American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · May 2002
ReviewVentilation-induced lung injury and mechanotransduction: stretching it too far?
The Acute Respiratory Distress Syndrome Network clinical trial on ventilation of critically ill patients has drawn attention to the potential side effects of mechanical ventilation. Both clinical and basic research have demonstrated that injurious ventilation strategies can initiate or perpetuate local and systemic inflammatory responses. ⋯ Stress failure of the plasma membrane causes necrosis, which leads to liberation of both preformed inflammatory mediators and agents that stimulate other cells that are still intact to produce such mediators. 2) Stress failure of the barriers causes loss of compartmentalization with spread of mediators and bacteria throughout the body as a consequence. 3) Less injurious ventilation strategies that do not cause tissue destruction can elicit release of mediators by more specific mechanisms, presumably through activation of stretch-activated signaling cascades (mechanotransduction). 4) Ventilation with increasing positive pressures raises the pressure in the pulmonary circulation and thus vascular shear stress, both of which are known stimuli for endothelial cells. These different mechanisms should be taken into account in the design and the interpretation of studies on molecular mechanisms of ventilation-induced lung injury.
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Am. J. Physiol. Lung Cell Mol. Physiol. · May 2002
Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells.
Accumulating data support the view that sepsis is associated with an acquired intrinsic derangement in the ability of cells to consume O(2), a phenomenon that has been termed "cytopathic hypoxia." We sought to use an in vitro "reductionist" model system using cultured cells stimulated with proinflammatory cytokines to test the hypothesis that cytopathic hypoxia is mediated, at least in part, by depletion of intracellular levels of NAD(+)/NADH secondary to activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). We measured O(2) consumption by Caco-2 enterocytes growing on microcarrier beads after cells were incubated for 24 h under control conditions or with cytomix, a mixture of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Immunostimulated cells consumed O(2) at about one-half the rate of control cells, but this effect was largely prevented if any one of the following pharmacological agents was present during the period of incubation with cytomix: 4,5-dihydroxy-1,3-benzene disulfonic acid, a superoxide radical anion scavenger; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger; 5,10,15,20- tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III], a peroxynitrite (ONOO(-)) decomposition catalyst; urate, an ONOO(-) scavenger; 3-aminobenzamide, a PARP inhibitor; or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide HCl, a chemically dissimilar and more potent PARP inhibitor. ⋯ The decrease in cellular NAD(+)/NADH content and the decrease in O(2) uptake induced by cytomix were completely abrogated if liposome-encapsulated NAD(+) was added to the cultures during immunostimulation. Empty liposomes also increased O(2) uptake by immunostimulated Caco-2 cells, but much less effectively than liposomes containing NAD(+). These data are consistent with the view that enterocytes exposed to proinflammatory cytokines consume less O(2) due to NAD(+)/NADH depletion secondary to activation of PARP by ONOO(-) or other oxidants.