Abstract 196: Matrix Metalloproteinases Regulation in Thrombus Resolution Is Independent of TGF-β in a PAI-1 Ko Mouse Model of Venous Thrombosis
Bibliographic record
Abstract
Introduction: Plasminogen activator inhibitor (PAI-1) is the primary regulator of urokinase (u-PA) and tissue (t-PA) plasminogen activators. Observations in mice with impaired fibrinolysis have demonstrated an alternate pathway of thrombus resolution by matrix metalloproteinase (MMP)- 9 and 2. TGF-β is a potent inducer of TIMP-1 expression and is found in both thrombus and vein wall post-thrombosis. Hypothesis: PAI-1 deficiency and resulting hyperfibrinolytic state will improve thrombus resolution and result in reciprocal downregulation of MMP-2 and MMP-9 via TGF-beta induction of TIMP-1, resulting in decreased vein wall fibrosis. Methods: Inferior vena cava (IVC) ligation was performed in wild-type (WT) mice (N=194) and PAI-1 deficent mice (N=164). IVC, thrombus and blood samples were collect at 2, 6 and 14 days post procedure. The IVC and thrombus were assessed for thrombus weight and samples collected for zymography (MMP-2 and MMP-9), ELISA (TIMP-1, TGF-β) and histology. Results: PAI-1 deficient mice had similar thrombus weight (TW) versus WT at 2 days, but smaller at days 6 (p<0.0001) and 14 (p=0.0085). In thrombus and vein wall (VW), active MMP-9 was decreased in acute thrombosis (p<0.0001), and MMP-2 was decreased during late thrombus resolution (p<0.05). TIMP-1 levels in VW were elevated across all time points (p<0.05), whereas VW TGF-beta was not different compared to WT. Neutrophils were decreased at day 2 (p = 0.0309) and monocytes decreased at day 14 (p = 0.0028). Conclusions: (1) PAI-1 deficient mice exhibit a hyperfibrinolytic phenotype with normal thrombotic response to IVC ligation, but improved thrombus resolution when compared to WT mice. (2) MMP-9 and MMP-2 were suppressed, confirming a reciprocal relationship between plasmin and MMP activation as mediators of thrombus resolution. (3) TIMP-1 production was elevated in vein wall independent of TGF-beta. (4) Decreased neutrophils at day 2 correlated with decreased MMP-9 and decreased monocytes at day 14 correlated with decreased MMP-2, suggesting a plasmin-induced inhibition of leukocyte recruitment. (5) Final histology showed no difference in vein wall fibrosis or thickness at chronic time points, indicating that improved thrombus resolution does not lessen vein wall fibrosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".