Identification of genes and pathways associated with multiple organ dysfunction syndrome by microarray analysis.

Multiple organ dysfunction syndrome (MODS) is characterized by the development of progressive physiological dysfunction of ≥2 organs or organ systems and is responsible for the majority of the morbidity and mortality among patients in intensive care units. The aim of the present study was to investigate the potential genes and pathways associated with MODS. The microarray dataset GSE60088 was downloaded from the Gene Expression Omnibus and used to identify differentially expressed genes (DEGs) between organ tissues (lung, liver and kidney) obtained from a murine model of MODS and healthy controls. The interactions between DEGs in lungs, liver and kidneys were revealed by Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, protein­protein interaction (PPI) data for DEGs were obtained from the Search Tool for the Retrieval of Interacting Genes and a PPI network was constructed. Additionally, DEGs that were common among the three organs were screened and transcription factors that regulated them were predicted using the iRegulon plugin. A total of 943, 267 and 227 DEGs were identified in lung, liver and kidney samples, respectively, between mice with MODS and healthy controls. In lung and liver samples, two pathways that were enriched with DEGs were identified and were common between lung and liver samples, including 'cytokine­cytokine receptor interaction' and 'Jnk­STAT signaling pathway', and examples of DEGs associated with these pathways include C­X­C motif chemokine ligand (Cxcl)1 and Cxcl10, and signal transducer and activator of transcription (Stat)1, respectively. Furthermore, two common pathways were identified in liver and kidney samples, which included 'MAPK signaling pathway' and 'p53 signaling pathway', and DEGs associated with these pathways included growth arrest and DNA damage­inducible α. A total of 18 DEGs were common among lung, liver and kidney tissues, including CCAAT/enhancer binding protein ß (Cebpb) and olfactomedin­like 1 (Olfml1). Cebpb modulated various other DEGs, such as Cxcl1, and Olfml1 was regulated by Stat5A. These genes and pathways may serve roles in the progression of MODS and may be considered to be potential therapy targets for MODS.

mTOR enhances foam cell formation by suppressing the autophagy pathway.

Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications.

[Effects of peroxisome proliferators-activated receptor-gamma on the function of the vital organs in rats with pancreatitis].

OBJECTIVE: To observe the effects of peroxisome proliferators-activated receptor-gamma (PPARgamma) on the function of the vital organs in rats with pancreatitis. METHODS: Acute pancreatitis (AP) was induced in 30 male SD rats by ductal injection of 4% sodium taurocholate at 1.0 ml/kg. The rats received subsequent intravenously injection of 0.3 mg/kg of PPARgamma ligand (rosiglitazone, n=10), PPARgamma antagonist (GW9662, n=10) followed 10 min later by rosiglitazone administration at 0.3 mg/kg, or left untreated (AP model group, n=10). Another 10 male SD rats receiving no particular treatment served as the control group. The rats were sacrificed 6 h after the operation, and blood samples were collected for measurement of the biochemical indices of the vital organs. The histological changes of the pancreas and portal vein blood endotoxin content were examined. RESULTS: The rats in AP group and GW9662 group showed significantly higher level of the biochemical indices for the vital organs, pathological scores of the pancreas and portal vein blood endotoxin content were significantly higher in the control group and roglitazone-treated groups (P<0.05). CONCLUSION: PPARgamma ligand roglitazone can significantly ameliorate multiple organ injuries and effectively protect the functions of the organs in rats with experimental pancreatitis.

[Study on vascular endothelial injuries and inflammation related cytokines in patients with multiple organ dysfunction syndrome].

OBJECTIVE: To investigate the relationship between the circulating endothelial cell (CEC), coagulation, fibrinolysis indexes and inflammation related cytokines in patients with multiple organ dysfunction syndrome (MODS). METHODS: Thirty-five patients with MODS (MODS group) and 20 healthy individuals (control group) were enrolled for study. CECs were harvested by isopycnic centrifugation method. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FG), D-dimer, and serum tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) were determined simultaneously. The relationship between dynamic changes in CEC, TNF-alpha, IL-6 and that in PT, APTT, FG, D-dimer was analyzed. RESULTS: Compared to the control group, CEC numbers, serum TNF-alpha, IL-6 levels and plasma D-dimer level significantly increased, PT and APTT were prolonged, and FG significantly decreased in MODS group (all P<0.05). The quantity of CEC and serum levels of TNF-alpha and IL-6 elevated with the lapse of time. Correlation analysis revealed a significant positive correlation between CEC and serum levels of TNF-alpha and IL-6 (r(1)=0.536, P(1)=0.000; r(2)=0.412, P(2)=0.002), and the same correlation between serum TNF-alpha, IL-6 levels and PT, APTT. CONCLUSION: Elevation of serum inflammation related cytokines and vascular endothelial cell damage occur in MODS patients. Serum inflammation related cytokines play an important role in endothelial damage, and an increase in CEC number may be attributed to vessel injury.