Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats

Zeeh, JM; Procaccino, Frank; Hoffmann, Péter; Aukerman, SL; McRoberts, James A.; Soltani, S; Pierce, GF; Lakshmanan, J.; Lacey, David L.; Ve, Eysselein

doi:10.1053/gast.1996.v110.pm8612996

Cited by 124 publications

(75 citation statements)

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“…Interestingly, no difference in the extent of UVB damage was seen in these mice in the absence of exogenous KGF. This finding is consistent with our result that -in contrast to many other situations where KGF expression is upregulated upon epithelial injury (Werner et al, 1992;Zeeh et al, 1996;Baskin et al, 1997;Charafeddine et al, 1999;Adamson and Bakowska, 1999) -enhanced KGF expression upon UV irradiation could be detected neither in murine skin nor in cultured fibroblasts (our unpublished data).…”

Section: Discussionsupporting

confidence: 93%

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Braun

Krampert²,

Bodó

et al. 2006

Journal of Cell Science

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Owing to its potent cytoprotective properties for epithelial cells, keratinocyte growth factor (KGF) is successfully used for the treatment of chemotherapy- and radiotherapy-induced oral mucositis in cancer patients. It is therefore of major interest to determine possible clinical applications of KGF in other organs and in different stress situations and to unravel common and organ-specific mechanisms of KGF action. Here we show that KGF protects human keratinocytes from the toxicity of xenobiotics with electrophilic and oxidative properties and reduces the cell death induced by UV irradiation. In contrast to other cell types, cytoprotection of keratinocytes by KGF is not a direct anti-apoptotic effect but requires de novo protein synthesis. The in vitro findings are clinically relevant because KGF protected keratinocytes in organ-cultured human scalp hair follicles from the toxicity of the xenobiotic menadione. Moreover, injection of KGF into murine back skin markedly reduced cell death in the epidermis after UVB irradiation. This activity is dependent on FGF receptor signaling because it was abrogated in transgenic mice expressing a dominant-negative FGF receptor mutant in keratinocytes. Taken together, our results encourage the use of KGF for skin protection from chemical and physical insults.

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Section: Discussionsupporting

confidence: 93%

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Braun

Krampert²,

Bodó

et al. 2006

Journal of Cell Science

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“…Administration of exogenous KGF resulted in rapid (24-h) induction of epithelial cell proliferation. Morphological changes to noninflamed colon included an increase in colonic wet weight and colonic crypt depth and in the number of goblet cells per villi (19,48). The mechanism(s) by which KGF can modulate epithelial cell renewal are still unclear.…”

Section: Discussionmentioning

confidence: 99%

Interactions between stromal cell--derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.

Bajaj-Elliott¹,

Poulsom²,

Pender³

et al. 1998

J. Clin. Invest.

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Immune reactions in the gut are associated with increased epithelial cell proliferation. Here we have studied the role of keratinocyte growth factor (KGF; FGF7) and transforming growth factor-␣ (TGF-␣ ) in the epithelial cell hyperplasia seen in explants of fetal human small intestine after activation of lamina propria T cells with the superantigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEB to the explants there is a 10-fold increase in KGF mRNA by 72 h of culture. KGF transcripts were abundant in the lamina propria using in situ hybridization and the culture supernatants contained elevated amounts of KGF protein. SEB had no direct effect on KGF mRNA and protein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-␣ . Accompanying the increase in KGF there was also an increase in TGF-␣ precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue. Increased TGF-␣ precursor proteins were also detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-␣ enhanced epithelial cell proliferation and antibodies against KGF and TGF-␣ partially inhibited SEB-induced crypt hyperplasia. These results suggest molecular cross-talk between the KGF/KGFR and the TGF-␣ /EGFR in immunemediated crypt cell hyperplasia. ( J. Clin. Invest. 1998. 102: 1473-1480.)

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“…It has been demonstrated, that keratinocyte growth factor (KGF) has an important function in wound reepithelialization [43] and KGF expression is strikingly increased in surgical specimens from patients suffering from Crohn's disease and ulcerative colitis [44] . Furthermore, in an experimental model of colitis, administration of KGF after but not before induction of colitis significantly ameliorated tissue damage demonstrating that exogenous KGF might promote IBD [45] . However, clinical studies treating patients with CD or UC with exogenous KGF have not been performed yet.…”

Section: The Role Of Regulatory Peptides For Intestinal Epithelial Womentioning

confidence: 92%

Epithelial restitution and wound healing in inflammatory bowel disease

Sturm¹,

Dignaß²

2008

WJG

288

260

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disorders including inflammatory bowel diseases and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface. THE MUCOSAL DEFENSE SYSTEMThe surface of the digestive tract is covered by epithelial cells that constitute an efficient physical barrier between the dietary and enteric flora pathogens found in the intestinal lumen and the individuum, but also allows an exchange between nutrients and the systemic circulation [1] . The epithelial defense mechanism can be categorized into three key components: pre-epithelial, epithelial and post-epithelial, the latter is represented by the lamina propria [2] . The pre-epithelial mucus barrier is composed of mucin associated with other proteins and lipids and forms a continuous gel into which a bicarbonate-rich fluid is secreted, maintaining a neutralizing pH at the epithelial surface. Phosphatidylcholine is the predominant surface bioactive phospholipid found within the gastrointestinal tract [3] . Intestinal epithelial cells secrete mucins and glycocalyx, which contain membrane-anchored negatively charged mucin-like glycoproteins and hydrophobic phospholipids [4] . The tight adherence of mucin to the apical surfaces of epithelia is owed to the existence of the specific complex between mucin oligosaccharides and the mucin binding protein of the apical mucosal membrane [5] . AbstractInflammatory bowel disease is characterized by a chronic inflammation of the intestinal mucosa. The mucosal epithelium of the alimentary tract constitutes a key element of the mucosal barrier to a broad spectrum of deleterious substances present within the intestinal lumen including bacterial microorganisms, various dietary factors, gastrointestinal secretory products and drugs. In addition, this mucosal barrier can be disturbed in the course of various intestinal disorders including inflammatory bowel diseases. Fortunately, the integrity of the gastrointestinal surface epithelium is rapidly reestablished even after extensive destruction. Rapid resealing of the epithelial barrier following injuries is accomplished by a process termed epithelial restitution, followed by more delayed mechanisms of epithelial wound healing including increased epithelial cell proliferation and epithelial cell differentiation. Restitution of the intestinal surface epithelium is modulated by a range of highly divergent factors among them a broad spectrum of structurally distinct regulatory peptides, variously described as growth factors or cytokines. S e ve ra l re g u l a t or y pe pt ide fac t or s ac t from t he basolateral site of the epithelial surface and enhance epithelial cell restitution through TGF-β-dependent pathways. In contrast, members of the trefoil factor family (TFF peptides) appear to stimulate epithelial restitution in conjunction with mucin glycoproteins through a TGF-β-independent mechanism from...

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Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats

Cited by 124 publications

References 0 publications

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Interactions between stromal cell--derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.

Epithelial restitution and wound healing in inflammatory bowel disease

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