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Abstract: Previous studies in our lab have identified pre-B-cell colony enhancing factor (PBEF) as a novel biomarker in acute lung injury. This study continues to elucidate the underlying molecular mechanism of PBEF in the pathogenesis of acute lung injury in pulmonary cell culture models. Our results revealed that IL-1β induced PBEF expression in pulmonary vascular endothelial cells at the transcriptional level and a −1535 T-variant in the human PBEF gene promoter significantly attenuated its binding to an IL-1β-induced unknown transcription factor. This may underlie the reduced expression of PBEF and thus the lower susceptibility to acute lung injury in −1535T carriers. Furthermore, overexpression of PBEF significantly augmented IL-8 secretion and mRNA expression by more than 6-fold and 2-fold in A549 cells and HPAEC, respectively. It also significantly augmented IL-1β-mediated cell permeability by 44% in A549 cells and 65% in endothelial cells. The knockdown of PBEF expression significantly inhibited IL-1β-stimulated IL-8 secretion and mRNA level by 60% and 70%, respectively, and the knockdown of PBEF expression also significantly attenuated IL-1β-induced cell permeability by 29% in epithelial cells and 24% in endothelial cells. PBEF expression also affected the expression of two other inflammatory cytokines (IL-16 and CCR3 genes). These results suggest that PBEF is critically involved in pulmonary vascular and epithelial inflammation and permeability, which are hallmark features in the pathogenesis of acute lung injury. This study lends further support to our finding that PBEF is a potential new target in acute lung injury. [Copyright &y& Elsevier]

Abstract Human ribonuclease inhibitor (hRI) can inhibit angiogenesis by reversibly binding angiogenin, a member of the RNaseA superfamily, and by suppressing the expression of basic fibroblast growth factor (bFGF). Angiogenesis is necessary for the growth and metastasis of tumors. To study the links between hRI, angiogenesis, and melanoma growth, the hRI gene was intravenously administered to mice in a recombinant retroviral vector, and expression of the hRI gene was induced to block melanoma angiogenesis. Expression, distribution, and contribution of the target gene in mice were assayed. The results showed that the tumors of mice in the hRI treatment group grew slower with less vascularity than those of mice in control groups. The introduced hRI gene inhibited tumor growth without causing significant side effects in the animals. More hRI expression in vimentin-positive cells of the tumor than in melanoma cells suggested that mesenchymal cells in the fibrous envelope of the tumor play important roles in this gene therapy. [ABSTRACT FROM AUTHOR]