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Hypoxia dysregulates fibrinolytic pathways in cultured human mesothelial cells (HMCs): Implications for intraabdominal adhesion formation
Author(s) -
Currie Brian,
Heydrick Stanley J,
Stucchi Arthur F
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.717.2
Subject(s) - thrombomodulin , fibrin , extravasation , hypoxia (environmental) , tissue factor pathway inhibitor , tissue factor , chemistry , thrombin , medicine , endocrinology , immunology , platelet , coagulation , organic chemistry , oxygen
Abdominal surgery induces mesothelial injury and the extravasation of a fibrinous exudate into the peritoneum. The ensuing deposition of a fibrin matrix serves as a precursor to adhesions. Our aim was to determine the mechanism(s) by which injury‐induced hypoxia and/or inflammation contribute to the formation of the fibrin matrix, the precursor of adhesions. Cultured HMCs were treated with either an inflammatory cytokine cocktail of TGFβ+IL‐1β+IFN‐γ (C), the hypoxia mimetic dimethyloxaloglycine (D) or both, and mRNA levels for vascular endothelial growth factor (VEGF; extravasation), protein c receptor (PrCR; inhibits Protein C activation), thrombomodulin (TM; inhibits thrombin), and tissue factor (TF; activates thrombin) were measured at 1, 3, 6, 12 & 18 hrs via RT‐PCR. VEGF mRNA was increased by both D (peak: 6hr, 8±2.3 fold vs. control), and C (peak 12 hr: 7±0.1 fold, both p<.01) at all times, and the combination was additive. Hypoxia reduced PrCR mRNA levels to a min at 18 hr (0.5±0.06 fold, p<.05) and elevated TF mRNA levels to a max at 18 hr (3.5±0.9 fold; p<.05). TM mRNA levels were decreased by D and D+C to a min at 18 hr (0.25±0.06 fold, p<.05). These data show that hypoxia impairs fibrinolytic pathways in HMCs and may promote adhesion formation. Funded by Cooper‐Tyler Endowment, Department of Surgery, Boston University Medical Center.