Extinguishing Egr-1-dependent inflammatory and thrombotic cascades after lung transplantation.
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.
Okada
M
M
College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA; and, Harvard Medical School, Boston, Massachusetts 02115, USA.
Fujita
T
T
Sakaguchi
T
T
Olson
K E
KE
Collins
T
T
Stern
D M
DM
Yan
S F
SF
Pinsky
D J
DJ
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016373:DNA, Antisense / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins; D007249:Inflammation / Q000503:physiopathology*; D007375:Interleukin-1 / Q000235:genetics; D016040:Lung Transplantation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics; D013927:Thrombosis / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014157:Transcription Factors; D005337:Fibrin; D013925:Thromboplastin