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Extinguishing Egr-1-dependent inflammatory and thrombotic cascades after lung transplantation.

Abstract
Hypoxic induction of the early growth response-1 (Egr-1) transcription factor initiates proinflammatory and procoagulant gene expression. Orthotopic/isogeneic rat lung transplantation triggers Egr-1 expression and nuclear DNA binding activity corresponding to Egr-1, which leads to increased expression of downstream target genes such as interleukin-1b, tissue factor, and plasminogen activator inhibitor-1. The devastating functional consequences of Egr-1 up-regulation in this setting are prevented by treating donor lungs with a phosphorothioate antisense oligodeoxyribonucleotide directed against the Egr-1 translation initiation site, which blocks expression of Egr-1 and its gene targets. Post-transplant graft leukostasis, inflammation, and thrombosis are consequently diminished, with marked improvement in graft function and recipient survival. Blocking expression of a proximal transcription factor, which activates deleterious inflammatory and coagulant effector mechanisms, is an effective molecular strategy to improve organ preservation.
AuthorsM Okada, T Fujita, T Sakaguchi, K E Olson, T Collins, D M Stern, S F Yan, D J Pinsky
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 15 Issue 14 Pg. 2757-9 (Dec 2001) ISSN: 1530-6860 [Electronic] United States
PMID11606484 (Publication Type: Journal Article)
Chemical References
  • DNA, Antisense
  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Immediate-Early Proteins
  • Interleukin-1
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Transcription Factors
  • Fibrin
  • Thromboplastin
Topics
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • DNA, Antisense (pharmacology)
  • DNA-Binding Proteins (genetics, physiology)
  • Early Growth Response Protein 1
  • Fibrin (drug effects, metabolism)
  • Gene Expression
  • Gene Expression Regulation (drug effects)
  • Graft Survival (drug effects, physiology)
  • Immediate-Early Proteins
  • Inflammation (physiopathology)
  • Interleukin-1 (genetics)
  • Lung Transplantation
  • Plasminogen Activator Inhibitor 1 (genetics)
  • RNA, Messenger (genetics, metabolism)
  • Rats
  • Signal Transduction
  • Thromboplastin (genetics)
  • Thrombosis (physiopathology)
  • Transcription Factors (genetics, physiology)

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