a growth factor with potential importance not only for the liver but for other tissues such as the kidney, placenta, brain, lung, pancreas and hemopoietic tissues. This editorial will attempt to correlate the findings of the two HGF papers presented in this issue of HEPATOLOGY, summarize the existing literature on HGF and provide a synthetic overview for its role in the liver and other tissues. Several specific features already described set HGF aside in comparison with other growth factors in terms of structure and function.
Epidermal growth factor, and its human homologue urogastrone (EGF/URO), are secreted by the gut-associated salivary and Brunner's glands. Recombinant EGF/URO is a powerful stimulator of cell proliferation and differentiation in the rodent and neonatal human intestine. But EGF/URO is not absorbed from the adult gut and has no action when given through the gut lumen; thus the role of secreted EGF/URO is unknown. We now report that ulceration of the epithelium anywhere in the human gastrointestinal tract induces the development of a novel cell lineage from gastrointestinal stem cells. This lineage initially appears as a bud from the base of intestinal crypts, adjacent to the ulcer, and grows locally as a tubule, ramifying to form a new small gland, and ultimately emerges onto the mucosal surface. The lineage produces neutral mucin, shows a unique lectin-binding profile and immunophenotype, is nonproliferative, and contains and secretes abundant immunoreactive EGF/URO. We propose that all gastrointestinal stem cells can produce this cell lineage after mucosal ulceration, secreting EGF/URO to stimulate cell proliferation, regeneration and ulcer healing. This cell lineage is very commonly associated with gastrointestinal mucosal ulceration, and we conclude that a principal in vivo role for EGF/URO is to stimulate ulcer healing throughout the gut through induction of this cell lineage in the adjacent mucosa.
Metallothionein-directed expression of TGF alpha in transgenic mice induced a spectrum of changes in the growth and differentiation of certain adult tissues. First, TGF alpha promoted a uniform epithelial hyperplasia of several organs without otherwise causing major alterations in tissue architecture. Second, in pancreas it promoted proliferation of both acinar cells and fibroblasts and focally altered acinar cell differentiation. The magnitude of this response was proportional to the level of local, tissue-specific TGF alpha expression and was reproduced when expression of TGF alpha was placed under the control of the elastase promoter, implying an autocrine or paracrine mechanism. Third, TGF alpha was oncogenic in vivo. It caused dramatic hyperplasia and dysplasia of the coagulation gland epithelium, which displayed evidence of carcinoma in situ, and in postlactational mammary gland it induced secretory mammary adenocarcinomas. Thus, TGF alpha displays characteristics of both a potent epithelial cell mitogen and an oncogenic protein in vivo.
Mammalian tissue development and regeneration take place within a milieu of regulatory growth factors. These affect many parameters of cell development, such that survival, proliferation, differentiation, and certain aspects of cell behavior are all influenced by a balance between stimulatory and inhibitory signals. The precise effect of any given factor is determined by the responding cell type, the concentration of factor, and the presence of other stimuli, such that some growth factors may fulfill a variety of functions under different circumstances. Classically, growth factor stimuli are transmitted into the cell via activation of specific, transmembrane receptors that modify key regulatory proteins in the cytoplasm. These in turn affect the decisions controlling proliferation and differentiation, including changes in gene expression and reactivity to other factors. There are indications that some factors may function both extra- and intracellularly and that this characteristic is correlated with potential oncogenicity. The relatively low transforming ability of extracellular factors alone is probably attributable to the limitations imposed by down-regulation of their cell surface receptors. Aberrant production of secreted growth factors can, however, play decisive roles in tumorigenesis by increasing the proliferation rate and degree of cellular autonomy and extending the area available for tumor expansion.
The release of a variety of biologically active peptides into the gastrointestinal lumen via gastric, duodenal and intestinal secretions, as well as in the saliva, pancreatic juice and bile, has been explored. The key features of luminal secretion of peptides such as secretion at high concentrations, neurohormonal regulation, luminal orientation of stimulated secretion, stability of peptides in the gastrointestinal lumen, altered secretion under pathophysiological conditions, and biological activity of luminally administered peptides are discussed. This review develops a detailed picture of the current understanding of luminal secretion of peptides and their possible biological functions under normal and pathophysiological conditions.
To define the role of TGF alpha in normal tissue function and in pathogenesis, transgenic mice have been generated bearing a fusion gene consisting of the mouse metallothionein 1 promoter and a human TGF alpha cDNA. In these mice, human TGF alpha RNA and protein are abundant in many tissues and TGF alpha is detectable in blood and urine. The effects of TGF alpha overproduction in transgenic mice are pleiotropic and tissue specific. The liver frequently contains multifocal, well-differentiated hepatocellular carcinomas that express enhanced levels of human TGF alpha RNA. The mammary gland exhibits impeded morphogenetic penetration of epithelial duct cells into the stromal fat pad. The pancreas shows progressive interstitial fibrosis and a florid acinoductular metaplasia, during which acinar cells appear to degranulate, dedifferentiate, and assume characteristics of intercalated or centroacinar duct cells. TGF alpha therefore plays an important role in cellular proliferation, organogenesis, and neoplastic transformation.
Epidermal growth factor (EGF) is a 6,000 Da polypeptide hormone produced by glands of the gastrointestinal tract, namely the salivary and Brunner's glands. It is found in a wide variety of external secretions as well as in blood and amniotic fluid. In fetal and neonatal life, EGF appears to play an important role in the development of the oral cavity, lungs, gastrointestinal tract and eyelids. Its presence in cells of the central nervous system suggests that it also plays a role in modulating the development of this system. In adult animals, the function of EGF is much less well understood. In rodents, it apparently modulates acid secretion from parietal cells in the stomach, and it undoubtedly plays an important role in wound healing, either through its localization within skin or by the licking of wounds with EGF-containing saliva. Considerable evidence now suggests that it may be one of the key factors in initiating liver regeneration after partial hepatectomy or chemical injury. The liver appears to be the principal organ which regulates the circulating level of EGF. In fact, EGF is cleared so efficiently by the liver that only the peripheral cells of the lobule (zone 1) sequester EGF, and little remains in the circulation for cells in the more distal zones (zones 2 and 3). In the liver, EGF normally binds to a plasma membrane receptor and is internalized within the liver cell, where the vast majority of EGF and its receptor are destroyed in lysosomes. A small but consistent quantity of EGF enters the bile intact. In the regenerating liver, however, the lysosomal pathway appears to be shut down, and the EGF is diverted to hepatocyte nuclei prior to the initiation of DNA synthesis. Nuclear EGF is found free as well as bound to a high-molecular-weight protein which has many characteristics identical to the plasma membrane EGF receptor. The plasma membrane receptor is a large transmembrane glycoprotein of 170,000 Da containing four domains: an extracellular EGF-binding portion, a hydrophobic membrane-spanning segment, a proximal cytoplasmic domain which binds ATP and protein substrates containing tyrosine for phosphorylation and a terminal cytoplasmic portion with 3 tyrosines which undergo autophosphorylation after EGF binding.(ABSTRACT TRUNCATED AT 400 WORDS)
Cet article de synthese etudie les interactions cellule-cellule durant la morphogenese. Il propose une identification et une classification des facteurs de croissance, leur action d'induction sur le mesoderme
Expression of transforming growth factor alpha (TGF alpha), and transforming growth factor beta (TGF beta) was assessed in isolated primary rat intestinal epithelial cells as well as a rat intestinal crypt cell-derived cell line (IEC-6). A gradient in TGF beta was present, with high concentrations of a 2.5-kb transcript found in undifferentiated crypt cells and progressively lower amounts of the TGF beta transcript in increasingly differentiated villus cell populations. In contrast, the concentration of 4.5-kb TGF alpha transcript was higher in differentiated villus cells than in mitotically active, undifferentiated populations of crypt epithelial cells. The concentrations of transforming growth factors alpha and beta as determined by radioreceptor binding inhibition assay and direct assessment of transforming growth factor biological activity correlated with Northern blot analysis. Although gradients in the expression of the TGFs were present, equivalent binding was observed in the different intestinal cell populations when assessed with 125I-TGF beta and 125I-EGF (TGF alpha). No EGF transcripts were detected in any intestinal cell population, suggesting that the true ligand of the EGF receptor was TGF alpha. IEC-6 cells expressed both TGF alpha and TGF beta transcripts. In addition to the transcripts identified in the primary intestinal cells, this cell line contained an additional larger TGF alpha transcript (4.8 kb) and smaller TGF beta transcripts (2.2 and 1.8 kb). TGF alpha and TGF beta may play a significant role in the regulation of the balance between proliferative and differentiated cell compartments in the intestinal epithelium through both autocrine and paracrine mechanisms.
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Mice and cells lacking the epidermal growth factor receptor (EGFR) were generated to examine its physiological role in vivo. Mutant fetuses are retarded in growth and die at mid-gestation in a 129/Sv genetic background, whereas in a 129/Sv x C57BL/6 cross some survive until birth and even to postnatal day 20 in a 129/Sv x C57BL/6 x MF1 background. Death in utero probably results from a defect in the spongiotrophoblast layer of the placenta. Newborn mutant mice have open eyes, rudimentary whiskers, immature lungs, and defects in the epidermis, correlating with the expression pattern of the EGFR as monitored by beta-galactosidase activity. These defects are probably cell-autonomous because chimeric mice generated with EGFR-/- embryonic stem cells contribute small amounts of mutant cells to some organs. These results indicate that the EGFR regulates epithelial proliferation and differentiation and that the genetic background influences the resulting phenotype.
Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent
on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the
inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background,
the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The
multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular
activities.
Since the discovery that epidermal growth factor (EGF) can accelerate opening of the eyelids, the EGF receptor (EGF-R) has been extensively studied and is now considered to be a prototype tyrosine kinase receptor. Binding of EGF or of transforming growth factor-alpha (TGF-alpha) or other related factors activates the receptor and induces cell proliferation and differentiation. Although it is not found on haematopoietic cells, the EGF-R is widely expressed in mammals and has been implicated in various stages of embryonic development. Here we investigate the developmental and physiological roles of this receptor and its ligands by inactivating the gene encoding EGF-R. We find that EGF-R-/- mice survive for up to 8 days after birth and suffer from impaired epithelial development in several organs, including skin, lung and gastrointestinal tract.
G rowth factor biology has been one of the most exciting areas of gastroenterological research in recent years. Although many fundamental questions about growth factors and their relevance to the gastrointestinal tract remain unanswered and unexplored, the available data point to major clinical significance in a large number of gastrointestinal disorders. This report reviews the biology and significance of the epidermal growth factor (EGF) family, with particular emphasis on understanding the integrated function of the family and the relationships between family members in the context of gastroin-testinal physiology and pathophysiology.
Human milk contains many hormone and hormone-like peptides. The gastrointestinal tract of newborn infants exhibits lower proteolytic activity than in adults and higher "permeability" for macromolecules. Studies in experimental animals demonstrate that several peptides (epidermal growth factors, insulin-like growth factor I and bombesin) after orogastric administration exhibit effects on the small intestine and other organs (liver or pancreas). Few studies performed in human neonates suggest a "survival" of epidermal growth factor in their gastric content. Further studies are needed to evaluate the role of milk-borne hormonally active peptides. This need is stressed by the fact that several of those known to be present in human milk were found to be low or not detectable in infant formulae (epidermal growth factor, insulin-like growth factor I, insulin, parathyroid hormone-related peptide.
Hepatocyte growth factor/scatter factor (HGF/SF) functions as a mitogen, motogen and morphogen for a variety of cultured cells. The genes for HGF/SF and its receptor (the c-met proto-oncogene product) are expressed in many tissues during the embryonic periods and in the adult. HGF/SF is thought to mediate a signal exchange between the mesenchyme and epithelia during mouse development. To examine the physiological role of HGF/SF, we generated mutant mice with a targeted disruption of the HGF/SF gene. Here we report that homozygous mutant embryos have severely impaired placentas with markedly reduced numbers of labyrinthine trophoblast cells, and die before birth. The growth of trophoblast cells was stimulated by HGF/SF in vitro, and the HGF/SF activity was released by allantois in primary culture of normal but not mutant embryos. These findings suggest that HGF/SF is an essential mediator of allantoic mesenchyme-trophoblastic epithelia interaction required for placental organogenesis.
Epidermal growth factor (EGF) has documented trophic effects on several tissues, including small bowel (SB) mucosa. The purpose of this study was to determine the effect of EGF on intestinal adaptation after massive resection. Young Sprague-Dawley rats (weight, 154 +/- 8.6 g) underwent a 75% proximal SB resection, with primary reanastomosis, and were continuously infused with equivalent volumes of either saline or human recombinant EGF (6.25 micrograms/kg/h) via a subcutaneous osmotic pump. In other animals, the SB was transected and reanastomosed without resection and either saline or EGF was infused. The animals were allowed standard rat chow and water ad libitum and were killed after 28 days. SB was harvested and subjected to histological examination. Intestinal mucosa was analyzed for total DNA and protein contents. After massive SB resection, subcutaneous administration of EGF resulted in significantly increased animal weight (294.5 +/- 16 v 242.8 +/- 14g; P < .05), SB weight (52.8 +/- 7.0 v 37.2 +/- 6.0 cm; P < .05), SB length (14.0 +/- 1.3 v 7.4 +/- 1.6 g; P < .05), and mucosal thickness (1.04 +/- 0.2 v 0.68 +/- 0.2 mm; P < .05). DNA and protein analyses suggest that EGF may augment the mucosal hyperplasia response to massive SB resection. Administration of EGF after massive SB loss may be of nutritional benefit to the host through its enhancement of the normal postresection intestinal response.
After the loss of small bowel through disease or surgery the residual bowel adapts by increasing its functional capacity. This process of adaptation involves dilatation, hypertrophy and mucosal hyperplasia, particularly distal to the area of bowel loss or disease. The response of the residual bowel is mediated by a complex interplay of factors including luminal nutrition, pancreaticobiliary secretions, luminal or local growth factors and also humoral or endocrine factors. The experimental model commonly used to characterize the adaptive response, massive small bowel resection (MSBR), involves 80% resection of the small bowel in the rat. Of the various putative humoral factors, most work has focused on the products of the ileal L cells: enteroglucagon and peptide YY. Plasma levels of both hormones are increased after MSBR and indeed their mRNA levels are also increased as a result of an increase in the amount of message per L cell. Whilst PYY probably serves as an 'ileal brake' to slow the movement of the luminal contents and hence increase their mucosal contact time, the role of the enteroglucagon is unresolved. The molecular cloning of the proglucagon gene has revealed, firstly, that there are a number of biologically active peptides which derive from the propeptide and, secondly, that tissue-specific differential processing occurs. Most studies do not clearly define which of these products of proglucagon is being measured and is termed as glucagon-like or enteroglucagon immunoreactivity. The insulin-like growth factors (IGF) have a potent mitogenic action on the bowel. Their role after MSBR is likely to be largely paracrine. Though IGF-I mRNA levels do not increase after MSBR, the precipitous and early fall in ileal IGF-binding protein-3 (IGFBP-3) mRNA levels suggests a fall in IGFBP-3 levels may increase local IGF-I bioactivity. Polyamine synthesis is a critical component of the adaptive response, although the stimulus to their dramatic increase in synthesis after MSBR remains to be elucidated. Other humoral factors such as cholecystokinin, neurotensin and bombesin probably have minor indirect roles in the adaptive response. Components of the epidermal growth factor/transforming growth factor alpha response pathway family of growth factors may be involved as paracrine regulators. There is thus strong evidence that humoral factors play an important role in intestinal adaptation; characterization of the nature of the humoral factors and their relationship with other influences such as luminal nutrition and pancreatic biliary secretions may facilitate the development of new therapeutic strategies for the short bowel syndromes.
Excerpt
Novel growth factors have often been given names which relate to their original site of discovery or their first known target cell or biological action. Subsequent studies have frequently shown such nomenclature to be misleading as more is learned about the factor concerned. Epidermal growth factor (EGF) and fibroblast growth factor (FGF) which in fact act as mitogens for a great variety of cell types and transforming growth factor-β (TGFβ) which is better recognized as a growth inhibitor are all typical examples. Moreover, in addition to their growth regulatory roles, peptide growth factors also serve to modulate cell differentiation and function. The recently characterized hepatocyte growth factor (HGF) joins this illustrious family of cytokines which have proven rather more versatile than their original descriptive title suggests.
Characterization Hepatocyte growth factor was originally identified and characterized by three independent experimental approaches.
(a) Michalopoulos described a mitogenic activity in the serum of
Intestinal proglucagon is thought to be synthesized primarily by the distal gut, although the role of proglucagon-derived glucagon-like peptide I (GLP-I) as a major physiological incretin would seem to be associated with production in proximal small bowel. To better characterize the sites of production of proglucagon and GLP-I in the small intestine and evaluate nutrient regulation of small bowel proglucagon and derived peptides, we evaluated the effects of fasting for 72 h and subsequent refeeding or jejunal infusion of long-chain triglyceride (LCT) for 24 h on local expression of proglucagon in proximal and distal small bowel. Proglucagon mRNA abundance and cellular localization were determined and correlated with wet weight of bowel. In jejunum, proglucagon mRNA abundance decreased by 40% with fasting (P < 0.005) and increased with refeeding to levels similar to those of ad libitum-fed animals. In ileum, fasting resulted in a 20% decrease in proglucagon mRNA (P < 0.005); in contrast to jejunum, refeeding did not result in a significant rise in ileal proglucagon mRNA abundance from fasting values. In jejunum, signal intensity of proglucagon mRNA per cell, determined by in situ hybridization, decreased with fasting (P < 0.05) and increased with refeeding (P < 0.005) in proportion to changes in mRNA abundance. Plasma enteroglucagon and GLP-I levels correlated with jejunal proglucagon mRNA. Intrajejunal infusion of LCT increased expression of proglucagon to a greater extent in jejunum than in ileum. In conclusion, enteral nutrient intake stimulates small bowel proglucagon expression; this effect is greater in jejunum than ileum, consistent with greater intraluminal nutrient exposure and the role of jejunum as a source of the major incretin GLP-I.
The unique three-loop structure of the trefoil motif, formed by intrachain disulfide bonds in a 1-5, 2-4, 3-6 configuration between six conserved cysteine residues, is the defining feature of a recently recognized family of peptides. Expression of trefoil peptides is closely related to that of mucin glycoproteins in diverse biological sources. Three distinct members of the family (pS2, intestinal trefoil factor, and spasmolytic polypeptide) are produced in the mammalian gastrointestinal tract by mucus-secreting cells and targeted primarily for luminal secretion. The compact structure of the trefoil motif may be responsible for marked resistance of trefoil peptides to proteolytic digestion, enabling them to function in the harsh environment of the gastrointestinal lumen. Trefoil peptides are ectopically expressed adjacent to areas of inflammation within the gastrointestinal tract and may play an important role in both maintaining the barrier function of mucosal surfaces and facilitating healing after injury.
The mechanisms that maintain the epithelial integrity of the gastrointestinal tract remain largely undefined. The gene encoding intestinal trefoil factor (ITF), a protein secreted throughout the small intestine and colon, was rendered nonfunctional in mice by targeted disruption. Mice lacking ITF had impaired mucosal healing and died from extensive colitis after oral administration of dextran sulfate sodium, an agent that causes mild epithelial injury in wild-type mice. ITF-deficient mice manifested poor epithelial regeneration after injury. These findings reveal a central role for ITF in the maintenance and repair of the intestinal mucosa.
Octreotide (SMS) is a somatostatin analogue utilized in patients with short bowel syndrome (SBS) to decrease output. It may inhibit small bowel adaptation by blocking the secretion of trophic hormones such as epidermal growth factor (EGF). This study delineates the effects of SMS and EGF on nutrient transport in SBS.
One week after 70% jejunoileal resection, 20 New Zealand White rabbits (2 kg) received subcutaneous infusions of saline or EGF (1.5 micrograms/kg/hr) and injections of saline or SMS s.q.b.i.d. The study groups were EGF/saline, saline/saline, saline/SMS, and EGF/SMS. After 7 days of infusion, intestinal brush border membrane vesicles were prepared and nutrient transport measured.
SMS reduced active nutrient transport. Kinetics confirmed this was secondary to a reduction in functional carriers in the brush border membrane, without a change in carrier affinity. The coinfusion of EGF ameliorated this effect. On an individual basis, EGF alone did not significantly increase nutrient transport, but when taken as a group, nutrients transport was upregulated 26%.
SMS is detrimental to small bowel adaptation. EGF reverses this effect and may benefit patients with SBS who require SMS to control high intestinal output.
This article has no abstract; the first 100 words appear below.
Microorganisms and other agents continually threaten the intestinal mucosa, calling for the gut to prevent damage, restore epithelium in regions in which cells are lost, and suppress inflammation. How does the intestine tackle these problems? Although cytokines deep in the lamina propria moderate immune responses and inflammatory injury, other repair factors operate on the apical side of the epithelial cells — the front line where mucosa and the outside world really interact. Since restoration of epithelial continuity occurs early in mucosal healing, agents that help reseal mucosal wounds must undoubtedly influence cell proliferation and perhaps accelerate the migration of proliferating . . .
Andrew G. Plaut, M.D.
Tufts–New England Medical Center, Boston, MA 02111
Supported by a grant from the National Institutes of Health (NIDR 06977), a grant from the Core Center for Digestive Diseases of the Center for Gastroenterology Research on Absorptive and Secretory Processes (DK34928), and by the Nutricia Corporation, the Netherlands.
Hepatocyte growth factor (HGF) and its receptor c-Met are presumed to play a morphogenic role during embryogenesis. The possible implication of HGF and c-Met during the digestive system development was approached by investigating their ontogeny, distribution, and functionality in human fetal tissues.
Thirty fetuses, 7-24 weeks old, were obtained. HGF and c-Met messenger RNAs and proteins were detected in liver, pancreas, esophagus, stomach, and small and large intestine. Tyrosine phosphorylation assays were realized on homogenates and membrane preparations from fetal tissues.
The temporal appearance of HGF and c-Met was established between 7 and 8 weeks of gestation in digestive tissues. Immunoblot analysis showed the presence of the c-Met beta-subunit 145-kilodalton band and of the HGF alpha-subunit 70-kilodalton band. c-Met was localized in epithelia, especially in fundic parietal cells, pancreatic and gut endocrine cells, and in muscular layers. HGF immunoreactivity was first detected in epithelia and then in mesenchyme and muscular layers. In young fetal stages, the c-Met immunoprecipitated 145-kilodalton band showed tyrosine phosphorylation after HGF stimulation.
This study provides evidence for HGF and c-Met expression early in all human fetal digestive tissues and implicates HGF-c-Met in the digestive system morphogenesis.
Overexpression of TGF␣ in transgenic mice: induction of epithelial GROWTH FACTORS AND THE GASTROINTESTINAL TRACT hyperplasia, pancreatic metaplasia, and carcinoma of the breast
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Sandgren EP, Luetteke NC, Plamiter RD, Brinster RL, Lee DC. Overexpression of TGF␣ in transgenic mice: induction of epithelial GROWTH FACTORS AND THE GASTROINTESTINAL TRACT hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990;61:1121
Nonmitogenic actions of growth factors
- Uribe
Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver
- Marti
TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas
- Jhappan
Targeted disruption of the mouse EGF receptor
- Threadgill
Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor
- Uehara