Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p21WAF/CIP1 is an important regulator of cell cycle progression (1-4). When induced, p21WAF/CIP1 protein inhibits cell cycle progression at the G1/S interface, resulting in growth arrest of the cell. To determine if p21WAF/CIP1 is involved in growth arrest and lung injury during hyperoxia, several cell lines were exposed to high levels of hyperoxia. p21WAF/CIP1 was found to be induced by 72 h in all three cell lines. Next, using an in vivo model, p21WAF/CIP1 was found to be induced at both the mRNA and protein level in neonatal murine lung born and maintained in hyperoxia. Localization of p21WAF/CIP1 was found in the peripheral airway cells. Hyperoxia-induced p21WAF/CIP1 expression was then shown to be mediated through the p53 pathway, using adult p53 mutant mice. These studies demonstrated that p21WAF/CIP1 is induced both in cells grown in culture and in neonatal and adult lung exposed to high levels of hyperoxia. Localization of p21WAF/CIP1 expression to the peripheral airway cells suggests that p21WAF/CIP1 may act to inhibit growth of alveoli in neonatal lung and delay repopulation of alveolar cells during hyperoxic administration.
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PMID:Induction of p21WAF/CIP1 during hyperoxia. 947 4

Hyperoxia increases free radical production, leading to DNA damage. Recent studies indicate that oxygen augments the expression of p53 and p21(WAF1/CIP1), and increases apoptotic labeling of airway epithelial cells. Similar changes in regulatory gene products have not been reported in other pulmonary cells, nor have these changes been investigated in conjunction with alterations in cell-cycle distribution. The present study was conducted to determine whether oxygen alters the expression of p53 and p21(WAF1/CIP1) in human bronchial smooth-muscle cells (BSMC). BSMC placed in room air (RA), 40% O(2), or 95% O(2) were examined for 3 d to determine cell number, thymidine incorporation, cell-cycle distribution, and lactate dehydrogenase release. Apoptosis was assessed through the terminal deoxynucleotidyl transferase-deoxyuridine triphosphate end-nick labeling (TUNEL) technique, and p53 and p21(WAF1/CIP1) protein levels were determined through enzyme-linked immunosorbent assay. Exposure of BSMC to 95% O(2) decreased proliferation and DNA synthesis within 24 h, and was accompanied by an increase in S-phase cells (72 h; RA: 12.9 +/- 4.6%, versus 95% O(2): 34.6 +/- 7.0%; P < 0.01). By comparison, exposure to 40% O(2) resulted in decreased proliferation at 48 h without significant alterations in cell-cycle distribution. Both p53 and p21(WAF1/CIP1) levels were increased by 95% O(2), with maximal differences noted at 24 and 48 h, respectively. All atmospheres showed < 8% cell death and few TUNEL-positive cells. Our results indicate that oxygen-mediated alterations in BSMC proliferation are time- and concentration-dependent. Furthermore, high oxygen levels induce S-phase arrest and increased expression of p53 and p21(WAF1/CIP1). Activation of these genes may prevent replication without inducing apoptosis to allow for the repair of oxidative damage.
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PMID:Oxygen induces S-phase growth arrest and increases p53 and p21(WAF1/CIP1) expression in human bronchial smooth-muscle cells. 1046 Jul 57

This study explores the role of ERK activation in regulating G(1) and S-G(2)/M delays during hyperoxia. We demonstrate here that exposing A549 human alveolar type 2 adenocarcinoma cells to hyperoxia (95% O(2)) for 0.5-24 h time-dependently increases phospho-ERK, phospho-p53(Ser15), p53, and p21(CIP1) protein levels. Decreasing phospho-ERK with the pharmacological inhibitors, PD98059 and U0126, markedly suppresses hyperoxia-stimulated phospho-p53(Ser15), p53, and p21(CIP1), and also restores the hyperoxia-reduced kinase activities of cyclin D1/E1-Cdks. Our results suggest that ERK activation during hyperoxia contributes to the p53/p21-mediated G(1) checkpoint. However, inhibition of ERK signaling during hyperoxia further delays S-phase entry and progression. Hyperoxia induces significant expression of cyclin A/B1 and translocation of cyclin A into nuclei while marginally decreasing cyclin A/B1-Cdks kinase activities, which may be related to nuclear association with p21. Interestingly, inhibition of ERK signaling markedly suppresses the elevation of cyclin A/B1 proteins and cyclin A/B1-Cdks kinase activities during hyperoxia. Taken together, the results presented here suggest that hyperoxia-activated ERK acts upstream of p53 and p21 to suppress G(1)-Cdk activities; however, it is also required for induction of cyclin A/B1 and maintenance of cyclin A/B1-Cdk activities that oppose delays in S-phase entry and progression.
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PMID:Dual and opposing roles of ERK in regulating G(1) and S-G(2)/M delays in A549 cells caused by hyperoxia. 1521 49

Lung epithelium in cystic fibrosis (CF) patients is characterized by structural damage and altered repair due to oxidative stress. To gain insight into the oxidative stress-related damage in CF, we studied the effects of hyperoxia in CF and normal lung epithelial cell lines. In response to a 95% O2 exposure, both cell lines exhibited increased reactive oxygen species. Unexpectedly, the cyclin-dependent kinase inhibitor p21WAF1/CIP1 protein was undetectable in CF cells under hyperoxia, contrasting with increased levels of p21WAF1/CIP1 in normal cells. In both cell lines, exposure to hyperoxia led to S-phase arrest. Apoptotic features including nuclear condensation, DNA laddering, Annexin V incorporation, and elevated caspase-3 activity were not readily observed in CF cells in contrast to normal cells. Interestingly, treatment of hyperoxia-exposed CF cells with two proteasome inhibitors, MG132 and lactacystin, restored p21WAF1/CIP1 protein and was associated with an increase of caspase-3 activity. Moreover, transfection of p21WAF1/CIP1 protein in CF cells led to increased caspase-3 activity and was associated with increased apoptotic cell death, specifically under hyperoxia. Taken together, our data suggest that modulating p21WAF1/CIP1 degradation may have the therapeutic potential of reducing lung epithelial damage related to oxidative stress in CF patients.
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PMID:Oxidative stress response results in increased p21WAF1/CIP1 degradation in cystic fibrosis lung epithelial cells. 1633 81