and specific aims): Infection and ARDS are major causes of mortality following trauma and hemorrhage. The application hypothesizes that increased generation of O2 radicals following hemorrhage is responsible for activation of nuclear transcriptional regulatory factors and increased proinflammatory and immunoregulatory cytokine expression among pulmonary macrophage, T and B cell populations, which then induce subsequent depression in bacterial antigen specific pulmonary B cell function. A murine hemorrhage and resuscitation model will be used to pursue the following specific aims: 1) to determine if O2 radicals increase pulmonary cytokine mRNA and protein expression following hemorrhage; 2) to examine the sources of O2 radical generation following hemorrhage by determining if hemorrhage induced O2 radicals are produced through pulmonary or extrapulmonary XO dependent mechanisms and/or derived from neutrophils; 3) to examine if non-oxidant dependent mechanisms, specifically catecholamines and complement activation, affect cytokine expression in the lungs following hemorrhage; 4) to determine if hemorrhage-induced O2 radicals, complement activation, and/or catecholamine release activate the nuclear transcriptional regulatory factors NF-kb, NF-IL-6 and/or AP-1, which mediate gene transcription; and 5) to determine if O2 radicals, complement activation, and/or catecholamines depress bacterial antigen specific pulmonary B cell function following blood loss and resuscitation. The proposed experiments could provide new information which will help elucidate the sequence of events leading from blood loss to increased susceptibility to infection and acute lung injury.
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