transforming-growth-factor-alpha and Colitis

Growth factors and their receptors play important roles in cell proliferation, migration, tissue injury repair and ulcer healing. In gastric mucosa, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) by activating their common receptor, control cell proliferation. TGF-alpha predominantly plays this role under normal conditions and after acute injury, while EGF exerts its actions mainly during healing of chronic ulcers. During regeneration of injured gastric mucosa, these growth factors serve predominantly to restore the epithelial component. Other growth factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serve to promote restoration of the connective tissue and microvessels (angiogenesis) in injured mucosa. During healing of chronic ulcers, a new epithelial lineage secreting EGF and other growth peptides develops and the majority of cells lining the ulcer margin overexpress the EGF receptor. Activation of the EGF receptor induces dramatic increases in MAP (Erk -1 and -2) kinase activity and phosphorylation levels. Inhibition of this signaling pathway dramatically delays ulcer healing. Granulation connective tissue, which grows under the stimulation of bFGF and VEGF is the major source for regeneration of connective tissue lamina propria and microvessels within the ulcer scar. Other growth factors such as insulin - like growth factor, keratinocyte growth factor, hepatocyte growth factor and trefoil peptides have been implicated in gastrointestinal (gastric ulcers, colitis) regeneration following injury. This paper is intended to provide an overview of the role of growth factors in gastrointestinal mucosal regeneration.

Topics: Animals; Cell Division; Colitis; Epidermal Growth Factor; Gastric Mucosa; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Intestinal Mucosa; Neovascularization, Physiologic; Regeneration; Signal Transduction; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model.. Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR.. Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa.. Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression.

Topics: Acetic Acid; Acetylcysteine; Amphiregulin; Animals; Apoptosis; Caspase 3; Claudin-1; Colitis; Colitis, Ulcerative; Colon; Dietary Supplements; Dinoprostone; Disease Models, Animal; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Free Radical Scavengers; Glycoproteins; Intercellular Signaling Peptides and Proteins; Interleukin-6; Intestinal Mucosa; Swine; Toll-Like Receptor 4; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha

Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis.. LacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM).. Recovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. β-Galactosidase-positive cells, which expressed α-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for α-SMA in MSCs where TEM demonstrated myogenic lineage differentiation.. We found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease.

Topics: Actins; Analysis of Variance; Animals; Apoptosis; beta-Galactosidase; Body Weight; Cell Cycle; Cell Differentiation; Cell Lineage; Colitis; Colon; Cytokines; Desmin; Dextran Sulfate; Disease Models, Animal; Intestinal Mucosa; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rats; Rats, Inbred Lew; RNA, Messenger; Signal Transduction; Transforming Growth Factor alpha; Vimentin

Epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) protect gastrointestinal mucosa against injury. Having shown earlier, that TGFalpha but not EGF is locally increasingly expressed after mucosal injury in the colon, we now wanted to explore the pattern of expression of EGF and TGFalpha in the remaining gastrointestinal tract and to infer from the pattern of expression, to possible signals for the induction of the growth factor expression and further mechanisms for mucosal protection.. The trinitrobenzene sulfonic acid/ethanol-induced model of colitis in rats was used. TGFalpha-mRNA and EGF-mRNA expression was evaluated in inflamed and noninflamed colon, in the ileum, jejunum, duodenum, stomach, and in the submandibulary glands.. A significant increase of TGFalpha-mRNA and EGF-mRNA expressions was detected in the duodenal mucosa and a significant increase in TGFalpha-mRNA expression was observed in the inflamed colonic mucosa after mucosal injury in the colon within the first hours of colitis.. The increased expression of EGF and TGFalpha in the duodenum may lead to neutralization of gastric acid and proteolytic enzymes in the upper gastrointestinal tract during the course of colitis. Possible signals for the increased expression of EGF and TGFalpha presumably are fasting, parasympathetic, or adrenergic parts of the enteric nervous system or yet unknown mechanisms.

Topics: Animals; Colitis; Colon; Duodenum; Epidermal Growth Factor; Ethanol; Gene Expression; Intestinal Mucosa; Male; Models, Animal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha; Trinitrobenzenesulfonic Acid

Transforming growth factor-alpha (TGF-alpha) is a key mediator of colonic mucosal protection and/or repair mechanisms in orally induced acute dextran sodium sulphate (DSS) colitis. However, it also has been suggested that TGF-alpha may contribute to malignant transformation in the colon. The aim of the studies was to determine whether TGF-alpha is needed for malignant transformation in orally induced chronic DSS colitis using TGF-alpha deficient mice (wa-1) and Balb/c mice, a strain competent in TGF-alpha.. Chronic colitis was induced by oral administration of DSS (5%) for 7 days followed by drinking water for 10 days in wa-1 and Balb/c mice (n = 20, per group). In the two subsequent cycles (7 days DSS, 10 days water) 3% DSS-water was utilized due to a high mortality in the wa-1 group. Mucosal injury severity was assessed histologically and graded (three grades). A crypt damage score (CDS) reflecting all three grades of mucosal pathology was calculated. Mucosal dysplasia and cancerous lesions were noted.. Seven per cent of the entire colonic mucosa was completely destroyed in wa-1 animals compared to 3% in Balb/c mice (P < 0.05). The CDS was 10.2 +/- 0.4 and 4.8 +/- 0.3 in wa-1 and Balb/c mice, respectively (P < 0.05). Fifteen incidences of mucosal dysplasia were found in the 10 surviving wa-1 animals and 31 incidences were found in 20 Balb/c animals. In both groups, one fully developed adenomatous cancerous lesion was present.. The markedly increased severity of mucosal injury in chronic induced DSS colitis in TGF-alpha deficient wa-1 mice compared to Balb/c mice further substantiates that endogenous TGF-alpha is a pivotal mediator of protection and/or healing mechanisms in the colon. The appearance of dysplastic and cancerous lesions in TGF-alpha deficient animals suggests that TGF-alpha per se is not essential for malignant mucosal cell transformation in colitis.

Topics: Animals; Cell Transformation, Neoplastic; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Probability; Radioimmunoassay; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric; Transforming Growth Factor alpha

It has been reported that epithelial growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) play an important role in colonic mucosal defense and repair. Waved-2 (wa-2) mice harboring a defect EGF-R and phenotypically similar to TGF-alpha knockout mice provide a novel approach to study the role of EGF-R ligands in the maintenance and repair of colonic mucosa.. Acute colonic mucosal injury was induced by oral administration of dextran sodium sulfate (DSS: 5 g%) given for 6 days ad libitum to wa-2 homozygotes and their genetic controls (n = 10, each group), as well as to wa-2 mice with and without exogenous EGF administration. Severity of colonic injury was assessed histologically of the entire colon and graded. A crypt damage score (CDS) reflecting all three grades of mucosal pathology was calculated. Decrease in total body weight, colon length and colonic blood content was determined for all groups.. Thirty-eight percent of the entire colonic mucosa was destroyed in wa-2 animals compared to 15% in control mice. The CDS was 16.0 +/- 1.4 and 9.6 +/- 0.8 in wa-2 and control mice, respectively. EGF application to wa-2 mice did not reduce the severity of mucosal injury (CDS: 18.9 +/- 1.7 and 19.4 +/- 2.1 in EGF and vehicle injected mice, respectively).. The increased susceptibility of wa-2 mice to DSS demonstrates the pivotal role of EGF-R ligands such as EGF and TGF-alpha in preserving the integrity of the colonic mucosa against mucosal injury. The missing beneficial effect of exogenous EGF administration in these mice further underlines the importance of an intact ligand/EGF-R pathway.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Epidermal Growth Factor; ErbB Receptors; Female; Genetic Predisposition to Disease; Homozygote; Intestinal Mucosa; Mice; Mice, Knockout; Mice, Mutant Strains; Transforming Growth Factor alpha

Transforming growth factor alpha (TGF-alpha) knockout mice have increased susceptibility to dextran sodium sulphate (DSS) induced colitis.. To substantiate the findings that TGF-alpha is a key mediator of colonic mucosal protection and/or repair mechanisms by evaluating the susceptibility of mice overexpressing TGF-alpha to DSS induced colitis.. TGF-alpha overexpression was induced in transgenic mice by ZnSO4 administration in drinking water (TG+). Three groups were used as controls: one transgenic group without ZnSO4 administration (TG-), and two non-transgenic littermate groups receiving ZnSO4 (Non-TG+) or only water (Non-TG-). Acute colitis was induced in all groups by administration of DSS (5%, w/v) in drinking water for six days and libitum.. About 35-39% of the entire colonic mucosa was destroyed in Non-TG-, Non-TG+, and TG- animals compared with 9% in TG+ mice. the crypt damage score was 18.7 (0.9), 18.2 (1.0), 18.9 (0.8), and 6.8 (1.5) (means (SEM)) in Non-TG-, Non-TG+, TG-, and TG+ mice respectively. Mucin and bromodeoxyuridine staining were markedly enhanced in colons of TG+ mice compared with controls, indicating increased mucosal protection and regeneration.. The significantly reduced susceptibility of mice overexpressing TGF-alpha to DSS further substantiates that endogenous TGF-alpha is a pivotal mediator of protection and/or healing mechanisms in the colon.

Topics: Acute Disease; Animals; Body Weight; Cell Division; Colitis; Colon; Dextran Sulfate; Disease Susceptibility; Intestinal Mucosa; Male; Mice; Mice, Transgenic; Radioimmunoassay; Statistics, Nonparametric; Transforming Growth Factor alpha; Zinc

There is indirect evidence that transforming growth factor alpha (TGF-alpha) is an important mediator of mucosal defense and repair. TGF-alpha knockout mice and TGF-alpha-deficient mice (wa-1) provide novel approaches to evaluate the role of TGF-alpha in preserving the integrity of the colon.. Colitis was induced by oral administration of dextran sodium sulfate (DSS, 5 g/dL) to knockout mice, their genetic controls (GC), wa-1 mice, and BALB/c mice. TGF-alpha was also administered intraperitoneally to wa-1 mice to evaluate the effect of exogenous TGF-alpha in DSS colitis.. In response to DSS, nearly 60% of the entire colonic mucosa was destroyed in knockout and wa-1 mice, compared with 22% in GC mice and 16% in BALB/ c mice. Body weight loss was doubled in knockout (28%) and wa-1 mice (23%) compared with GC (11%) and Balb/c mice (12%). TGF-alpha application to wa-1 mice reduced the severity of mucosal injury by almost 70% compared with controls.. The marked susceptibility of TGF-alpha knockout and wa-1 mice to DSS and the obvious amelioration of the colonic injury by exogenous TGF-alpha application in wa-1 mice suggest that TGF-alpha is a mediator of protection and/or healing mechanisms in the colon.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Drinking; Female; Genetic Predisposition to Disease; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Mutant Strains; Reference Values; Solutions; Transforming Growth Factor alpha

Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha), members of the EGF family of growth factors, protect rat gastric and colonic mucosa against injury. Having shown previously that exogenously applied EGF protects rat colonic mucosa against injury, the aim of the present study was to evaluate the endogenously expressed ligand mediating the protective effect of EGF/TGF-alpha in vivo.. In an experimental model of trinitrobenzene sulphonic acid (TNBS)/ethanol induced colitis in rats EGF and TGF-alpha expression was evaluated using a ribonuclease protection assay, northern blot analysis, western blot analysis, and immunohistochemistry.. TGF-alpha mRNA increased 3-4 times at 4-8 hours after induction of colitis and returned to control levels within 24 hours. TGF-alpha immunoreactive protein with a molecular size of about 28 kDa representing TGF-alpha precursors increased markedly after induction of colitis with a peak at 8-12 hours. No fully processed 5.6 kDa TGF-alpha protein was detected in normal or inflamed colon tissue. Only a weak signal for EGF mRNA expression was detected in the rat colon and no EGF protein was observed by immunohistochemistry or western blot analysis.. TGF-alpha precursors are the main ligands for the EGF receptor in acute colitis. It is hypothesised that TGF-alpha precursors convey the biological activity of endogenous TGF-alpha peptides during mucosal defence and repair.

Topics: Acute Disease; Animals; Blotting, Northern; Blotting, Western; Colitis; DNA Primers; Epidermal Growth Factor; Ethanol; Gene Expression Regulation; Immunohistochemistry; Male; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor alpha; Trinitrobenzenesulfonic Acid

Transforming growth factor alpha (TGF-alpha), a member of the epidermal growth factor family, has been proposed to mediate protection against mucosal injury and promote healing of the gastrointestinal mucosa. TGF-alpha acts via a plasma membrane receptor, which is distributed throughout the digestive system with the highest density in epithelia. The aim of this study was to investigate the pattern of TGF-alpha binding sites in the normal and inflamed rabbit colon.. The immune complex/formalin model of acute colitis and tissue section receptor autoradiography were used. Inflammation was characterized by cellular infiltration, edema, and necrosis. TGF-alpha binding relative density was determined by densitometry on film autoradiograms.. The normal colon had a low to moderate density of specific TGF-alpha binding sites in the mucosa and external muscle. TGF-alpha binding density was significantly increased in the mucosa at 4 hours and remained higher than normal for up to 48 hours. The density of binding sites in the mucosa and the inflammatory index returned to near normal values at 96 hours, when colitis had subsided.. The increase in TGF-alpha binding in the mucosa during experimental colitis supports the hypothesis that members of the epidermal growth factor family play a role in inflammation, perhaps acting as mediators of mucosal protection and repair.

Topics: Acute Disease; Animals; Autoradiography; Binding Sites; Colitis; Colon; Disease Models, Animal; ErbB Receptors; Image Processing, Computer-Assisted; Immune Complex Diseases; Intestinal Mucosa; Male; Rabbits; Transforming Growth Factor alpha; Up-Regulation