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

We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.
 ...
PMID:GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress. 1689 99

Pulmonary expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) is critically important for normal functional maturation of alveolar macrophages. We found previously that lung GM-CSF is dramatically suppressed in mice exposed to hyperoxia. Alveolar epithelial cells (AEC) are a major source of GM-CSF in the peripheral lung, and in vivo hyperoxia resulted in greatly reduced expression of GM-CSF protein by AEC ex vivo. We now explore the mechanisms responsible for this effect, using primary cultures of murine AEC exposed to hyperoxia in vitro. Exposure of AEC to 80% oxygen/5% CO(2) for 48 h did not induce overt toxicity, but resulted in significantly decreased GM-CSF protein and mRNA expression compared with cells in normoxia. Similar effects were seen when AEC were stressed with serum deprivation, an alternative inducer of oxidative stress. The effects in AEC were opposite those in a murine lung epithelial cell line (MLE-12 cells), in which hyperoxia induced GM-CSF expression. Both hyperoxia and serum deprivation resulted in increased intracellular reactive oxygen species (ROS) in AEC. Hyperoxia and serum deprivation induced significantly accelerated turnover of GM-CSF mRNA. Treatment of AEC with catalase during oxidative stress preserved GM-CSF protein and mRNA and was associated with stabilization of GM-CSF mRNA. We conclude that hyperoxia-induced suppression of AEC GM-CSF expression is a function of ROS-induced destabilization of GM-CSF mRNA. We speculate that AEC oxidative stress results in significantly impaired pulmonary innate immune defense due to effects on local GM-CSF expression in the lung.
 ...
PMID:Mechanisms of suppression of alveolar epithelial cell GM-CSF expression in the setting of hyperoxic stress. 2003 63

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is critically important for normal pulmonary innate immunity and for functional maturation of alveolar macrophages. Alveolar epithelial cells (AEC) are a major source of GM-CSF in the lung and express this growth factor constitutively, whereas most other cells, including T cells, express GM-CSF following inflammatory stimulation. AEC expression of GM-CSF is suppressed by oxidative stress, at least in part through induction of microRNA leading to increased mRNA turnover. In this report, we compare and contrast the effect of hyperoxia on transcriptional aspects of gene regulation of GM-CSF in lung epithelia and T cells of human and mouse origin. Similar to primary murine AEC, human H820 cells that express multiple characteristics of normal alveolar epithelial cells express GM-CSF constitutively, with decreased expression and increased mRNA turnover following exposure to hyperoxia. In contrast, hyperoxia induces augmented GM-CSF expression in human and murine activated T cells, in association with enhanced GM-CSF mRNA stability. Alveolar epithelial cells demonstrate constitutive transcription, with the proximal promoter in an open configuration in normoxia, without change in hyperoxia. Conversely, in both human and murine T cells, hyperoxia increased GM-CSF gene transcription. The proximal promoter was in a closed configuration in unstimulated T cells but became accessible upon activation and still more accessible in activated T cells exposed to hyperoxia. These fundamental differences in molecular regulation of GM-CSF expression highlight the distinctive niche of alveolar epithelial cell expression of GM-CSF and offer insights into the biology of GM-CSF in the setting of acute lung injury.
...
PMID:Contrasting effects of hyperoxia on GM-CSF gene transcription in alveolar epithelial cells and T cells. 2574 88