Translational research : the journal of laboratory and clinical medicine
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Disruption of epithelial and endothelial barriers found in patients with acute lung injury often results in the need for the support of mechanical ventilation. High tidal volume (V(T)) mechanical ventilation can increase lung damage through lung inflammation, but the mechanisms are unclear. We hypothesized that a colloid supply with hydroxyethyl starch would decrease neutrophil infiltration, lung edema, and vascular endothelial growth factor (VEGF) production in mice exposed to high V(T) mechanical ventilation. ⋯ High V(T) ventilation induced the increases of microvascular permeability, neutrophil influx, expressions of VEGF mRNA and VEGF, production of VEGF protein, positive staining of VEGF in epithelium, and apoptotic epithelial cell death. Lung injury induced by high V(T) ventilation was attenuated with the supply of hydroxyethyl starch and pharmacologic inhibition of VEGF expression by siRNA. We conclude that hydroxyethyl starch reduces high V(T) mechanical ventilation-induced lung injury and neutrophil infiltration through an inhibition of VEGF expression.
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MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. Expression profiles of specific miRNAs have improved cancer diagnosis and classification as well as provided prognostic information in many human cancers, including lung cancer. Tumor-suppressive and oncogenic miRNAs were uncovered in lung carcinogenesis. ⋯ Tumor-suppressive and oncogenic miRNAs that were identified in lung cancer will be reviewed here. Emphasis is placed on highlighting those functionally validated miRNAs that are not only biomarkers of lung carcinogenesis but also candidate pharmacologic targets. How these miRNA findings advance an understanding of lung cancer biology and how they could improve lung cancer therapy are discussed in this article.
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In this review, we describe the recent advances in the understanding of the role of microRNAs in idiopathic pulmonary fibrosis (IPF), a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in IPF lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17∼92 cluster among the upregulated mir-155 and mir-21. ⋯ As a result, their aberrant expression leads to a release of inhibitions on the TGFβ1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in IPF reveals enrichment of the TGFβ1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the IPF lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in IPF.
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Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and nongenetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Because gene expression is an intermediate phenotype that resides between the DNA sequence variation and the higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks potentially could enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. ⋯ Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. Although this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well as environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease.
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Zinc is an essential trace element and cofactor for many cellular processes. Uptake of ionized divalent zinc (Zn(2+)) in peripheral tissues depends on its total content in the circulation and on mechanisms facilitating delivery to tissues in its labile form. Understanding mechanisms of Zn(2+) delivery has been hindered by the absence of techniques to detect labile Zn(2+) in the circulation. ⋯ Affinity of the filtrate fraction was rapidly and reversibly responsive to anesthesia alone, decreasing significantly at 4 h and recovering at 24 h; in animals subjected to moderate surgical stress, this responsiveness was lost. These findings are the first reported measurements of labile Zn(2+) in the circulation in any form of mild systemic stress. Zinc undergoes substantial redistribution in the plasma as a response to surgical stress, leading to increased availability in lower molecular weight fractions and in its labile form.