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Results for “Fibroblast Growth Factor 7”

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PubMed2000

Increased platelet-activating factor receptor gene expression by corneal epithelial wound healing.

PURPOSE: Platelet activating factor (PAF) is a potent inflammatory mediator the synthesis of which increases in the cornea after injury. The effects of PAF are mediated by receptors (PAF-R), which are present in target cells. This study was undertaken to investigate the effects of wound healing, PAF, and growth factors on modulating PAF-R mRNA levels in corneal epithelial cells. METHODS: Cultures of rabbit corneal epithelial (RCE), rabbit limbal epithelial (RLE), rabbit corneal fibroblast (RCF), and rabbit corneal endothelial (RCEn) cells, as well as rabbit corneal keratocytes (RCKs) were used. For the in vivo wound-healing experiments, a 7-mm central corneal deepithelialization was performed in anesthetized rabbits. For the in vitro experiments, wounded rabbit corneas were maintained in organ culture. Corneas were stimulated with 120 nM PAF or preincubated with PAF antagonists, cyclohexamide (CHX) or actinomycin D (AcD) before adding PAF. RCE cells were stimulated with transforming growth factor (TGF)-beta1, -beta2, and, -beta3, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF); and hepatocyte growth factor (HGF). Total RNA was isolated and PAF-R expression evaluated by reverse transcription-polymerase chain reaction (RT-PCR), Northern blot analysis, and quantitative RT-PCR. RESULTS: PAF-R mRNA was expressed in RCE, RLE, and RCEn cells and RCKs, but not in RCFs. After epithelial injury, PAF-R expression increased from 2.5 to 4 times, both in vitro and in vivo. Addition of cPAF further stimulated PAF-R gene expression in epithelium, which was abolished by PAF antagonists. Quantitative RT-PCR revealed that PAF stimulated PAF-R mRNA threefold after injury. The induction of PAF-R by its agonist required previous injury and was inhibited by AcD but not by CHX. Treatment of RCE cells with TGF-beta1, -beta2, or -beta3, HGF, and KGF increased mRNA in PAF-R; however, bFGF had no effect. CONCLUSIONS: Corneal injury produces changes in PAF-R mRNA expression. Whereas stroma fibroblastic cells lost the PAF-R gene expression found in keratocytes, corneal epithelial injury upregulated PAF-R mRNA. These results suggest that activation of selective growth factors and increases in PAF synthesis after injury stimulate PAF-R gene transcription and constitute important feedback mechanisms needed to maintain the inflammatory process and regulate epithelial wound healing.

Animals↗

PubMed2004

Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair.

Keratinocyte growth factor (KGF) is a paracrine-acting, epithelial mitogen produced by cells of mesenchymal origin. It is a member of the fibroblast growth factor (FGF) family, and acts exclusively through a subset of FGF receptor isoforms (FGFR2b) expressed predominantly by epithelial cells. The upregulation of KGF after epithelial injury suggested it had an important role in tissue repair. This hypothesis was reinforced by evidence that intestinal damage was worse and healing impaired in KGF null mice. Preclinical data from several animal models demonstrated that recombinant human KGF could enhance the regenerative capacity of epithelial tissues and protect them from a variety of toxic exposures. These beneficial effects are attributed to multiple mechanisms that collectively act to strengthen the integrity of the epithelial barrier, and include the stimulation of cell proliferation, migration, differentiation, survival, DNA repair, and induction of enzymes involved in the detoxification of reactive oxygen species. KGF is currently being evaluated in clinical trials to test its ability to ameliorate severe oral mucositis (OM) that results from cancer chemoradiotherapy. In a phase 3 trial involving patients who were treated with myeloablative chemoradiotherapy before autologous peripheral blood progenitor cell transplantation for hematologic malignancies, KGF significantly reduced both the incidence and duration of severe OM. Similar investigations are underway in patients being treated for solid tumors. On the basis of its success in ameliorating chemoradiotherapy-induced OM in humans and tissue damage in a variety of animal models, additional clinical applications of KGF are worthy of investigation.

Amino Acid Sequence↗

PubMed2005

Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta.

Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1beta is the most potent inducer of KGF in fibroblasts, acting through the c-Jun pathway. We evaluated in vitro KGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 10) and from control subjects (n = 7) at baseline and after IL-1beta stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1beta increased c-Jun expression, c-Jun activation, and KGF secretion. SP600125, a specific c-Jun N-terminal kinase (JNK) inhibitor, inhibited the effect of IL-1beta. By contrast, in IPF fibroblasts, IL-1beta did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1beta similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1beta-stimulated IPF and control fibroblasts. IL-1beta increased phosphorylated JNK in control and IPF fibroblasts, but this increase was weaker and heterogeneous in IPF. Altogether, our results demonstrate a dysregulation of KGF secretion by IPF fibroblasts. The weak response to IL-1beta is associated with a defect of c-Jun expression and activation and a defect of JNK activation.

Adult↗

PubMed2003

Induction of urothelial cell proliferation by fibroblast growth factor-7 in RAG1-deficient mice.

Fibroblast growth factor-7 (FGF-7, keratinocyte growth factor, KGF) is a 163 amino acid glycoprotein synthesized and secreted by mesenchymal cells (e.g. fibroblasts/fibrocytes) in epithelial organs, thereby functioning as a paracrine mediator of epithelial cell proliferation. In the urinary bladder, FGF-7 is transported from the lamina propria across the urothelial basement membrane to where it ultimately binds to splice variants of the FGFR2 receptor present on the basolateral surface of transitional epithelial cells. We administered 100 micrograms/ml (i.p.) recombinant FGF-7 (rFGF-7) to RAG1-deficient mice (n = 3) for 7 days and observed a striking expansion of the urinary bladder urothelium. This expansion was characterized by a layer of stratified urothelium > 20 cells thick and by positive immunostaining for the proliferation marker Ki-67. In contrast, RAG1-deficient mice (n = 3) that received only buffer injection did not exhibit detectable urothelial expansion. rFGF-7 was detected by immunoblot analyses in the serum, but not in the urine, from RAG1-deficient mice that received the recombinant protein. Mice that have a targeted disruption in the gene encoding the V(D)J recombination activation gene RAG1 have small lymphoid organs with no mature B and T lymphocytes, due to the inability of cell progenitors to perform V(D)J recombination. The biological activity of FGF-7 in RAG-1 mice indicates that immuno-dependent mechanisms are not required for the induction of urothelial cell proliferation by this epithelial cell-specific growth factor.

Animals↗

PubMed2000

Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein.

BACKGROUND & AIMS: Genetic diseases reflecting abnormal hepatocyte function are potentially curable through gene therapy. Retroviral vectors offer the potential for permanent correction of such conditions. These vectors generally require cell division to occur to allow provirus entry into the nucleus, initiated in many experimental protocols by partial hepatectomy. We have explored methods to improve the efficiency of retroviral gene transfer that avoid the need for liver damage. METHODS: Triiodothyronine (T3) and keratinocyte growth factor (KGF) were used to induce hepatic proliferation in rats. The effects of intraportal and peripheral administration of a modified retrovirus that encoded the Lac Z gene during growth factor-induced liver hyperplasia were analyzed. RESULTS: T3 initiated hepatocyte proliferation midzonally; after KGF, proliferation was more diffuse. Optimal concentrations of T3 and KGF acted synergistically to induce proliferation in 61% of hepatocytes in the intact liver. This enabled in vivo hepatocyte transduction, leading to gene expression by up to 7.3% of hepatocytes after intraportal retroviral vector administration and 7. 1% after peripheral venous administration. CONCLUSIONS: T3 and KGF act synergistically to induce hepatocyte proliferation in undamaged liver. The liver can be simply transduced with integrating vectors via the peripheral venous system during a wave of growth factor-induced proliferation.

Animals↗

PubMed1999

Effects of keratinocyte growth factor-2 (KGF-2) on wound healing in an ischaemia-impaired rabbit ear model and on scar formation.

Keratinocyte growth factor-2 (KGF-2), also described as fibroblast growth factor-10 (FGF-10), is a member of the fibroblast growth factor family. KGF-2 shares 57 per cent sequence homology to previously reported KGF-1 (FGF-7). In skin, both growth factors are expressed in the dermal compartment. KGF-1 and KGF-2 bind to the same receptor with high affinity, the KGFR isoform of FGFR2, which is exclusively expressed by epithelial cells. This study examines the in vivo function of topically applied KGF-2 on wound healing using an ischaemia-impaired rabbit dermal ulcer model, in young and aged animals. Histological analysis of the wounds showed that KGF-2 significantly promoted re-epithelialization in both young and old animals. Similar results have been observed with KGF-1 in this model. In addition, KGF-2 enhanced granulation tissue formation in both young and old rabbits, a biological effect not found with KGF-1, suggesting a possible indirect mechanism which enhances neo-granulation tissue formation. Immunohistological staining of day 7 wounds with proliferating cell nuclear antigen (PCNA) antibody demonstrated a significant increase of dermal cell proliferation in KGF-2-treated wounds compared with placebo wounds. These results suggest a mesenchymal-epithelial interaction that is mediated by a paracrine feedback loop of KGF-2. Because of the wound healing impairment observed with ageing, the wound healing response to KGF-2 was also studied in ischaemic wounds of aged animals. Administration of KGF-2 led to significant stimulation of epithelial growth and granulation tissue formation. The effects seen in the old animals were delayed compared with the young animals. Lastly, the effect of KGF-2 was examined in a rabbit model of scar formation. Quantification of scar elevation index showed no significant differences in scar formation when KGF-2 was compared with buffer placebo. Compared with other growth factors, including KGF-1 and TGF-beta which have previously been examined in these models, KGF-2 is the most effective and causes no obvious scarring.

Age Factors↗

PubMedDate not supplied

Success and limitations of a naked plasmid transfection protocol for keratinocyte growth factor-1 to enhance cutaneous wound healing.

Our group and others have previously reported enhancement of cutaneous wound healing following the transfection of tissue with plasmid vectors expressing the DNA for growth factors. In these experiments, growth factor treated animals were usually compared to animals treated with control plasmid vector. To achieve consistent transfection, high DNA plasmid load and repeated penetrations of the wound by needle or gene gun were required. In the current experiments, we assessed the effect of the plasmid load and repeated tissue penetrations on wound healing of excisional wounds in diabetic C57 mice. Animals received 5 mm excisional wounds, and were assigned to the following groups, no treatment, phosphate buffered saline solution injections, and plasmid vector injection with and without the keratinocyte growth factor-1 gene. Intradermal injections of 100 microg plasmid were given adjacent to the wounds at days 1-5, 7 and 11. At day 9, wound closure was more advanced in keratinocyte growth factor-1 treated animals compared to those treated with control plasmid. But a detrimental effect of the DNA plasmid injection was evident from a comparison of the DNA control group versus the non-injected group. Therefore, the challenge for developing an effective system for the enhancement of wound healing lies in improving transfection efficiency.

Animals↗

PubMed1999

Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cells in vivo is resolved by differentiation into type I cells and by apoptosis.

Keratinocyte growth factor (KGF) is a potent mitogen of alveolar epithelial type II cells (AEII). AEII hyperplasia is resolved within several days following intratracheal instillation of KGF by unknown mechanism(s). AEII hyperplasia was induced in rat lungs by intrabronchial instillation of 5 mg recombinant human (rh)KGF x kg body weight(-1) or an equivalent amount of diluent. Epithelial architecture, cell proliferation, transformation of AEII into type I cells (AEI) and apoptosis were investigated by means of immunohistochemistry, stereology, double immunofluorescence microscopy, electron microscopy and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) technique in lungs fixed 1, 2, 3 and 7 days after treatment. After 1 day of rhKGF instillation, an increase was observed in the nuclear antigen Ki-67, a proliferation marker detected by the antibody MIB-5-expressing surfactant protein (SP)-B, -C, -D-positive AEII. The incidence of mitosis was increased by day 2, resulting in AEII micropapillae with intense basolateral expression of the exon 6 containing isoform (v6) of CD446 (CD44v6), a marker for AEII. By day 3, monolayers of AEII exhibiting lateral CD44v6 covered 45% of the alveolar surface. After 7 days, there were numerous intermediate AEII/AEI cells characterized by a flat elongated shape, staining for SP-D, apical appearance of AEI marker Lycopersicon esculentum lectin and lateral staining for AEII marker CD44v6. Increased numbers of TUNEL-positive epithelial cells were seen at days 2-7. In conclusion, restoration of normal alveolar epithelium after instillation of recombinant human keratinocyte growth factor is accomplished by terminal differentiation and apoptosis of hyperplastic alveolar epithelial type II cells in vivo.

Animals↗

PubMed2002

Effect of keratinocyte growth factor-2 on proliferation of human adult keratinocytes.

OBJECTIVE: To investigate the proliferative effect of keratinocyte growth factor (KGF-2) on human adult keratinocytes. METHODS: The standard medium was keratinocyte growth medium without bovine pituitary extract (BPE), hydrocortisone or epidermal growth factor (EGF). Keratinocytes from a 48-year-old subject were cultured and seeded on dishes with standard medium of EGF in cell density of 2 x 10(4)/32 mm(2). After 24 hours, the medium was replaced by the standard medium with 0, 4, 16, 125 and 500 ng/ml KGF-2, respectively. The standard medium with EGF was used as the positive control and the standard medium without EGF or KGF-2 was used as the negative controls. The growth of keratinocytes was monitored by 3-(4,5-dimethythiazol-2-yl)-2,5 dipheyl tetrazolium bromide (MTT) assay and by photographs on days 3, 5 and 7, respectively. RESULTS: KGF-2 in concentrations of 4-500 ng/ml showed a significant proliferative effect on days 5 and 7 as compared with that of the negative controls (P < 0.01). On day 3 the cells were proliferated to 1.5-2.5-fold, on day 5 to 3-5-fold and on day 7 to 3-12-fold in KGF-2 medium as that of the negative controls. The optimal response occurred when the concentration of KGF-2 was 125 ng/ml on day 7. Cell proliferation was also consistently higher in all KGF-2 concentrations as compared with that of the positive controls. CONCLUSIONS: KGF-2 has significant effects on the proliferation of adult keratinocytes, which are more effective than that of EGF. This study supports KGF-2 can improve the healing of chronic wounds in adults in clinic.

Analysis of Variance↗

PubMed2001

Expression of hepatocyte growth factor, keratinocyte growth factor and their receptors in experimental chronic pancreatitis.

BACKGROUND: Hepatocyte (HGF) and Keratinocyte growth factors (KGF) are key factors of tissue organization and regeneration. These peptide growth factors and their receptors c-met and keratinocyte growth factor receptor (KGFR) are overexpressed in pancreatic cancer. AIM: Expression and localization of ligands and receptors were investigated during the development of experimental chronic pancreatitis. METHODS: Chronic pancreatitis was induced in rats by intravenous injection of dibutyltin dichloride. One to 60 days after treatment, the expression of growth factors and receptors was analysed by competitive polymerase chain reaction, Western blot analysis and immunohistochemistry. RESULTS: HGF mRNA expression increased (10-fold) until days 7-14 followed by a decrease to control level. Expression of c-met mRNA constantly increased (15-fold). KGF and KGFR mRNA expression were increased after 14-28 days (5-fold) and then returned to control levels. mRNA expression patterns correlated with changes in the protein expression, whereas protein levels of KGF remained unchanged. Ligands were localized in mesenchymal cells and their receptors on epithelial cells. CONCLUSIONS: The significant increase of HGF and c-met expression suggests an essential role of this growth factor in the morphological changes during the development of chronic pancreatitis. Changes in the expression of KGF and KGFR are less pronounced.

Animals↗

PubMed1998

Mammogenic hormones differentially modulate keratinocyte growth factor (KGF)-induced proliferation and KGF receptor expression in cultured mouse mammary gland epithelium.

Stromally derived keratinocyte growth factor (KGF) can play an important role in mammary gland development as a mesenchymal/stromal mediator of epithelial growth and morphogenesis. However, the possible coordinate regulation of mammary gland development by mammogenic hormones and KGF is unexplored. In these studies, the direct effect of mammogenic hormones on KGF-mediated mammary epithelial mitogenesis and expression of the KGF receptor was examined using primary mouse mammary epithelium growing in serum-free, collagen gel cell culture. Addition of KGF produced an average 7-fold increase in cell number after 10 days of culture. This effect of KGF was further increased in the presence of PRL (9-fold) or progesterone (P; 15-fold), with the combination of P and PRL (22-fold) producing the strongest synergistic stimulation. Estrogen did not show any additional stimulation of growth either alone or in combination with PRL and/or P. Ribonuclease protection analysis showed that epithelial cells grown in medium supplemented with P, but not PRL or estrogen, exhibited a 10-fold higher steady state level of KGF receptor (KGFR) messenger RNA (mRNA). KGFR expression was not induced by short term P exposure, suggesting an effect on mRNA stability rather than transcriptional activation. Time-course studies showed that an early decrease in the level of KGFR mRNA in basal cultures was significantly reduced by P addition. Measurement of RNA turnover after actinomycin D treatment showed that P increased the t(1/2) of KGFR mRNA compared with basal medium. Thus, P and PRL may differentially potentiate the direct mitogenic effect of KGF: P partly by elevation of the level of KGFR mRNA, and PRL principally by intracellular pathways not affecting KGFR expression.

Animals↗

PubMed2004

The water-soluble extract of Illicium anisatum stimulates mouse vibrissae follicles in organ culture.

It is well known that reduced blood flow in the scalp is a cause of alopecia. We have shown previously that the extract of Illicium anisatum increases subcutaneous blood flow in mice. In the present study, we used an organ culture system to examine whether this extract promoted hair follicle elongation. B6C3HF1 mouse vibrissae follicles were cultured in serum-free medium for 7 days at 31 degrees C. Follicles treated with water-soluble (WS) extracts of the leaves, fruits and roots of Illicium anisatum or shikimic acid grew significantly longer than controls. In contrast, ethyl acetate-soluble (AS) extracts and n-hexane-soluble (HS) extracts of the leaves, fruits and roots of the plant inhibited hair follicles and shaft growth. Fractionation of the WS fruit extract showed that the number 1 and number 2 fractions possessed hair follicle elongation activity. GC/MS analysis revealed that the number 1 fraction contained shikimic acid, and that the number 2 fraction was a mixture of many components including glycosides and polysaccharides. Reverse transcription-polymerase chain reaction analysis demonstrated that shikimic acid also induced mRNA expression of insulin-like growth factor-1, keratinocyte growth factor, and vascular endothelial growth factor in the hair follicles. These results suggest that the WS extract of Illicium anisatum promotes hair growth and may be a useful additive in hair growth products.

Acetates↗

PubMed2001

Modulation of pulmonary alveolar type II cell phenotype and communication by extracellular matrix and KGF.

The alveolar epithelium consists of two cell types, alveolar type I (AT1) and alveolar type II (AT2) cells. We have recently shown that 7-day-old cultures of AT2 cells grown on a type I collagen/fibronectin matrix develop phenotypic characteristics of AT1 cells, display a distinct connexin profile, and coordinate mechanically induced intercellular Ca(2+) changes via gap junctions (25). In this study, we cultured AT2 cells for 7 days on matrix supplemented with laminin-5 and/or in the presence of keratinocyte growth factor. Under these conditions, cultured AT2 cells display AT2 type morphology, express the AT2-specific marker surfactant protein C, and do not express AT1-specific cell marker aquaporin 5, all consistent with maintenance of AT2 phenotype. These AT2-like cells also coordinate mechanically induced intercellular Ca(2+) signaling, but, unlike AT1-like cells, do so by using extracellular nucleotide triphosphate release. Additionally, cultured cells that retain AT2 cell-specific markers express connexin profiles different from cultured cells with AT1 characteristics. The parallel changes in intercellular Ca(2+) signaling with cell differentiation suggest that cell signaling mechanisms are an intrinsic component of lung alveolar cell phenotype. Because lung epithelial injury is accompanied by extracellular matrix and growth factor changes, followed by extensive cell division, differentiation, and migration of AT2 progenitor cells, we suggest that similar changes may be vital to the lung recovery and repair process in vivo.

Adenosine Triphosphate↗

PubMed2002

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo.

Keratinocyte growth factor (KGF) is a potent mitogen of pulmonary bronchial and alveolar epithelial cells. However, it is unclear which type(s) of airway epithelial cells (AEC) proliferate(s) in response to KGF. AEC proliferation was induced in rats by either endobronchial instillation of 5 mg recombinant human (rHu) KGF per kg body weight or by adenoviral transfer of the human KGF gene (Ad5-HuKGF). Alterations in terminal airway AEC were followed for up to 7 days after rHuKGF, and for up to 28 days after Ad5-HuKGF. Cell proliferation, as assessed by immunohistochemistry (IHC) for incorporated 5-bromo-2'-deoxyuridine (BrdU) and quantified by stereology, peaked at days 1-2 and was resolved by day 7 after rHuKGF and by day 21 after Ad5-HuKGF. Double immunofluorescence labelling for BrdU or Ki-67 on the one hand, and for Clara cell specific protein 10 (CC10) and calcitonin-gene related peptide on the other hand, demonstrated that Clara cells, not pulmonary neuroendocrine cells, proliferated in response to human KGF. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling) method in conjunction with IHC for MNF116 failed to detect significant numbers of apoptotic AEC. IHC in conjunction with stereology revealed transient phenotypic alterations with a decrease in CC10, an increase in surfactant protein D and an increase in CD44v6 in AEC. The authors conclude that Clara cells responded to human keratinocyte growth factor in vivo by proliferation as well as by changes in protein expression, whereas no significant response was observed in pulmonary neuroendocrine cells. As Clara cells are intimately involved in airway epithelial repair, ion and fluid transport, and modulate lung inflammation, the potential of human keratinocyte growth factor to protect the lung may in part rely on the response of Clara cells.

Animals↗

PubMed1995

Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats.

Alveolar type II cell proliferation occurs after many forms of lung injury and is thought to play a critical role in alveolar epithelial repair. Keratinocyte growth factor/fibroblast growth factor 7 (KGF) has been shown to promote alveolar type II cell growth in primary culture and alveolar epithelial hyperplasia in vivo. In this study, we used immunohistochemical analysis to determine the intrapulmonary distribution and cellular localization of recombinant human KGF (rhKGF) instilled into the trachea of rats. 6 h after administration, immunoreactive KGF was observed within the lung parenchyma and along alveolar epithelial cell membranes. By 18-24 h, KGF was detected intracellularly in alveolar epithelial cells and intraalveolar macrophages. Immunoreactive KGF was not demonstrable 48 h after delivery or in lung sections from PBS-treated animals. Intratracheal instillation of 5 mg/kg rhKGF stimulated a marked, time-dependent increase in the alveolar type II cell specific labeling index to a maximum level of 33 +/- 3% 48 h after rhKGF administration compared with 1.3 +/- 0.3% after PBS instillation. In addition, this increase in type II cell proliferation in vivo was documented by flow cytometric analysis of isolated type II cells which revealed a nearly fivefold increase in the proportion of cells traversing through the S and G2/M phases of the cell cycle. To test the hypothesis that KGFs effects on type II cells in vivo might affect the response to lung injury, rats were treated with rhKGF and exposed to hyperoxia. Animals that received 1 or 5 mg/kg rhKGF exhibited dramatically reduced mortality (P < 0.001, for both doses). Survival for animals treated with 0.1 mg/kg rhKGF was not significantly different from either untreated rats or animals treated with heat-denatured rhKGF. The lungs of rhKGF-treated animals that survived hyperoxia exposure had minimal hemorrhage and no exudate within the intraalveolar space. These experiments established that intratracheal administration of rhKGF stimulated alveolar type II cell proliferation in vivo and reduced hyperoxia-induced lung injury in rats. Directed delivery of KGF to the lungs may provide a therapeutic strategy to preserve or restore the alveolar epithelium during exposure to hyperoxia or other injurious agents.

Animals↗

PubMed2000

Thyroid organoid formation in simulated microgravity: influence of keratinocyte growth factor.

The generation of artificial human thyroid tissues in suspension (low-shear environment, present in simulated microgravity [MG] and generated by a rotary cell culture system [RCCS]), was enhanced by increasing medium kinematic viscosity with a (3% v/v) suspension of extracellular matrix (basement membrane extract [BME]) in serum-free medium to generate artificial human thyroid organoids. Recombinant human keratinocyte growth factor (KGF, 7 ng/mL) facilitated human thyrocyte aggregation and three-dimensional (3-D) differentiation. There was an MG-associated decrease in extractable DNA that was reversed after addition of keratinocyte growth factor (KGF). In simulated MG, the increase in extractable DNA after KGF addition was up to 170% over non-KGF control cultures. In contrast, monolayer cultures in unit gravity showed a maximum DNA increase of 39% after KGF addition. Morphologically, differentiated thyroid neofollicles displayed polarization and were located in close proximity after 2 weeks of culture. Immunogold labeling with antibody to human thyroglobulin (Tg) revealed staining of follicular lumina and secretory vesicles, and a time-dependent increase in human Tg was detected in the culture media. Culture under simulated MG thus allowed direct visualization of KGF-facilitated thyrocyte/extracellular matrix interaction. Such artificial human thyroid organoids-generated in MG and in the presence of KGF-structurally resembled natural thyroid tissue. The above findings may have implications for autoimmune thyroid disease where KGF (if, for example, secreted locally by intraepithelial gammadelta T cells among other cells) may contribute to thyroid cell growth.

Cell Adhesion Molecules↗

PubMed2002

Amelioration of acute oral mucositis by keratinocyte growth factor: fractionated irradiation.

PURPOSE: The aim of the present study was to quantify the protective efficacy of recombinant human keratinocyte growth factor (rHuKGF) in oral mucosa. METHODS AND MATERIALS: Mouse tongue mucosal ulceration was analyzed as the clinically relevant end point. Fractionated irradiation of the snout with 5 daily fractions of 3 Gy was followed by graded test doses, given to a test area of the lower tongue, on Day 7. rHuKGF was injected s.c. in daily doses of 5 mg/kg before radiotherapy, during radiotherapy, over the weekend break, or a combination. Moreover, single rHuKGF injections (5 or 15 mg/kg) were given on Day -1 or on Day 4. RESULTS: In a single-dose control experiment, the ED50, i.e., the dose after which ulcer induction is expected in 50% of the mice, was 10.9 +/- 0.7 Gy. Fractionated irradiation without keratinocyte growth factor rendered an ED50 for test irradiation of 5.6 +/- 3.7 Gy. Keratinocyte growth factor increased the ED50 values to 7.8 +/- 3.3 Gy (Days -3 to -1, p = 0.01), 8.3 +/- 1.6 Gy (Days -4 to -2, p = 0.0008), 10.5 +/- 1.4 Gy (Days 0 to +2, p = 0.0002), 11.0 +/- 0.5 Gy (Days 0 to +4, p = 0.002), 10.6 +/- 1.4 Gy (Days +4 to +6, p = 0.0021), 10 +/- 0.07 (Days -3 to +1, p = 0.0001) or 11.0 +/- 0.02 (Days +4 to +8, p = 0.0001). This is equivalent to compensation of approximately 1.5 fractions of 3 Gy when rHuKGF is given before radiotherapy and 3-4 fractions in all other protocols by rHuKGF treatment. Single rHuKGF injections were similarly (5 mg/kg) or more (15 mg/kg) effective. CONCLUSIONS: In conclusion, these results indicate a marked increase in oral mucosal radiation tolerance by rHuKGF, which is most pronounced if the growth factor is applied during fractionated radiotherapy. The effect seems to be based on complex mechanisms, predominantly changes in both epithelial proliferation and differentiation processes.

Animals↗

PubMed2002

Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation.

Decreased thymopoietic capacity contributes to the severe and clinically significant immune deficiency seen after bone marrow transplantation (BMT). One mechanism for thymopoietic failure is damage to the interleukin 7 (IL-7)-producing thymic epithelial cells (TECs) by irradiation and chemotherapy, which can be partially treated by IL-7 administration. Pretreatment of BMT recipients with keratinocyte growth factor (KGF, or Fgf7), an epithelial cell-specific growth factor, protects mucosal, cutaneous, and pulmonary epithelial cells from cytotoxic therapy-induced damage in experimental murine models. Like other epithelial cells, TECs specifically express KGF receptors. Because KGF specifically protects KGF receptor-bearing epithelial cells and post-BMT immune deficiency is caused by loss of TECs, we hypothesized that KGF pretreatment would improve post-BMT thymic function. To test the hypothesis, BMT recipient mice were given KGF or placebo prior to congenic or allogeneic BMT. Administration of KGF before murine BMT significantly increased the capacity of the thymus to generate donor-derived thymocytes. KGF pretreatment also normalized the proportion of thymic subpopulations, increased the number of naive T cells in the periphery, and improved the response to neoantigen immunization. KGF treatment caused increased production of intrathymic IL-7, and the thymopoietic effects of KGF required an intact IL-7 signaling pathway. These results demonstrate that KGF may have immunomodulatory effects by a unique mechanism of protection of TECs. Furthermore, thymic injury and prolonged posttransplantation immune deficiency in BMT recipients can be prevented by KGF administration.

Animals↗