Mechanisms of suppression of alveolar epithelial cell GM-CSF expression in the setting of hyperoxic stress.

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.

Critical roles of inflammation and apoptosis in improved survival in a model of hyperoxia-induced acute lung injury in Pneumocystis murina-infected mice.

Pneumocystis infections increase host susceptibility to additional insults that would be tolerated in the absence of infection, such as hyperoxia. In an in vivo model using CD4-depleted mice, we previously demonstrated that Pneumocystis murina pneumonia causes significant mortality following an otherwise nonlethal hyperoxic insult. Infected mice demonstrated increased pulmonary inflammation and alveolar epithelial cell apoptosis compared to controls.

Disparate mechanisms of sICAM-1 production in the peripheral lung: contrast between alveolar epithelial cells and pulmonary microvascular endothelial cells.

Membrane-associated intercellular adhesion molecule-1 (mICAM-1; CD54) is constitutively expressed on the surface of type I alveolar epithelial cells (AEC). Soluble ICAM-1 (sICAM-1) may be produced by proteolytic cleavage of mICAM-1 or by alternative splicing of ICAM-1 mRNA. In contrast to inducible expression seen in most cell types, sICAM-1 is constitutively released by type I AEC and is present in normal alveolar lining fluid.

GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress.

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.

Shedding of soluble ICAM-1 into the alveolar space in murine models of acute lung injury.

Intercellular adhesion molecule-1 (ICAM-1; CD54) is an adhesion molecule constitutively expressed in abundance on the cell surface of type I alveolar epithelial cells (AEC) in the normal lung and is a critical participant in pulmonary innate immunity. At many sites, ICAM-1 is shed from the cell surface as a soluble molecule (sICAM-1). Limited information is available regarding the presence, source, or significance of sICAM-1 in the alveolar lining fluid of normal or injured lungs.

Lysosomal phospholipase A2 is selectively expressed in alveolar macrophages.

Lung surfactant is the surface-active agent comprised of phospholipids and proteins that lines pulmonary alveoli. Surfactant stabilizes the alveolar volume by reducing surface tension. Previously, we identified a lysosomal phospholipase A2, termed LPLA2, with specificity toward phosphatidylcholine and phosphatidylethanolamine.

Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury.

Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in pulmonary homeostasis, with effects on both alveolar macrophages and alveolar epithelial cells. We hypothesized that overexpression of GM-CSF in the lung would protect mice from hyperoxic lung injury by limiting alveolar epithelial cell injury. Wild-type C57BL/6 mice and mutant mice in which GM-CSF was overexpressed in the lung under control of the SP-C promoter (SP-C-GM mice) were placed in >95% oxygen.

Pneumocystis pneumonia increases the susceptibility of mice to sublethal hyperoxia.

Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal.

Sublethal hyperoxia impairs pulmonary innate immunity.

Supplemental oxygen is often required in the treatment of critically ill patients. The impact of hyperoxia on pulmonary host defense is not well-established. We hypothesized that hyperoxia directly impairs pulmonary host defense, beyond effects on alveolar wall barrier function.

The toxicity of fluoranthene to Hyalella azteca in sediment and water-only exposures under varying light spectra.

In the US Environmental Protection Agency methods for sediment toxicity testing, the light regimen is specified as a 16:8 light dark cycle with 500-1000 lx. The potential for photoinduced toxic effects from this requirement is evaluated. Hyalella azteca were exposed to fluoranthene in both water only and sediment to examine the impact of light spectra on the toxicity of fluoranthene.

ICAM-1 facilitates alveolar macrophage phagocytic activity through effects on migration over the AEC surface.

We postulate that intercellular adhesion molecule-1 (ICAM-1) on type I alveolar epithelial cells (AEC) facilitates phagocytic activity of alveolar macrophages (AM) in the alveolus. When wild-type and ICAM-1-deficient mice were inoculated intratracheally with FITC-labeled microspheres, AM phagocytosis of beads (after 1 and 4 h) was significantly reduced in ICAM-1-/- mice compared with controls. To focus on ICAM-1-mediated interactions specifically involving AM and AEC, rat AM were placed in culture with rat AEC treated with neutralizing anti-ICAM-1 F(ab')(2) fragments.