Effect of ionizing radiation on cellular procoagulability and co-ordinated gene alterations.
OBJECTIVE
Ionizing radiation (IR) is associated with thrombotic vascular occlusion predicting a poor clinical outcome. Our study examined whether IR induced tissue factor (TF) expression and procoagulability. We further investigated coordinated gene alterations associated with TF upregulation in the myelomonocytic leukemia THP-1 cells.


METHODS
TF expression was determined by quantitative Reverse Transcriptase (TaqMan) PCR, TF ELISA and TF activity by a two stage chromogenic assay in the time course of days 1, 3, 7, 10, and 17 post IR. To detect IR-induced alterations in gene expression, Affymetrix HG U133 Plus 2.0 microarrays were used. RESULTS IR induced a significant increase in TF/GAPDH mRNA ratios and cellular TF protein on days 3 and 7 post IR (20 Gy [p>or=0.01] and 40 Gy [p <or=0.01 vs. control]), suggesting a late and persistent induction of TF. An increase in cellular TF activity was already found 1 day post IR (20 Gy and 40 Gy [p>or=0.001] vs. control respectively), suggesting IR immediately alters the cellular thrombogenicity. TF upregulation post IR was confirmed in PBMNCs. Gene expression profiling showed IR increased the expression of inflammatory and apoptosis-related pathways known to be involved in the regulation of TF expression.


CONCLUSIONS
TF upregulation together with inflammation and apoptosis may increase the thrombogenicity of tissues. The demonstrated upregulation of TF might play a pivotal role in radiation associated thrombosis.
Goldin-Lang
Petra
P
Department of Cardiology and Pneumology,Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany ursula.rauch@charite.de.
Pels
Klaus
K
Tran
Quoc-Viet
QV
Szotowski
Bjoern
B
Wittchen
Frank
F
Antoniak
Silvio
S
Willich
Tobias
T
Witt
Henning
H
Hummel
Michael
M
Lenze
Dido
D
Poller
Wolfgang
W
Schultheiss
Heinz-Peter
HP
Rauch
Ursula
U
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001779:Blood Coagulation Factors / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000378:metabolism / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D015951:Factor Xa / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000528:radiation effects*; D006801:Humans; D007249:Inflammation; D015479:Leukemia, Myelomonocytic, Acute / Q000097:blood / Q000150:complications / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010315:Particle Accelerators; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology; D019851:Thrombophilia / Q000209:etiology*; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001779:Blood Coagulation Factors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013450:Sulfones; C045072:macrophage procoagulant activity; D013925:Thromboplastin; D015951:Factor Xa