Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protective in oxygen toxicity, we compared the effects of 100% O2 on transgenic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O2 with 100% of transgene (-) animals dying within 72-96 h and > 90% of transgene (+) animals surviving for more than 10 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Significant differences in copper zinc superoxide dismutase and catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals. Glutathione reductase, glutathione peroxidase, and manganese superoxide dismutase activities were slightly higher in transgene (+) as versus (-) mice after 100% O2 exposure, and IL-11 diminished hyperoxia-induced expression of IL-1 and TNF. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-11 markedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demonstrate this protection is associated with small changes in lung antioxidants, diminished hyperoxia-induced IL-1 and TNF production, and markedly suppressed hyperoxia-induced DNA fragmentation.
Summary
The platelet‐mapping assay of the thromboelastograph was used to measure platelet aggregation and to examine the effect of cardiopulmonary bypass on multiple platelet receptors and the role of altered receptor activity in postoperative bleeding. The percentage platelet aggregation for collagen, adenosine diphosphate and arachidonic acid was measured in 40 patients divided post‐hoc into high‐ or low‐bleeding groups depending on postoperative 24‐h chest tube output. Platelet aggregation was lower after cardiopulmonary bypass compared to before it using collagen (mean (SD) 45 (25) vs 19 (12) %, p < 0.001), adenosine diphosphate (76 (23) vs 35 (24) %, p < 0.001), and arachidonic acid (61 (33) vs 31 (35) %, p < 0.001). Only platelet aggregation as measured using collagen pre‐ and post‐cardiopulmonary bypass was significantly less in the high‐ compared to the low‐bleeding group. This finding was significantly correlated with the 24‐h chest tube drainage, and it predicted postoperative bleeding with a sensitivity of 83% and a specificity of 68%. Therefore, platelet aggregation is reduced following cardiopulmonary bypass, and this may play a role in predicting postoperative blood loss.
Cysteine availability is rate limiting for the synthesis of glutathione, an important antioxidant in the lung. We used rat alveolar epithelial type II cells to study the mechanism of cysteine and cystine uptake. Consistent with carrier-mediated transport, each uptake process was saturable with Michaelis-Menten kinetics and was inhibited at 4°C and by micromolar levels of amino acids or analogs known to be substrates for a specific transporter. A unique system XAG was found that transports cysteine and cystine (as well as glutamate and aspartate, the only substrates previously described for system XAG). We also identified a second Na+-dependent cysteine transporter system, system ASC, and two Na+-independent transporter systems, system xc for cystine and system L for cysteine. In the presence of glutathione at levels measured in rat plasma and alveolar lining fluid, cystine was reduced to cysteine and was transported on systems ASC and XAG, doubling the transport rate. Cysteinylglycine, released from glutathione at the cell surface by γ-glutamyl transpeptidase, also stimulated uptake after reduction of cystine. These findings suggest that, under physiological conditions, cysteine and cystine transport is influenced by the extracellular redox state.
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