Keratinocyte Growth Factor Group Research Articles

Effects of silencing NLRP3 gene on proliferation of psoriasis-like HaCaT cells and expressions of cytokines.

We aimed to explore the effects of silencing NOD-like receptor protein 3 (NLRP3) on proliferation of psoriasis-like HaCaT cells and expressions of cytokines. HaCaT cells were treated with human keratinocyte growth factor (KGF) and were divided into KGF group, negative control group, NLRP3-RNAi group and control group. Cells proliferation was detected by CCK8, cell clone formation rate was detected by clone formation assay, distribution of cells cycle was detected by flow cytometry, expressions of cyclin B1 (Cyclin B1), cyclin-dependent kinase 2 (CDK2), Ki67 and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot, and levels of interleukin (IL)-17, IL-23, IL-6 and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay. Compared with control group, expressions of NLRP3 mRNA and protein, proliferation rate and clonal formation rate were increased in KGF group, percentage of cells in G0/G1 phase was decreased, percentage of cells in S phase was increased, expressions of Cyclin B1, CDK2, Ki67 and PCNA proteins were increased, and levels of IL-17, IL-23, IL-6 and TNF-α were increased. Compared with negative control group, expressions of NLRP3 mRNA and protein, proliferation rate and clonal formation rate were decreased in NLRP3-RNAi group, percentage of cells in G0/G1 phase was increased, percentage of cells in S phase was decreased, expressions of Cyclin B1, CDK2, Ki67 and PCNA proteins were decreased, and levels of IL-17, IL-23, IL-6 and TNF-α were decreased. Silencing NLRP3 gene can inhibit the proliferation of psoriasis-like HaCaT cells, arrest cell cycle, inhibit the expressions of cell proliferation-related proteins and reduce levels of pro-inflammatory factors.

Keratinocyte growth factor ameliorates mycophenolate mofetil-induced intestinal barrier disruption in mice

ObjectivesAlthough mycophenolate mofetil-induced (MMF) effectively improves long-term graft survival, the gastrointestinal (GI) side effects due to MMF-induced GI barrier damage limit its use in clinic. Keratinocyte growth factor (KGF) plays a crucial role in the intestinal protection and repair process. This study is designed to investigate the protective effect of KGF on MMF-induced intestinal mucosal barrier disruption and the potential mechanism. MethodsThirty adult male C57BL/6 mice were assigned to one of the following groups: the MMF group, the MMF + KGF group, and the control group (n = 10 in each group). Animals in the MMF group received MMF (500 mg/kg) by gavage once daily for 15 consecutive days; animals in the MMF + KGF group received MMF (500 mg/kg) by gavage and KGF (5 mg/kg) by intraperitoneal injection once daily for 15 consecutive days; and control mice were given an equal volume of vehicle during the 15-day experimental period. In each group, intestinal paracellular permeability, histopathological changes and shifts in tight junction (TJ) protein were evaluated; further, proliferation and apoptosis of intestinal epithelial cells (IECs) were assessed, and intraepithelial lymphocytes (IELs) were isolated and analyzed by flow cytometry. ResultsMMF caused intestinal mucosal injury, increased intestinal mucosal permeability, and altered expression of TJ protein. Moreover, MMF treatment inhibited IEC proliferation and increased apoptosis. MMF treatment resulted in a lower proportion of γδ+ T cells in IELs (γδ+ IELs). Conversely, concurrent administration of KGF with MMF effectively alleviated MMF-induced intestinal mucosal disruption, inhibited the increase in intestinal permeability, and maintained TJ protein expression. KGF also reversed the MMF-mediated inhibition of proliferation and promotion of apoptosis in IECs. In addition, KGF significantly enhanced the proportion of γδ+ IELs. ConclusionOur findings suggest that MMF induces intestinal epithelial barrier disruption in mice. KGF may play a protective role to ameliorate the disruption and provide a therapeutic intervention for gastrointestinal disorders induced by MMF.

Keratinocyte Growth Factor Reduces Injury and Leads to Early Recovery from Cyclophosphamide Bladder Injury

Keratinocyte growth factor (KGF) improves cyclophosphamide-induced bladder injury. To understand the mechanisms, we subcutaneously administered KGF to mice 24 hours before i.p. cyclophosphamide administration, followed by histologic assays and immunostaining. In vehicle (phosphate-buffered saline)-pretreated mice, nonapoptotic superficial cell death from 2 to 6 hours and apoptosis in intermediate and basal cells from 4 to 24 hours was observed after cyclophosphamide. Despite superficial cell loss, KGF suppressed intermediate and basal cell apoptosis, likely via AKT signaling. At 6 and 24 hours after cyclophosphamide, KGF-pretreated mice also had apparent extracellular signal-regulated kinase (ERK)-driven proliferation of mostly keratin 5 (KRT5)+/KRT14- intermediate cells. At 1 to 28 days after cyclophosphamide treatment, mostly KRT14+ basal progenitor cells proliferated in response to injury, peaking at 3 days in both treatment groups; however, proliferation rates were lower in the KGF group at 3 days, consistent with less injury. Three days after injury, unlike controls, KGF-pretreated mice had regenerated superficial cells. At 10 and 28 days after cyclophosphamide treatment, KGF-pretreated mice had little proliferation and marked restoration of urothelial layers, whereas the phosphate-buffered saline group had ongoing regeneration. Administration of KGF to uninjured mice reproduced ERK-driven KRT5+/KRT14- proliferation seen in injured mice; KRT14+ cells were unaffected. KGF pretreatment blocks cyclophosphamide-induced intermediate and basal cell apoptosis, likely by phosphorylated AKT, and drives phosphorylated ERK-mediated KRT5+/KRT14- cell proliferation, leading to early urothelial regeneration.

Protective effects and mechanism of keratinocyte growth factor combined with hypoxia inducible factor-1α on intestinal crypt epithelial cells of rats with hypoxia stress

Protective effects and mechanism of keratinocyte growth factor combined with hypoxia inducible factor-1α on intestinal crypt epithelial cells of rats with hypoxia stress

Adenovirus vector expressing keratinocyte growth factor using CAG promoter impairs pulmonary function of mice with elastase-induced emphysema.

Pulmonary emphysema impairs quality of life and increases mortality. It has previously been shown that administration of adenovirus vector expressing murine keratinocyte growth factor (KGF) before elastase instillation prevents pulmonary emphysema in mice. We therefore hypothesized that therapeutic administration of KGF would restore damage to lungs caused by elastase instillation and thus improve pulmonary function in an animal model. KGF expressing adenovirus vector, which prevented bleomycin-induced pulmonary fibrosis in a previous study, was constructed. Adenovirus vector (1.0 × 109 plaque-forming units) was administered intratracheally one week after administration of elastase into mouse lungs. One week after administration of KGF-vector, exercise tolerance testing and blood gas analysis were performed, after which the lungs were removed under deep anesthesia. KGF-positive pneumocytes were more numerous, surfactant protein secretion in the airspace greater and mean linear intercept of lungs shorter in animals that had received KGF than in control animals. Unexpectedly, however, arterial blood oxygenation was worse in the KGF group and maximum running speed, an indicator of exercise capacity, had not improved after KGF in mice with elastase-induced emphysema, indicating that KGF-expressing adenovirus vector impaired pulmonary function in these mice. Notably, vector lacking KGF-expression unit did not induce such impairment, implying that the KGF expression unit itself may cause the damage to alveolar cells. Possible involvement of the CAG promoter used for KGF expression in impairing pulmonary function is discussed.

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

Data from in-vitro, animal, and human lung injury models suggest that keratinocyte growth factor (KGF) might be beneficial in acute respiratory distress syndrome (ARDS). The objective of this trial was to investigate the effect of KGF in patients with ARDS. We did a double-blind, allocation concealed, randomised, placebo-controlled phase 2 trial in two intensive care units in the UK, involving patients fulfilling the American-European Consensus Conference Definition of ARDS. Patients were randomly assigned (1:1) by computer-generated randomisation schedule with variable block size stratified by site and presence of severe sepsis requiring vasopressors to receive either recombinant human KGF (palifermin 60 μg/kg) or placebo (0·9% sodium chloride solution) daily for a maximum of 6 days. Both patients and investigators were masked to treatment. The primary endpoint was oxygenation index (OI) at day 7. Analyses were by intention to treat. The trial is registered with International Standard Randomised Controlled Trial Registry, number ISRCTN95690673. Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility for inclusion in the trial. Of the 60 patients recruited, 29 patients were randomly assigned to receive KGF and 31 to placebo; all were included in the analysis of the primary outcome. There was no significant difference between the two groups in OI at day 7 (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI -5·6 to 44·0, p=0·13). Of interest, although not defined as outcome measures a priori, the KGF group, compared with placebo, had fewer median ventilator-free days (1 day [IQR 0 to 17] in the KGF group vs 20 days [13-22] in the placebo group; difference -8 days, 95% CI -17 to -2; p=0·0002), a longer median duration of ventilation in survivors to day 90 (16 days [IQR 13-30] in the KGF group vs 11 days [8-16] in the placebo group; difference 6 days, 95% CI 2 to 14; p=0·002), and a higher mortality at 28 days (nine [31%] vs three [10%] deaths; risk ratio 3·2, 95% CI 1·0 to 10·7, p=0·054). Adverse events were more frequent in the KGF group than the placebo group (14 vs 5 events; odds ratio 4·9, 95% CI 1·3 to 20·3, p=0·008). The two adverse events assessed as related to KGF were due to pyrexia. KGF did not improve physiological or clinical outcomes in ARDS and might be harmful to patient health. The Northern Ireland Public Health Agency Research and Development Division.

Adenovirus-Mediated Expression of Keratinocyte Growth Factor Promotes Secondary Flap Necrotic Wound Healing in an Extended Animal Model

No effective treatments have been found for flap necrosis. Animal models that focus on the initial flap viability are inappropriate for necrotic wound studies. Keratinocyte growth factor (KGF) promotes keratinocyte proliferation with stronger activity and fewer complications and thus may be useful for necrotic flap wound healing. Rats with modified flap necrosis were randomly divided into four groups. An adenoviral vector expressing KGF was injected subdermally in the back of the animals after necrosis began. The expression and effect of KGF was assessed by real-time polymerase chain reaction, enzyme-linked immunoassay, and transwell, and wound healing was monitored. The plasmid and adenovirus were able to express KGF and stimulate epithelial cell growth (p = 0.029). Histology showed that the necrosis healed fastest in the KGF administration group than in the control groups (p < 0.01). The adenovirus-mediated KGF (Ad-KGF) group had the thickest epithelium on days 15 (p = 0.044) and 25 (p = 0.014). The KGF level in the blood serum soared 10 and 15 days postoperatively (p < 0.01) but returned to baseline by day 25 (p = 0.561). The KGF mRNA levels in vivo increased dramatically in the Ad-KGF group (p = 0.037). The extended flap model is applicable in necrotic wound study. Keratinocyte growth factor can promote secondary necrotic flap wound healing, and administration of KGF can be achieved by an adenoviral vector.

Keratinocyte Growth Factor Improves Epithelial Structure and Function in a Mouse Model of Intestinal Ischemia/Reperfusion

BackgroundIntestinal ischemia/reperfusion (I/R) induces the desquamation of the intestinal epithelium, increases the intestinal permeability, and in patients often causes fatal conditions including sepsis and multiple organ failure. Keratinocyte growth factor (KGF) increases intestinal growth, although little is known about KGF activity on intestinal function after intestinal I/R. We hypothesized that KGF administration would improve the intestinal function in a mouse model of intestinal I/R.MethodsAdult C57BL/6J mice were randomized to three groups: Sham, I/R group and I/R+KGF group. Mice were killed on day 5, and the small bowel was harvested for histology, wet weight, RNA and protein content analysis. Epithelial cell (EC) proliferation was detected by immunohistochemistry for PCNA, and apoptosis was determined by TUNEL staining. The expressions of Claudin-1 and ZO-1 were detected by immunohistochemistry. Epithelial barrier function was assessed with transepithelial resistance (TER).ResultsKGF significantly increased the intestinal wet weight, contents of intestinal protein and RNA, villus height, crypt depth and crypt cell proliferation, while KGF resulted in the decrease of epithelial apoptosis. KGF also stimulated the recovery of mucosal structures and attenuated the disrupted distribution of TJ proteins. Moreover, KGF attenuated the intestinal I/R-induced decrease in TER and maintained the intestinal barrier function.ConclusionKGF administration improves the epithelial structure and barrier function in a mouse model of intestinal I/R. This suggests that KGF may have clinical applicability.

The protective effect of keratinocyte growth factor on lipopolysaccharide-induced acute lung injury in rat

To investigate the protective effect of keratinocyte growth factor (KGF) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its potential mechanism in rats. Thirty-six Sprague-Dawley (SD) rats were randomly divided into three groups, each group with 12 rats. LPS (5 mg/kg) was injected intravenously to induce ALI in model group, and same amount of normal saline was injected in control group and KGF group. The rats in KGF group were treated with KGF (5 mg/kg) intratracheally after injection of LPS. The rats were sacrificed after 8 hours, histologic assessments, wet/dry weight (W/D) ratio, pulmonary vascular permeability, lung epithelial cell permeability, the proliferation and repair capacity of type II alveolar epithelial cells (ATII) were analyzed. Under optical microscope, it was found that KGF could reduce injury to lung tissue induced by LPS. Compared with the model group, KGF could decrease pulmonary vascular permeability [(0.026+/-0.049)% vs. (0.087+/-0.027)%], lung epithelial cell permeability [(0.692+/-0.017)% vs. (0.931+/-0.029)%] and W/D ratio (4.778+/-0.243 vs. 6.869+/-0.153, P<0.05 or P<0.01), enhance the proliferation and repair capacity of ATII cells (ATII cells: 6.083+/-1.781 vs. 4.666+/-1.923, injury area (mm2): 2.946+/-0.453 vs. 6.181+/-0.975, P<0.05 and P<0.01). KGF could reduce the injury to the lung in LPS-induced ALI, and it plays a protective role through enhancing the proliferation and repair capacity of ATII cells.

Synergism Between Keratinocyte Growth Factor and Carboxymethyl Chitosan Reduces Pericardial Adhesions

Mesothelial injury is the pivot in the development of adhesions. An increase in the proliferation of mesothelial cells was verified by in vitro studies with the use of keratinocyte growth factor (KGF). This study investigated the influence of KGF associated with thermo-sterilized carboxymethyl chitosan (NOCCts) in the reduction of pericardial adhesions. An induction model of pericardial adhesion was carried out in 24 pigs. Animals were randomly allocated to receive topical application of KGF, KGF + NOCCts, NOCCts, or saline (control). At 8 weeks, intrapericardial adhesions were evaluated and a severity score was established. The time spent to dissect the adhesions and the amount of sharp dissection used, were recorded. Histologic sections were stained with sirius red for a morphometric evaluation using a computer-assisted image analysis system. Cytokeratin AE1/AE3 immunostaining were employed to identify mesothelial cells. The severity score expressed in median (minimum to maximum), in relation to the control group (17 [15 to 18]), was lower in the KGF + NOCCts group (7 [6 to 9], p < 0.01) followed by the KGF group (11.5 [9 to 12], 0.01 < p < 0.05) and the NOCCts group (12 [9 to 14], p > 0.05). The dissection time was significantly lower in the KGF + NOCCts group (7.1 + or - 0.6 vs 33.9 + or - 9.2 minutes, p < 0.001). A significantly less sharp dissection was also required in the KGF + NOCCts group. In the adhesion segment, a decreased collagen proportion was found in the KGF + NOCCts group (p < 0.05). Mesothelial cells were present more extensively in groups in which KGF was delivered (p = 0.01). The use of KGF associated with NOCCts resulted in a synergic action that decreases postoperative pericardial adhesions in a highly significant way.

Combining keratinocyte growth factor transfection into the airways and tracheal occlusion in a fetal sheep model of congenital diaphragmatic hernia

In utero tracheal occlusion (TO) has been developed to improve the lung hypoplasia associated with congenital diaphragmatic hernia (CDH). However, although TO stimulates fetal lung growth, it results in a decrease of alveolar type II cells (ATII) and surfactant production. Because keratinocyte growth factor (KGF) is a potent stimulus of ATII proliferation and maturation, we evaluated, in a fetal lamb model of CDH, a gene therapy strategy combining TO and ovine KGF transfection into the fetal airways using bisguanidinium-tren-cholesterol/dioleoyl-phosphatidylethanolamine (BGTC/DOPE) cationic liposomes. Three groups of sheep fetuses with CDH and a group of normal fetuses were studied. The fetuses of the three groups with CDH (KGF, Medium and Hernia groups) underwent surgery at 85 days of gestation to create a diaphragmatic hernia. The KGF and medium group fetuses underwent a second surgery step at day 125 to perform TO associated with injection of the KGF transfection mixture (KGF group) or control medium (Medium group), whereas the fetuses of the Hernia group were left untreated. Normal fetuses were used as a control (Normal group). All fetuses were euthanized at 132 days of gestation and various analytical studies [lung weight, radial alveolar count (RAC), KGF and surfactant protein B (SPB) expression, number of ATII cells] were performed to assess the efficiency of KGF transfection and its effects on fetal lung development. TO was associated with lung hyperplasia and increased RAC in the Medium and KGF groups versus the Hernia group. Expression of KGF was increased in the KGF group compared to all other groups and was associated with an increased synthesis of SPB by alveolar cells and an ectopic synthesis of SPB by bronchiolar cells compared to TO treatment alone. Thus, BGTC/DOPE liposomes can mediate efficient KGF transfection into the airways in a fetal sheep model of CDH. Furthermore, combining KGF transfection and TO resulted not only (as did TO alone) in the correction of the CDH-associated lung hypoplasia and decreased RAC, but also in increased SPB synthesis, suggesting a better maturation of the re-growing lung (compared to TO alone). Additional studies are required to further explore the therapeutic potential of such a combined strategy; in particular, studies evaluating the lung function of in utero-treated CDH lamb newborns.

Keratinocyte growth factor: a new mesothelial targeted therapy to reduce postoperative pericardial adhesions☆

Several methods have been utilized to prevent pericardial and retrosternal adhesions, but none of them evaluated the mesothelial regenerative hypothesis. There are evidences that the mesothelial trauma reduces pericardial fibrinolytic capability and induces an adhesion process. Keratinocyte growth factor (KGF) has proven to improve mesothelial cells proliferation. This study investigated the influence of keratinocyte growth factor in reducing post-surgical adhesions. Twelve pigs were operated and an adhesion protocol was employed. Following a stratified randomization, the animals received a topical application of KGF or saline. At 8 weeks, intrapericardial adhesions were evaluated and a severity score was established. The time spent to dissect the adhesions and the amount of sharp dissection used, were recorded. Histological sections were stained with sirius red and morphometric analyses were assessed with a computer-assisted image analysis system. The severity score was lower in the KGF group than in the control group (11.5 vs 17, p=0.005). The dissection time was lower in the KGF group (9.2+/-1.4 min vs 33.9+/-9.2 min, p=0.004) and presented a significant correlation with the severity score (r=0.83, p=0.001). A significantly less sharp dissection was also required in the KGF group. Also, adhesion area and adhesion collagen were significantly lower in the KGF group than in the control group. The stimulation of pericardial cells with KGF reduced the intensity of postoperative adhesions and facilitated the re-operation. This study suggests that the mesothelial regeneration is the new horizon in anti-adhesion therapies.

Keratinocyte Growth Factor Increases Thymic Output of Naïve T-Cells after Total Body Irradiation and Autologous Peripheral Blood Progenitor Cell Transplantation in Rhesus Macaques.

Opportunistic infections have an major impact on morbidity and mortality after peripheral blood progenitor cell transplantation, and are caused by deficient T cell numbers and activities, which correlate with thymic dysfunction. Keratinocyte growth factor (KGF) has been shown to protect thymic epithelial cells from injury induced by chemotherapy and radiation in mice, associated with improved thymopoiesis. We for the first time evaluated the effect of KGF on immune reconstitution after myeloablative total body irradiation (TBI) and autologous transplantation in non-human primates, a clinically relevant large animal model. Four animals received KGF 250mg/kg body weight given once (day −5) before TBI (low dose KGF) and CD34+ purified PBPC transplantation, and two animals received the same dose given 3 times (day −5, −4, −3) before and 3 times (day +1, +2, +3) after TBI (day −2, −1) and transplantation (day 0) (high-dose KGF). These KGF-treated animals were compared to an age and CD34+ cell dose-matched control group of five monkeys transplanted with purified CD34+ cells but without KGF treatment. We evaluated the reconstitution of T and B cells in blood and lymph nodes (LN) for a year post transplantation. All animals engrafted (neutrophils >500/ml) day by day 11 post transplantation. The animals treated with KGF had higher frequencies of naïve T cells in blood and in peripheral LN post transplantation as compared to the control animals, for instance at one month after transplantation the percentage of LN naïve CD4+ T-cells was 35±19% in the high dose KGF group, 14±2% in the low dose KGF group and 15±4% in the control group. At 3 months after transplantation the percentage of naïve CD4+ in LN was 56±5% in the high dose and 59±9% in the low dose KGF groups versus 27±7% in the control group. We observed similar findings in the CD8+ subset. All KGF treated animals had higher peripheral blood TREC levels, broader TCR repertoires as determined by spectratyping of the CDR3 region, and lower frequencies of Ki-67+ proliferating T cells, presumably due to a lower drive for peripheral expansion in animals with better thymic output of naïve T cells. The recovery of circulating B-cells was not altered with KGF treatment compared to the controls. At 12 months after transplantation there was uniform preservation of thymic architecture with proliferating thymocytes in the animals treated with KGF, in comparison to the control group of animals, with thymic atrophy seen in the majority. Thus, peri-TBI treatment with KGF resulted in protection of thymic epithelial cells, improved thymic repopulation, and increased naïve T-cell numbers in secondary lymphatic tissues, and correlated with better immune responses to newly induced (HIV envelope) as well as recall antigens including measles and CMV. KGF-mediated protection and preservation of thymic epithelial cells from TBI-mediated damage, with improved output of naïve T cells post-transplantation may improve immune reconstitution and thus outcomes in patients undergoing autologous or allogeneic transplantation.

Effect of exogenous keratinocyte growth factor on corneal epithelial migration after photorefractive keratectomy

Purpose: To investigate the effect of topical keratinocyte growth factor (KGF) on wound healing after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). Setting: Department of Ophthalmology, Rayne Institute, St. Thomas' Hospital, London, United Kingdom, St. Erick's Eye Hospital, Stockholm, Sweden, and the University of Regensberg, Regensberg, Germany. Methods: In a placebo-controlled trial, 24 New Zealand white female rabbits were divided into 3 equal groups. Group 1 (n = 8) had myopic PRK (6.0 diopters [D]) using the Technolas® 217z laser (Bausch & Lomb). Group 2 and Group 3 had myopic LASIK (6.0 D) with a flap depth of 140 μm and 180 μm, respectively. Topical KGF (20 μg/mL) was administered to half the treated eyes in each group intraoperatively and postoperatively; the other half received placebo eyedrops. Epithelial closure, corneal haze, and keratocyte activation in the rabbit eyes were analyzed and compared with those in placebo-controlled eyes for 5 weeks postoperatively. Results: In Group 1, the mean reepithelialization after PRK was 0.10 mm 2/h ± 0.02 (SD) in the KGF group and 0.33 ± 0.05 mm 2/h in the control group ( P = .001). There was no significant difference in the mean backscatter between the KGF eyes (154 ± 45.95) and the control eyes (141 ± 38.45) after PRK ( P = .42). Histology revealed reduced epithelial cell layers in the KGF group and comparable keratocyte density as in the control group. In Groups 2 and 3, there was no significant difference in backscatter, epithelial layers, and keratocyte density between KGF and control eyes after LASIK. Conclusions: Topical KGF (20 μg/mL) delayed reepithelialization after PRK. It had no effect on stromal wound healing in LASIK eyes with an intact epithelial barrier.

Keratinocyte growth factor pretreatment is associated with decreased macrophage inflammatory protein-2alpha concentrations and reduced neutrophil recruitment in acid aspiration lung injury.

A two-hit model of acid aspiration was used to examine the effect of keratinocyte growth factor (KGF) on chemokine levels and neutrophil recruitment into the lung. Mice were subjected to cecal ligation and puncture and then either KGF or saline, intratracheally (i.t.). Forty-eight hours later, the mice were given i.t. acid. After 8 h, neutrophil counts in bronchoalveolar lavage (BAL) fluid were significantly decreased in animals pretreated with KGF (23 +/- 4 x 10(3)/mouse) compared with saline (74 +/- 2 x 10(3)/mouse). In addition, the BAL fluid IL-6 levels were decreased in the KGF-treated group (88+/- 44 pg/mL) compared with the saline group (166 +/- 34 pg/mL). To examine the mechanism behind the KGF-induced reduction in neutrophil influx, the murine chemokines KC and macrophage inflammatory protein (MIP)-2alpha were measured. KC levels in plasma and BAL fluid were not significantly different between the treatment groups. Likewise, levels of MIP-2alpha in plasma were not affected by KGF treatment. However, 8 h after acid aspiration, MIP-2alpha concentrations were significantly lower in the KGF-treated group. The ratio of MIP-2alpha in BAL fluid versus plasma was lower in the KGF group (0.72 +/- 0.28) than in the saline group at 3 h (2.23 +/- 0.93) and also significantly lower in the KGF group (3.02 +/- 0.78) compared with the saline group (6.23 +/- 1.19) at 8 h. In this study, KGF pretreatment after acid aspiration was associated with reduced neutrophil recruitment into the lung and a decrease in MIP-2alpha gradients between BAL fluid and plasma.

Keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model.

Mechanical ventilation has been shown to produce lung injury characterized by noncardiogenic pulmonary edema. Keratinocyte growth factor (KGF) is a heparin-binding growth factor that causes alveolar type II pneumocyte hyperplasia. KGF pretreatment and the resultant pneumocyte hyperplasia reduce fluid flux in models of lung injury. We utilized the isolated perfused rat lung model to produce lung injury by varying tidal volume and the level of positive end-expiratory pressure during mechanical ventilation. Pretreatment with KGF attenuated ventilator-induced lung injury (VILI). This was demonstrated by lower wet-to-dry lung weight ratios and less lung water accumulation in the KGF group. Further, KGF prevented the decline in dynamic compliance and alveolar protein accumulation in VILI. KGF pretreatment reduced alveolar accumulation of intravascularly administered fluorescein isothiocyanate-labeled high-molecular-weight dextran. Thus, pretreatment with KFG attenuates injury in this ex vivo model of VILI via mechanisms that prevent increases in permeability.

Keratinocyte growth factor ameliorates dextran sodium sulfate colitis in mice.

Keratinocyte growth factor (KGF) is emerging as an important mediator of mucosal defense and repair in the colon. The aim of the present study was to evaluate and further characterize the effects of exogenous KGF administration utilizing the dextran sodium sulfate (DSS) model of colitis in mice. Colitis was induced via oral administration of DSS (5 g/100 ml) to Balb/c mice for eight days. Intraperitoneal administration of KGF (5 mg/kg, once daily) or vehicle (VEH) was initiated 1 hr prior to the induction of the colitis (N = 10, each group). Mucosal injury of the entire colon was histologically assessed and graded. An approximately fourfold reduction in the crypt damage score was noted in the KGF group when compared to controls (VEH) (2.8 +/- 1.03 and 11.4 +/- 0.78, respectively). The significant reduction of mucosal injury in KGF treated mice confirms that KGF is a key mediator maintaining the integrity of the colonic mucosa.