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Gene Expression Profiles of PBMC Characterize Inflammation Stages in the Acute Lung Injury in Mice

ABSTRACT: Acute respiratory distress syndrome (ARDS) carries about a 50 percent mortality and is frequently associated with an infection (sepsis). Life-support treatment with mechanical ventilation rescues many patients, although superimposed infection or multiple organ failure can result in death. The outcome of a patient developing sepsis highly depends on the degree of pre-existing inflammation prior to the infection. In this study, we describe each stage of the inflammation process using a transcriptional approach and an animal model. Femelle C57BL6/J mice received an intraveinous oleic acid injection to induce an acute lung injury. PBMC expression patterns have been analyzed using a 9900 cDNA mouse microarray (MUSV29K). Our gene-expression analysis revealed marked changes in the immune and inflammatory response metabolic pathways, notably lipid metabolism and transcription. The early pro-inflammatory stage (1H-1H30) is characterized by the release of immune response and activation of inflammatory mechanisms. Later (3H-4H), the immune cells migrate into inflamed tissues through interaction with vascular endothelial cells. Finally, at late stages of lung inflammation (18H-24H), metabolism is deeply disturbed. Highly expressed pro-inflammatory cytokines activate transcription of many genes as well as lipid metabolism. This global overview of critical events occuring during lung inflammation is essential to understand infectious pathologies such as sepsis where inflammation and infection are interwined. From now on, it becomes possible to isolate the impact of a pathogen at the transcriptional level from the global gene expression modifications resulting from the infection associated with the inflammation. Also, our work allowed to identify genes involved in the response to inflammation. Among those, several may be potential target for gene therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE19030 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA120629

REPOSITORIES: GEO

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Project description:Acute respiratory distress syndrome (ARDS) carries about a 50 percent mortality and is frequently associated with an infection (sepsis). Life-support treatment with mechanical ventilation rescues many patients, although superimposed infection or multiple organ failure can result in death. The outcome of a patient developing sepsis highly depends on the degree of pre-existing inflammation prior to the infection. In this study, we describe each stage of the inflammation process using a transcriptional approach and an animal model. Femelle C57BL6/J mice received an intraveinous oleic acid injection to induce an acute lung injury. PBMC expression patterns have been analyzed using a 9900 cDNA mouse microarray (MUSV29K). Our gene-expression analysis revealed marked changes in the immune and inflammatory response metabolic pathways, notably lipid metabolism and transcription. The early pro-inflammatory stage (1H-1H30) is characterized by the release of immune response and activation of inflammatory mechanisms. Later (3H-4H), the immune cells migrate into inflamed tissues through interaction with vascular endothelial cells. Finally, at late stages of lung inflammation (18H-24H), metabolism is deeply disturbed. Highly expressed pro-inflammatory cytokines activate transcription of many genes as well as lipid metabolism. This global overview of critical events occuring during lung inflammation is essential to understand infectious pathologies such as sepsis where inflammation and infection are interwined. From now on, it becomes possible to isolate the impact of a pathogen at the transcriptional level from the global gene expression modifications resulting from the infection associated with the inflammation. Also, our work allowed to identify genes involved in the response to inflammation. Among those, several may be potential target for gene therapy. Wild-type femelle C57Bl/6J mice, 7 weeks old, were obtained from Charles River and housed in a specific pathogen-free animal facility. We studied 39 mice divided into 6 groups. Each group was identified according to the incubation time: 1H, 1H30, 3H, 4H, 18H and 24H. The 1H group was made up of 6 mice (2 physiological serum and 4 OA); the 1H30 group was made up of 8 mice (2 physiological serum and 6 OA); the 3H group was made up of 7 mice (2 physiological serum and 5 OA); the 4H group was made up of 6 mice (2 physiological serum and 4 OA); the 18H group was made up of 6 mice (2 physiological serum and 4 OA); the 24H group was made up of 6 mice (2 physiological serum and 4 OA). Several RNA samples have been hybridized on 2 filters consisting in technical replicates. Data normalized by quantile without adjustment on physiological serum linked on Series record.

Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.

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Gene Expression Profiles of PBMC Characterize Inflammation Stages in the Acute Lung Injury in Mice

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