Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human platelets as cytotoxic mediators in sepsis-induced acute lung injury (ALI)

ABSTRACT: ALI is one of the most common disease processes in adult and pediatric intensive care units and results in significant morbidity and mortality. The pathophysiology of ALI begins with a massive pro-inflammatory response likely mediated by as yet uncharacterized platelet/endothelium interactions with macrophage activation. This leads to a cytokine/chemokine cascade producing endothelial disruption. Neutrophilic infiltration of the alveolar wall and alveolar space with a concomitant procoagulant state develops. Despite the fact that inadequate understanding of ALI pathophysiology remains a barrier to effective treatment, novel therapeutics including ventilatory manipulations and anti-inflammatory molecules are beginning to improve the morbidity and mortality associated with this disease process. Experiment Overall Design: Acute Lung Injury (ALI) represents a spectrum of critical pulmonary illness in which inflammatory processes lead to varying degrees of alveolar damage and respiratory failure. ALI is a common disease process in the intensive care unit (ICU) with high morbidity and mortality. Based on new insights into the molecular processes of lung injury, we hypothesize that a temporal analysis of cells of innate immunity and thrombosis will demonstrate changes in mRNA and protein expression that are significantly associated with progression of ALI. Additionally, the analysis of the resulting datasets will lead to an unprecedented understanding of the pathogenesis of ALI.

ORGANISM(S): Homo sapiens

SUBMITTER: Eric Hoffman

PROVIDER: E-GEOD-10361 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:With advances in supportive therapy in the last two decades, mortality rates from ALI/ARDS have improved somewhat, but remain around 30 to 40% with significant morbidity in survivors. Several promising treatments are in various stages of evaluation, but many have failed to prove beneficial in large randomized clinical trials (RCT). The first definitive step forward in ALI therapeutics occurred recently as a result of a large RCT demonstrating a mortality decrease from 40 to 31% with the use of low-volume ventilation strategies. From this, it is clear that the opportunity for successful intervention in ALI exists. However, therapeutic advances remain frustrated by the lack of complete understanding of ALI pathophysiology. This stresses the importance of integrating basic and clinical research of the molecular pathogenesis of this disease. The conclusions of a recent National Heart, Lung, and Blood Institute (NHLBI) Working Group on ALI support this type of research as a priority for future investigations of ALI. One of the areas of research given priority by this ALI Working Group is the issue of ALI severity progression and the role of cells of innate immunity in this process. Currently, the processes that determine which ALI patients progress to ARDS and which do not are unclear. As with many phenotype differences, there is most likely a genetic component involved. The basis for this has been demonstrated. For example, a surfactant protein B (SP-B) polymorphism appears to increase a patient’s risk of developing ALI from pneumonia. Additionally, a polymorphism in the promoter region of the gene for interleukin-6 (IL-6) has been associated with a poor prognosis in patients with ARDS. Understanding the intracellular processes of these genes and the cells expressing them in ALI progression could lead to the identification of molecular markers of ALI severity and eventually to the development of targeted therapies. An examination of genetically uniform animals will provide a clearer insight into the interaction between immune cells in ALI progression as well as guide future human experiments. Keywords: Time Series Design, ALI - acute lung injury, ARDS - acute respiratory distress syndrome, CLP - cecal ligation and puncture

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Transcription profiling of human platelets as cytotoxic mediators in sepsis-induced acute lung injury (ALI)

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