Intravenous keratinocyte growth factor protects  against experimental pulmonary injury

Guo, Jane; Yi, Eunhee S.; Havill, Andrew M.; Sarosi, Ildiko; Whitcomb, Lane; Su, Yin; Middleton, Scot; Piguet, P F; Ulich, Thomas R.

doi:10.1152/ajplung.1998.275.4.l800

Cited by 62 publications

(67 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the number of cells in control samples decreased throughout time likely due to cell death. In agreement with previous studies, [15][16][17][18][19][20][21] these results suggest that in addition to promoting proliferation, KGF, P-KGF, and PL-P-KGF may also promote cell survival.…”

Section: P-kgf and Plasmin-derived P-kgf Retain Biological Activitysupporting

confidence: 93%

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

Geer

Swartz

Andreadis

2005

The American Journal of Pathology

111

View full text Add to dashboard Cite

Exogenous keratinocyte growth factor (KGF) significantly enhances wound healing, but its use is hampered by a short biological half-life and lack of tissue selectivity. We used a biomimetic approach to achieve cell-controlled delivery of KGF by covalently attaching a fluorescent matrix-binding peptide that contained two domains: one recognized by factor XIII and the other by plasmin. Modified KGF was incorporated into the fibrin matrix at high concentration in a factor XIII-dependent manner. Cell-mediated activation of plasminogen to plasmin degraded the fibrin matrix and cleaved the peptides, releasing active KGF to the local microenvironment and enhancing epithelial cell proliferation and migration. To demonstrate in vivo effectiveness, we used a hybrid model of wound healing that involved transplanting human bioengineered skin onto athymic mice. At 6 weeks after grafting, the transplanted tissues underwent full thickness wounding and treatment with fibrin gels containing bound KGF. In contrast to topical KGF, fibrin-bound KGF persisted in the wounds for several days and was released gradually, resulting in significantly enhanced wound closure. A fibrinolytic inhibitor prevented this healing, indicating the requirement for cell-mediated fibrin degradation to release KGF. In conclusion, this biomimetic approach of localized, cell-controlled delivery of growth factors may accelerate healing of large full-thickness wounds and chronic wounds that are notoriously difficult to heal. Re-establishing an epithelial barrier in injured skin is a crucial wound-healing event that protects the body against further water loss and exposure to external pathogens. Skin epithelial cells or keratinocytes begin migrating to repair the epithelium ϳ18 to 24 hours after injury 1 carefully degrading a fibrin-rich clot through the activation of plasminogen into plasmin. 2 Transient interactions with extracellular matrix proteins in the wound such as collagen and fibronectin during fibrinolysis of the clot guide the keratinocytes into the wound space. Degranulating platelets are embedded in the fibrin matrix and release growth factors and cytokines, which activate keratinocytes to proliferate and migrate until they heal the defect.Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family (FGF-7), plays a prominent role in epithelial morphogenesis and wound healing. 3,4 Although initial studies restricted expression of KGF in cells of mesenchymal origin, 5,6 a recent study documented expression of KGF by dendritic epidermal T cells of the skin immediately after wounding, 7 suggesting that KGF may play an important role in epidermal immunity. The paracrine action of KGF on epithelial cells is mediated through the KGF receptor (KGFR or FGFR2IIIb), a splice variant of FGF-2 receptor encoded by the gene fgfr-2. 8,9 KGF is thought to be an important player in development and morphogenesis of epithelial tissues and a promoter of mesenchymal-epithelial interactions. 10,11 Targeting KGF expression to the basal keratinocyt...

show abstract

Section: P-kgf and Plasmin-derived P-kgf Retain Biological Activitysupporting

confidence: 93%

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

Geer

Swartz

Andreadis

2005

The American Journal of Pathology

111

View full text Add to dashboard Cite

show abstract

“…Airway epithelial proliferation, assessed by immunohistochemistry for Ki67 as well as for BrdU, reached highest levels at day 1-2 after both types of KGF treatment. Thus, proliferation of Clara cells peaked at a slightly earlier timepoint than the proliferation of alveolar epithelial type II cells (day 2-3) reported in previous studies [5,7,21,47]. This was even true for proliferation of the airway epithelium after adenoviral KGF gene transfer, where hyperplasia of type II cells also peaked at day 2-3 [30] (unpublished data).…”

Section: Discussionsupporting

confidence: 56%

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

Fehrenbach

Fehrenbach²,

Pan³

et al. 2002

European Respiratory Journal

View full text Add to dashboard Cite

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo. H. Fehrenbach, A. Fehrenbach, T. Pan, M. Kasper, R.J. Mason. #ERS Journals Ltd 2002. ABSTRACT: 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-29-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.

show abstract

“…In our opinion, it is not likely that the discrepancy between the growth promoting effect of KGF in human and rat beta cells could be due to the difference in receptor affinity between rats and humans. Several studies using recombinant human KGF in rat or mouse [33] and amphibians [34] have shown a statistically significant effect of KGF on those cells showing the existence of a high cross-reactivity for KGF and KGF receptor between different species. To explain the absence of a potent growth promoting effect of KGF on adult rat's islets compared to that seen in fetal pancreatic precursor cells in our study, it is interesting to note that it has been previously shown that systemic injection of KGF into adult rats enhanced the ductal cell proliferation without leading to an increased number of endocrine cells [5].…”

Section: Effect Of Kgf On Beta Cell and Ductal Cell Proliferationmentioning

confidence: 99%

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

et al. 2003

View full text Add to dashboard Cite

Aims and hypothesis. Keratinocyte growth factor (KGF) is a member of the heparin-binding fibroblast growth factor family with a high degree of specificity for epithelial cells in vitro and in vivo. Our aim was to study the effect of KGF on beta-cell growth and differentiation on islet-like cell clusters derived from human fetal pancreas. Methods. We investigated the effects of KGF, in vitro, on beta-cell differentiation from undifferentiated pancreatic precursor cells and in vivo after transplantating human fetal pancreatic cells into athymic rats treated with KGF. Results. Treatment of islet-like cell clusters with KGF in vitro did not change the number of insulin producing cells, as measured by the measurement of insulin content or DNA. The in vivo treatment of recipient rats with KGF increased the number of beta cells within the grafts 8 weeks after transplantation. At this time, glucose-stimulated insulin secretion was evaluated by glucose stimulation tests in rats bearing the transplants. Measurements of human C-peptide concentrations after glucose challenge showed that the newly differentiated beta cells in the KGF-treated group were functionally competent as opposed to the control group, where the graft failed to release insulin appropriately. Conclusion/interpretation. These findings suggest that in vivo, KGF is capable of inducing human fetal beta-cell expansion. The growth promoting effect of KGF on beta cells occurred mainly through the activation of ductal cell proliferation and their subsequent differentiation into beta cells. [Diabetologia (2003) 46:822-829]

show abstract

Intravenous keratinocyte growth factor protects against experimental pulmonary injury

Cited by 62 publications

References 13 publications

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

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

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

Contact Info

Product

Resources

About