The overall focus of the SCOR Program is sepsis-induced acute lung injury. The SCOR Program does not try to address all of the basic and clinical issues related to sepsis-induced acute lung injury. The specific focus and rationale for the SCOR Program is as follows. During gram-sepsis, endotoxin and bacterial DNA are released and stimulate macrophages to release TNF. Cell wall products of gram + organisms mimic the effects of endotoxin on macrophages. TNF can trigger organ and cellular dysfunction (decreased surfactant production) and/or injury (by apoptosis). The SCOR Program recognizes that other types of cells release mediators (including TNF) during sepsis and that mediators, other than TNF, are important for the pathogenesis of acute lung injury. We further realize that surfactant abnormalities are only one of the manifestations of organ dysfunction during acute lung injury and that injury to tissues can occur by mechanisms that do not involve apoptosis. This paradigm is only presented tot illustrate the focus and interrelationships in the SCOR Program. Projects 11 and 12 evaluate the regulation of cytokine genes (including TNF) in human alveolar macrophages and liver. Project 11 evaluates the role of MAPK' and Project 12 evaluates redox regulation of Nfkappab. T- cells regulate the sensitivity of macrophages to endotoxin via the secretion of pro-inflammatory mediators (like the TH-1 cytokine, interferon gamma) or anti-inflammatory mediators (like the TH-2 cytokines). The regulation of TH-1 and TH-2 populations of T-cells by CD95 ligands is evaluated in Project 13. Various tissues, like lung, may also protect themselves from invading T-cells or neutrophils during inflammation by expressing CD95 ligand. This is also explored in Project 13. Injury to tissues can also be triggered by expression of CD95 ligand and its receptor, as explored in Project 13. Project 14 explores TNF- induces suppression of surfactant lipid production. Surfactant abnormalities are a major manifestation of acute lung injury. The Clinical Core determines if bacterial DNA (a surrogate marker for infection) in blood or lung predicts continued inflammation and patient outcome in acute lung injury. The Clinical Core also provides human tissues and biometry support for each of the projects. This is a highly integrated program with many scientific interactions between the projects and cores. This SCOR has great potential to make a large number of highly novel basic and clinical observations related to acute lung injury.
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