Keratinocyte growth factor can enhance alveolar epithelial repair by nonmitogenic mechanisms

2002 ◽  
Vol 283 (1) ◽  
pp. L163-L169 ◽  
Author(s):  
Kamran Atabai ◽  
Masanobu Ishigaki ◽  
Thomas Geiser ◽  
Iris Ueki ◽  
Michael A. Matthay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Keratinocyte Growth Factor ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Epithelial Repair ◽  
Alveolar Epithelial ◽  
And Migration

Pretreatment with keratinocyte growth factor (KGF) ameliorates experimentally induced acute lung injury in rats. Although alveolar epithelial type II cell hyperplasia probably contributes, the mechanisms underlying KGF's protective effect remain incompletely described. Therefore, we tested the hypothesis that KGF given to rats in vivo would enhance alveolar epithelial repair in vitro by nonproliferative mechanisms. After intratracheal instillation (48 h) of KGF (5 mg/kg), alveolar epithelial type II cells were isolated for in vitro alveolar epithelial repair studies. KGF-treated cells had markedly increased epithelial repair (96 ± 22%) compared with control cells ( P < 0.001). KGF-treated cells had increased cell spreading and migration at the wound edge but no increase in in vitro proliferation compared with control cells. KGF-treated cells were more adherent to extracellular matrix proteins and polystyrene. Inhibition of the epidermal growth factor (EGF) receptor with tyrosine kinase inhibitors abolished the KGF effect on epithelial repair. In conclusion, in vivo administration of KGF augments the epithelial repair rate of alveolar epithelial cells by altering cell adherence, spreading, and migration and through stimulation of the EGF receptor.

Gene transfer of hepatocyte growth factor by electroporation reduces bleomycin-induced lung fibrosis

2007 ◽  
Vol 292 (2) ◽  
pp. L529-L536 ◽  
Author(s):  
Amiq Gazdhar ◽  
Patrick Fachinger ◽  
Coretta van Leer ◽  
Jaroslaw Pierog ◽  
Mathias Gugger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gene Transfer ◽  
Pulmonary Fibrosis ◽  
Wound Repair ◽  
Alveolar Epithelial Cells ◽  
Epithelial Repair ◽  
Alveolar Epithelial ◽  
Hepatocyte Growth

Abnormal alveolar wound repair contributes to the development of pulmonary fibrosis after lung injury. Hepatocyte growth factor (HGF) is a potent mitogenic factor for alveolar epithelial cells and may therefore improve alveolar epithelial repair in vitro and in vivo. We hypothesized that HGF could increase alveolar epithelial repair in vitro and improve pulmonary fibrosis in vivo. Alveolar wound repair in vitro was determined using an epithelial wound repair model with HGF-transfected A549 alveolar epithelial cells. Electroporation-mediated, nonviral gene transfer of HGF in vivo was performed 7 days after bleomycin-induced lung injury in the rat. Alveolar epithelial repair in vitro was increased after transfection of wounded epithelial monolayers with a plasmid encoding human HGF, pCikhHGF [human HGF (hHGF) gene expressed from the cytomegalovirus (CMV) immediate-early promoter and enhancer] compared with medium control. Electroporation-mediated in vivo HGF gene transfer using pCikhHGF 7 days after intratracheal bleomycin reduced pulmonary fibrosis as assessed by histology and hydroxyproline determination 14 days after bleomycin compared with controls treated with the same vector not containing the HGF sequence (pCik). Lung epithelial cell proliferation was increased and apoptosis reduced in hHGF-treated lungs compared with controls, suggesting increased alveolar epithelial repair in vivo. In addition, profibrotic transforming growth factor-β1 (TGF-β1) was decreased in hHGF-treated lungs, indicating an involvement of TGF-β1 in hHGF-induced reduction of lung fibrosis. In conclusion, electroporation-mediated gene transfer of hHGF decreases bleomycin-induced pulmonary fibrosis, possibly by increasing alveolar epithelial cell proliferation and reducing apoptosis, resulting in improved alveolar wound repair.

In Vivo and in Vitro Expression of Metallothionein in Injured Type II Alveolar Epithelial Cells

CHEST Journal ◽  
1994 ◽  
Vol 105 (3) ◽  
pp. 78S
Author(s):  
Bruce Piedboeuf ◽  
William Maniscalco ◽  
Stephen Hall ◽  
Maura Campbell ◽  
Richard Watkins ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
In Vitro Expression ◽  
Alveolar Epithelial

scholarly journals Keratinocyte growth factor reduces alveolar epithelial susceptibility to in vitro mechanical deformation

2001 ◽  
Vol 281 (5) ◽  
pp. L1068-L1077 ◽  
Author(s):  
Jane Oswari ◽  
Michael A. Matthay ◽  
Susan S. Margulies
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Lung Injury ◽  
Keratinocyte Growth Factor ◽  
Alveolar Type ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
And Control

Keratinocyte growth factor (KGF) is a potent mitogen that prevents lung epithelial injury in vivo. We hypothesized that KGF treatment reduces ventilator-induced lung injury by increasing the alveolar epithelial tolerance to mechanical strain. We evaluated the effects of in vivo KGF treatment to rats on the response of alveolar type II (ATII) cells to in vitro controlled, uniform deformation. KGF (5 mg/kg) or saline (no-treatment control) was instilled intratracheally in rats, and ATII cells were isolated 48 h later. After 24 h in culture, both cell groups were exposed to 1 h of continuous cyclic strain (25% change in surface area); undeformed wells were included as controls. Cytotoxicity was evaluated quantitatively with fluorescent immunocytochemistry. There was >1% cell death in undeformed KGF-treated and control groups. KGF pretreatment significantly reduced deformation-related cell mortality to only 2.2 ± 1.3% (SD) from 49 ± 5.5% in control wells ( P < 0.001). Effects of extracellular matrix, actin cytoskeleton, and phenotype of KGF-treated and control cells were examined. The large reduction in deformation-induced cell death demonstrates that KGF protects ATII cells by increasing their strain tolerance and supports KGF treatment as a potential preventative measure for ventilator-induced lung injury.

Alveolar epithelial type II cell apoptosis in vivo during resolution of keratinocyte growth factor-induced hyperplasia in the rat

2000 ◽  
Vol 114 (1) ◽  
pp. 49-61 ◽  
Author(s):  
Heinz Fehrenbach ◽  
Michael Kasper ◽  
Roland Koslowski ◽  
Tianli Pan ◽  
Dieter Schuh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Apoptosis ◽  
Keratinocyte Growth Factor ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Type Ii Cell

Migration and gelatinases in cultured fetal, adult, and hyperoxic alveolar epithelial cells

2001 ◽  
Vol 281 (2) ◽  
pp. L427-L434 ◽  
Author(s):  
S. Buckley ◽  
B. Driscoll ◽  
W. Shi ◽  
K. Anderson ◽  
D. Warburton
Keyword(s):  
Growth Factor ◽  
Lung Development ◽  
Alveolar Epithelial Cell ◽  
Lung Cancer Cell Line ◽  
Alveolar Epithelial Cells ◽  
Migratory Activity ◽  
Alveolar Epithelial ◽  
Control Adult

Alveolar epithelial cell (AEC) migration mediated by matrix metalloproteinases (MMPs) is required for lung development and repair after injury such as hyperoxia. Of specific interest in lung remodeling are the gelatinases, which are upregulated in AEC after hyperoxia. We correlated migration and gelatinase production in AEC cultured from fetal, adult, and hyperoxic rats. Fetal AEC (19–20 days) had higher MMP-2 and MMP-9 gelatinase expression than adult AEC, with fivefold higher MMP-9 activity, and were migratory through gelatin, responding to epidermal growth factor, keratinocyte growth factor, and fibroblast growth factor-10. MMP-2 and MMP-9 expression and migratory activity could be detected from the time of plating. In contrast, adult AEC migrated and expressed MMP-2 and MMP-9 proteins only after 48 h of culture. AEC from hyperoxic rats were significantly more migratory through gelatin than control adult AEC, with significantly higher MMP-9 activity. Inhibition of MMPs with doxycycline reduced the migration of AEC from hyperoxic rats to the level of control adult AEC. Fibronectin-cultured “hyperoxic” AEC acquired a temporary capacity for migration similar to the A549 lung cancer cell line, which is both highly migratory and invasive and is derived from the AEC type 2 lineage. These data suggest that MMP activity is associated with a migratory phenotype in fetal, hyperoxic, and transformed AEC in vitro, and we speculate that MMPs may play a key mechanistic role in AEC migration in vivo during lung development and repair.

Keratinocyte growth factor promotes cell motility during alveolar epithelial repair in vitro

2003 ◽  
Vol 283 (2) ◽  
pp. 215-229 ◽  
Author(s):  
Stéphane Galiacy ◽  
Emmanuelle Planus ◽  
Hélène Lepetit ◽  
Sophie Féréol ◽  
Valérie Laurent ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Motility ◽  
Keratinocyte Growth Factor ◽  
Epithelial Repair ◽  
Alveolar Epithelial

In vivo and in vitro expression of metallothionein in injured type II alveolar epithelial cells

1993 ◽  
Vol 15 (5) ◽  
pp. 503
Author(s):  
S. Horowitz ◽  
B. Piedboeuf ◽  
W. Maniscalco ◽  
S. Hall ◽  
M. Campbell ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
In Vitro Expression ◽  
Alveolar Epithelial

scholarly journals Pulmonary effects of keratinocyte growth factor in newborn rats exposed to hyperoxia

2009 ◽  
Vol 297 (5) ◽  
pp. L965-L976 ◽  
Author(s):  
Marie-Laure Franco-Montoya ◽  
Jacques R. Bourbon ◽  
Xavier Durrmeyer ◽  
Stéphanie Lorotte ◽  
Pierre-Henri Jarreau ◽  
...  
Keyword(s):  
Growth Factor ◽  
Therapeutic Potential ◽  
Alveolar Epithelial Cell ◽  
Keratinocyte Growth Factor ◽  
Alveolar Epithelial Cells ◽  
Cell Protection ◽  
Repair Capacity ◽  
Alveolar Epithelial ◽  
Neonatal Lung

Acute lung injury and compromised alveolar development characterize bronchopulmonary dysplasia (BPD) of the premature neonate. High levels of keratinocyte growth factor (KGF), a cell-cell mediator with pleiotrophic lung effects, are associated with low BPD risk. KGF decreases mortality in hyperoxia-exposed newborn rodents, a classic model of injury-induced impaired alveolarization, although the pulmonary mechanisms of this protection are poorly defined. These were explored through in vitro and in vivo approaches in the rat. Hyperoxia decreased by 30% the rate of wound closure of a monolayer of fetal alveolar epithelial cells, due to cell death, which was overcome by recombinant human KGF (100 ng/ml). In rat pups exposed to >95% O2 from birth, increased viability induced by intraperitoneal injection of KGF (2 μg/g body wt) every other day was associated with prevention of neutrophil influx in bronchoalveolar lavage (BAL), prevention of decreases in whole lung DNA content and cell proliferation rate, partial prevention of apoptosis increase, and a markedly increased proportion of surfactant protein B-immunoreactive cells in lung parenchyma. Increased lung antioxidant capacity is likely to be due in part to enhanced CAAT/enhancer binding protein α expression. By contrast, KGF neither corrected changes induced by hyperoxia in parameters of lung morphometry that clearly indicated impaired alveolarization nor had any significant effect on tissue or BAL surfactant phospholipids. These findings evidence KGF alveolar epithelial cell protection, enhancing effects on alveolar repair capacity, and anti-inflammatory effects in the injured neonatal lung that may account, at least in part, for its ability to reduce mortality. They argue in favor of a therapeutic potential of KGF in the injured neonatal lung.

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