transforming-growth-factor-beta and Ulcer

Polypeptide growth factors regulate cellular processes involved in wound healing. Application of exogenous growth factors can modify the healing process and, with recombinant DNA technology, growth factors can now be made in sufficient quantity to be used therapeutically. Several growth factors are showing promising results in clinical trials, especially in cases of impaired healing, such as chronic ulcers. Preclinical studies indicate that further growth factors may have therapeutic potential in a wide range of wound-healing applications. The use of specifically designed and modified growth factors, growth-factor inhibitors, and sequential and combinatorial dosing regimes offer further possibilities for enhancing wound healing.

Topics: Animals; Chronic Disease; Epidermal Growth Factor; Fibroblast Growth Factors; Growth Substances; Humans; Peptides; Platelet-Derived Growth Factor; Recombinant Proteins; Transforming Growth Factor alpha; Transforming Growth Factor beta; Ulcer; Wound Healing; Wounds and Injuries

Topics: Animals; Collagen Type I; Endoscopic Mucosal Resection; Esophageal Mucosa; Esophageal Stenosis; Esophagoscopy; Female; Fibrosis; Gene Silencing; Injections, Intralesional; Myofibroblasts; RNA, Messenger; RNA, Small Interfering; Sulfotransferases; Swine; Transforming Growth Factor beta; Ulcer

Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor beta (TGFbeta). Serum response factor (SRF) is a TGFbeta-inducible transcription factor that is important for wound healing. Injection of SRF expression plasmid into rat gastric ulcers significantly accelerated restoration of epithelium and smooth muscle structures.. To determine the role of SRF in oesophageal ulcer healing, especially in myofibroblast differentiation.. Rats (in vivo), oesophageal epithelial cells (Het1A) and fibroblasts (Rat1-R12) (in vitro) were used.. Oesophageal ulcers were induced in rats with acetic acid and subsequently treated by local injection of plasmids expressing either SRF or SRF antisense sequence. Rats were killed at 1, 3, 6, 9 and 14 days after treatment and tissues collected. For in vitro studies, both Het1A and Rat1-R12 cells were transfected with the plasmids used in ulcer treatment.. Upregulation of SRF increased the myofibroblast population in ulcer granulation tissue; knockdown of SRF suppressed this event. In addition, ulceration induced SRF and TGFbeta expression coordinately. In vitro studies showed that overexpression of SRF in either oesophageal epithelial cells or fibroblasts was sufficient to induce myofibroblast phenotype. Furthermore, the TGFbeta-induced myofibroblast phenotype required integrin-linked kinase (ILK)-mediated SRF activation, as either knockdown of SRF or inactivation of ILK prevented this action.. SRF is indispensable for myofibroblast differentiation during oesophageal ulcer healing and is required for TGFbeta-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGFbeta-induced SRF activation and subsequent myofibroblast differentiation. ILK is associated with SRF, and TGFbeta enhances this association.

Topics: Acetic Acid; Animals; Cell Differentiation; Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Esophageal Diseases; Fibroblasts; Genetic Therapy; Male; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Serum Response Factor; Transforming Growth Factor beta; Ulcer; Wound Healing

Hepatocyte growth factor (HGF) is a multifunctional cytokine that is involved in recovery process after organ injuries.. We studied HGF and the membrane bound receptor, c-met locally in patients who suffered from chronic leg ulcers (> or =1 year) caused by venous insufficiency.. Skin biopsies from the edge of the ulcers were taken from patients (n=13) and studied by immunohistochemical staining for detection of HGF and c-met. Skin biopsies from healthy volunteers (n=10) were used as the control material. Ulcer secretion from chronic ulcers (n=11) was examined for the presence of HGF by ELISA and the concentration of HGF was compared with acute ulcers in healthy controls (n=10) and in patients operated for a non-invasive breast cancer (n=12).. We observed that c-met expression in the ulcer area increased significantly in chronic ulcers compared to controls (p=0.005). Concentration of ulcer-HGF in the patients with chronic ulcer was significantly higher than acute ulcers (p<0.01). The biological activity of HGF in ulcer secret was assessed in-vitro in transferred, mouse skin epithelial cell monolayer. Enhanced migration and morphologic changes were seen after adding ulcer secret from acute ulcers (> 1 ng/mL) that was inhibited by anti-HGF antibodies. No biological activity was observed by adding ulcer secret from chronic ulcers irrespective HGF concentration.. We conclude that in chronic skin ulcers decreased biological activity of endogenous HGF and overexpression of c-met is seen which might explain fibrosis and delayed recovery. Administration of exogenous active HGF might contribute to accelerated healing in these patients.

Topics: Adult; Animals; Biopsy; Blotting, Western; Breast Neoplasms; Case-Control Studies; Cell Line; Cell Movement; Cytokines; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Leg Ulcer; Male; Mice; Proto-Oncogene Proteins c-met; Skin; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ulcer; Venous Insufficiency; Wound Healing

Ulceration is a common feature of inflammatory bowel diseases, where subepithelial cell growth is frequently necessary for resolution. In order to further understand the role of colonic fibroblasts in this process, we have used an in vitro model of wound repair to study the response of human colonic fibroblasts to several growth factors expressed in colonic tissues.. Proliferation was determined by [(3)H]thymidine incorporation into DNA in subconfluent fibroblast cultures. In vitro wound repair was determined in confluent fibroblast monolayers after mechanical denudation. The presence of growth factors secreted by fibroblasts was studied in conditioned medium by heparin affinity chromatography and immunodetection with specific antibodies.. Serum and platelet-derived growth factor (PDGF-BB) induced a dramatic increase in both colonic fibroblast proliferation and closure of wounded cell monolayers. Epidermal growth factor (EGF) stimulated both fibroblast activities, but the effect was less potent. However, colonic fibroblasts did not respond to transforming growth factor-beta(1). Conditioned medium stimulated fibroblast proliferation and wound repair activity, which was reverted by the addition of suramin. Furthermore, a PDGF-like factor was isolated from colonic fibroblast-conditioned medium.. EGF and PDGF-BB promote human colonic fibroblast-dependent wound repair activities. Human colonic fibroblasts may exert an autocrine regulation via the production of growth factors.

Topics: Cell Division; Cells, Cultured; Colon; Colonic Diseases; Culture Media, Conditioned; Epidermal Growth Factor; Fibroblasts; Humans; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Ulcer; Wound Healing

Barrier-raised transforming growth factor beta 1 (TGF beta 1)-deficient mice consistently die before 35 days of age of a severe multiorgan inflammatory disease that can affect the skeletal muscle, heart, liver, pancreas, salivary gland, lung, oesophagus and stomach. The underlying cause of this disease is not known. To determine whether abnormal responsiveness of the immune system to the presence of enteric flora plays a causative role, a colony of TGF beta 1-deficient and wild-type mice were raised in a sterile environment. Seven germ-free TGF beta 1-deficient and 5 germ-free TGF beta 1 wild-type mice were examined. Lesion development was analysed and compared with historical data on 50 barrier-raised TGF beta 1 mutant mice and 32 barrier-raised wild-type mice. All germ-free TGF beta 1-deficient mice died shortly after weaning, as do their barrier-raised counterparts. There was a significant delay in death in germ-free TGF beta 1-deficient mice compared with barrier-raised mutant mice. However, there was no difference in the type, severity or incidence of lesions between TGF beta 1 mutant mice raised under germ-free or barrier conditions. Germ-free wild-type mice had no lesions. It is concluded that microorganisms play a minimal role in disease induction in TGF beta 1-deficient mice.

Topics: Animals; Germ-Free Life; Hyperplasia; Inflammation; Longevity; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Stomach; Stomach Ulcer; Transforming Growth Factor beta; Ulcer

The molecular and cellular mechanisms that regulate the radiation-induced fibrotic response in the intestine are not known. In addition to increased amounts of connective tissue, inflammatory cell aggregates are often found, especially in conjunction with acute or chronic mucosal ulcerations. These inflammatory cells are a major source of cytokines that influence connective tissue metabolism. Hence, a possible link may exist between the cellular inflammatory response and fibrosis. This preclinical study examined the influence of fractionated irradiation on the expression of three inflammatory/fibrogenic cytokines in rat small intestine. A rat intestinal transposition model was used for localized fractionated irradiation of a 3-4-cm segment of small bowel. Fifty-nine male Sprague-Dawley rats were irradiated or sham irradiated with 9 daily fractions of 5.2 Gy. Expression of Interleukin 1 alpha (IL-1 alpha), Transforming growth factor beta 1 (TGF-beta 1), and Platelet derived growth factor-AA (PDGF-AA) was assessed by immunohistochemistry. Irradiated and unirradiated intestine was examined 24 h, 14 days, and 26 weeks after completion of irradiation. Unirradiated intestine exhibited immunohistochemical expression of IL-1 alpha, TGF-beta 1 and PDGF-AA that conformed to known staining patterns in normal tissue. Irradiated intestine showed increased expression of all three cytokines at all assessment times. The increased cytokine expression correlated with fibrosis and inflammatory cell infiltrates in irradiated intestine. This was particularly evident in areas with mucosal ulcerations. Fractionated irradiation of small intestine elicits increased expression of IL-1 alpha, TGF-beta 1, and PDGF-AA in areas of acute and chronic radiation injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cytokines; Endothelium, Vascular; Epithelium; Extracellular Matrix; Fibrosis; Gene Expression; Interleukin-1; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Muscle, Smooth; Platelet-Derived Growth Factor; Radiation Dosage; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ulcer

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which appears to be a consequence of the rate of epithelial proliferation. The beta transforming growth factors have been shown to be negative regulators of epithelial cell proliferation. Here we show that transforming growth factor beta 3 administration reduced proliferation of oral epithelium in vitro and in vivo. Topical application of transforming growth factor beta 3 to the oral mucosa of the Syrian golden hamster prior to chemotherapy significantly reduced the incidence, severity, and duration of oral mucositis, reduced chemotherapy-associated weight loss, and increased survival.

Topics: Animals; Cell Cycle; Cell Division; CHO Cells; Cricetinae; Disease Models, Animal; DNA; Epithelial Cells; Epithelium; Fluorouracil; Mesocricetus; Mink; Mouth Mucosa; Stomatitis; Transforming Growth Factor beta; Ulcer