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.
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Authors | M Okada, T Fujita, T Sakaguchi, K E Olson, T Collins, D M Stern, S F Yan, D J Pinsky |
Journal | FASEB 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 |
PMID | 11606484
(Publication Type: Journal Article)
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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
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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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