application): Acute lung injury is frequently associated with sepsis or blood loss. In preliminary studies, The investigators found that hemorrhage or endotoxemia cause rapid increases in the expression of proinflammatory cytokines IL-1, TNF, and MIP-2, and in activation of the transcriptional regulatory factors NF-kB and CREB in lung neutrophils. After endotoxemia, but not hemorrhage, adrenergic blockade increases expression of proinflammatory cytokines by lung neutrophils, adrenergic blockade increased CREB and decreased NF-kB activation after hemorrhage, but decreased CREB and increased NF-kB activation after endotoxemia. After hemorrhage, but not endotoxemia, the increased expression of proinflammatory cytokines by lung neutrophils was inhibited by blockade of xanthine oxidase. After hemorrhage, but not endotoxemia, blockade of xanthine oxidase increases CREB activation, but does not prevent NF-kB activation in lung neutrophils. They hypothesize that distinct mechanisms lead to activation of activation of NF-kB and CREB in lung neutrophils after hemorrhage or endotoxemia, modulating their ability to affect subsequent transcription of proinflammatory cytokines involved in the development of acute lung injury.
The specific aims are to determine: 1) the mechanisms involving alterations in nuclear and cytoplasmic I-kBs, NF-kB relevant kinases, and NF-kB subunit composition, which lead to hemorrhage or endotoxemia-induced activation of NF-kB in lung neutrophils; 2) the mechanisms involving CREB relevant kinases, CREB phosphorylation, CREM and ICER expression, which lead to hemorrhage or endotoxemia-induced activation of CREB in lung neutrophils; 3) the effects of hemorrhage or endotoxemia on binding interactions between CREB, NF-kB, and CBP in lung neutrophils; and 4) the mechanisms by which reactive oxygen intermediates or catecholamines modulate NF-kB and CREB activations as well as their interactions with CBP in lung neutrophils after hemorrhage or endotoxemia, and the effects of such modulation of NF-kB and CREB activity on the development of acute lung injury.
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