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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats. 756 96

Keratinocyte growth factor (KGF) has recently been shown to protect rats from hyperoxia-induced lung injury. However, the mechanism of the protective effect of KGF remains unclear. To elucidate the mechanism of action of KGF, we determined the effect of KGF on the barrier function of epithelial monolayers exposed to H(2)O(2). Calu-3 (human airway epithelial cells) were grown on Transwell membranes, and the permeability to fluorescein isothiocyanate-albumin was measured. Exposure to 0.5 mM H(2)O(2) significantly increased permeability from 1.50 +/- 0.09 to 24.8 +/- 1.5 (mean +/- SE x 10(-6) cm/s; P < 0.001). Incubation of monolayers with 50 ng/ml KGF for 24 h significantly reduced basal albumin flux (0.85 +/- 0.09; P < 0.001), and pretreatment with KGF completely abolished the H(2)O(2)-induced permeability increase (1.08 +/- 0.09). The protective effect of KGF was dose dependent and was observed at concentrations as low as 1 ng/ml. Partial amelioration of the H(2)O(2)-induced permeability increase occurred after 1 h of exposure to KGF. Treatment of cells with calphostin C, an inhibitor of protein kinase C (PKC), had no effect on the permeability of control or H(2)O(2)-treated cells. Calphostin C abolished both the KGF-mediated decrease in basal albumin flux and the protective effect of KGF against H(2)O(2)-induced increases in permeability. KGF pretreatment also prevented H(2)O(2)-induced disruption of F-actin staining patterns, suggesting stabilization of the cytoskeleton. These studies demonstrate that KGF decreases albumin flux across airway epithelial monolayers and prevents H(2)O(2)-induced increases in permeability by a PKC-dependent process that may involve stabilization of the cytoskeleton.
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PMID:KGF prevents hydrogen peroxide-induced increases in airway epithelial cell permeability. 914 42

Keratinocyte growth factor (KGF) administered by intratracheal instillation is well documented to stimulate the proliferation of alveolar and bronchial cells. In the present study, intravenous KGF was also shown to stimulate the proliferation of alveolar and bronchial cells in mice and rats, although to a lesser degree than intratracheal KGF. Despite the decreased potency of intravenous KGF on pulmonary cell 5-bromo-2'-deoxyuridine incorporation compared with intratracheal KGF, intravenous KGF was very effective in preventing experimental bleomycin-induced pulmonary dysfunction, weight loss, and mortality in either mice or rats and experimental hyperoxia-induced mortality in mice. The effectiveness of intravenous administration of KGF in preventing lung injury suggests that the mechanisms of the protective effect of KGF may involve more than pulmonary cell proliferation and also suggests the potential use of systemic KGF for clinical trials in settings of pulmonary injury.
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PMID:Intravenous keratinocyte growth factor protects against experimental pulmonary injury. 975 13

Keratinocyte growth factor (KGF) has been used successfully to prevent alveolar damage induced by oxygen exposure in rodents. However, this treatment was used intratracheally and before oxygen exposure, which limited its clinical application. In the present study, mice were treated with the recombinant human KGF intravenously before (days -2 and -1) or during (days 0 and +1) oxygen exposure. In both cases, lung damage was attenuated. KGF increased the number of cells incorporating bromodeoxyuridine (BrdU) in the septa and in bronchial epithelium of air-breathing mice but not of oxygen-exposed mice, indicating that the protective effect of KGF is not necessarily associated with proliferation. Oxygen-induced damage of alveolar epithelium and, unexpectedly, of endothelium was prevented by KGF treatment as seen by electron microscopy. We investigated the effect of KGF on different mechanisms known to be involved in oxygen toxicity. The induction of p53, Bax, and Bcl-x mRNAs during hyperoxia was to a large extent prevented by KGF. Surfactant proteins A and B mRNAs were not markedly modified by KGF. The anti-fibrinolytic activity observed in the alveoli during hyperoxia was to a large extent prevented by KGF, most probably by suppressing the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. As PAI-1 -/- mice are more resistant to hyperoxia, KGF might act, at least in part, by decreasing the expression of this protease inhibitor and by restoring the fibrinolytic activity into the lungs.
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PMID:Keratinocyte growth factor protects alveolar epithelium and endothelium from oxygen-induced injury in mice. 1032 1

The survival of type 2 alveolar epithelial cells (AEC2) in the lung after hyperoxic injury is regulated by signals from the cellular environment. Keratinocyte growth factor and Matrigel can ameliorate the hallmarks of apoptosis seen in hyperoxic AEC2 after 24-h culture on plastic [S. Buckley, L. Barsky, B. Driscoll, K. Weinberg, K. D. Anderson, and D. Warburton. Am. J. Physiol. 274 (Lung Cell. Mol. Physiol. 18): L714-L720, 1998]. We used the same model of in vivo short-term hyperoxia to characterize the protective effects of substrate attachment. Culture of hyperoxic AEC2 on various biological adhesion substrates showed reduced DNA end labeling in cells grown on all biological substrates compared with growth on plastic. In contrast, the synthetic substrate poly-D-lysine conferred no protection. Hyperoxic AEC2 cultured on laminin showed an increased ratio of expression of Bcl-2 to interleukin-1beta-converting enzyme compared with culture on plastic. Laminin also partially restored hyperoxia-depleted glutathione levels and conferred improved optimal mitochondrial viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Conversely, attachment to the nonphysiological substrate poly-D-lysine afforded no such protection, suggesting that protection against hyperoxia-induced damage may be associated with integrin signaling. Increased activation of extracellular signal-regulated kinase (ERK), as detected by increased ERK tyrosine phosphorylation, was seen in hyperoxic AEC2 as soon as the cells started to attach to laminin and was sustained after 24 h of culture in contrast to that in control AEC2. To confirm that protection against DNA strand breakage and apoptosis was being conferred by ERK activation, the cells were also plated in the presence of 50 microM PD-98059, an inhibitor of the ERK-activating mitogen-activating kinase. Culture for 24 h with PD-98059 abolished the protective effect of laminin. We speculate that after hyperoxic lung injury, signals through the basement membrane confer specific protection against oxygen-induced DNA strand breakage and apoptosis through an ERK activation-dependent pathway.
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PMID:ERK activation protects against DNA damage and apoptosis in hyperoxic rat AEC2. 1040 43

Transforming growth factor alpha (TGF(alpha)) stimulates type II alveolar epithelial cell proliferation and also is associated with fibrosis. We studied the changes in bronchoalveolar lavage (BAL) TGF(alpha) protein in a neonatal rabbit hyperoxia-fibrosis model (100% O(2) for 8 to 9 days, followed by 60% O(2) to 36 days of age). Hyperoxia increased TGF(alpha) protein and delayed the appearance of mature lower molecular weight (MW) TGF(alpha) isoforms at postnatal days 6 and 8 during the acute injury period. At 3 and 5 weeks, after chronic hyperoxia exposure, there was an increase in lower MW TGF(alpha) peptides during the fibrotic period. Keratinocyte growth factor (KGF) is also a type II cell mitogen. In vitro studies of keratinocytes suggest that KGF-induced proliferation is mediated through TGF(alpha). Intratracheal KGF instillation into adult wild-type and TGF(alpha)-null mice demonstrated that the KGF induced equivalent robust levels of proliferation in both TGF(alpha) deficient and wild-genotype mice. In conclusion, there are both quantitative and qualitative changes in TGF(alpha) protein in a hyperoxia-induced fibrosis neonatal rabbit model during periods of type II cell proliferation and fibrosis.
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PMID:Transforming growth factor alpha (TGF(alpha)) is increased during hyperoxia and fibrosis. 1209 30