Experimental pulmonary embolism: Effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin

Rectenwald, John E.; Deatrick, Kristopher B.; Sukheepod, Pasu; Lynch, Erin M.; Moore, Anne; Moaveni, Daria M.; Deywer, Nicholas A.; Luke, Catherine E.; Upchurch, Gilbert R.; Wakefield, Thomas W.; Kunkel, Steven L.; Henke, Peter K.

doi:10.1016/j.jvs.2005.12.010

Cited by 22 publications

(16 citation statements)

References 27 publications

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“…The most significantly regulated genes in a differential manner were related to cardiomyopathy and inflammation. Our results are consistent with recent studies reporting significant changes of pulmonary artery during PTE[51–53]. …”

Section: Discussionsupporting

confidence: 94%

“…It was reported more than 30 years ago that white blood cell count was significantly associated with incidence and mortality of coronary heart disease[58]. Recently, both epidemiological and clinical studies have shown that inflammatory and immune response play important roles in pulmonary embolism (PE): gene expression of type I and II IFN was significantly associated with PE[59]; protein levels of C-reactive protein (CRP), fibrinogene, and leukocyte count were associated with chronic obstructive pulmonary disease (COPD)[60]; gene expression profiling of lung tissues in PE has identified differentially expressed genes enriched in inflammatory, defense and immune response pathways[53]. …”

Section: Discussionmentioning

confidence: 99%

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Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

et al. 2016

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Acute pulmonary thromboembolism (PTE) refers to the obstruction of thrombus in pulmonary artery or its branches. Recent studies have suggested that PTE-induced endothelium injury is the major physiological consequence of PTE. And it is reasonal to use PTE-induced endothelium injury to stratify disease severity. According to the massive morphologic and histologic findings, rabbit models could be applied to closely mimic the human PE. Genomewide gene expression profiling has not been attempted in PTE. In this study, we determined the accuracy of rabbit autologous thrombus PTE model for human PTE disease, then we applied gene expression array to identify gene expression changes in pulmonary arteries under PTE to identify potential molecular biomarkers and signaling pathways for PTE. We detected 1343 genes were upregulated and 923 genes were downregulated in PTE rabbits. The expression of several genes (IL-8, TNF-α, and CXCL5) with functional importance were further confirmed in transcript and protein levels. The most significantly differentially regulated genes were related to inflammation, immune disease, pulmonary disease, and cardiovascular diseases. Totally 87 genes were up-regulated in the inflammatory genes. We conclude that gene expression profiling in rabbit PTE model could extend the understanding of PTE pathogenesis at the molecular level. Our study provides the fundamental framework for future clinical research on human PTE, including identification of potential biomarkers for prognosis or therapeutic targets for PTE.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

et al. 2016

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“…In the case of silicone embolism, the mediation of immunological agents is supported by findings in experimental animals, in which the introduction of solid silicone emboli has been followed by increased levels of inflammation mediators and hyperplasia of arterial intima [26]. In the present case, the triggering of inflammatory mechanisms by the presence of silicone in small blood vessels is suggested by the patient's high platelet count and sedimentation rate [27].…”

Section: Discussionsupporting

confidence: 65%

Pneumonitis caused by silicone gel following breast implant rupture

et al. 2009

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“…28 We measured proinflammatory IL-1β and profibrotic cytokine IL-13 to test this hypothesis in our model. We found no differences in vein wall IL-1β (Fig 5, A ), but intrathrombus IL-1β was significantly reduced in the WT mice treated with LMWH at days 2 and 6 and in PAI-l −/− mice treated with LMWH at day 6 ( P < .05; n = 4–5; Fig 5, B ).…”

Section: Resultsmentioning

confidence: 99%

Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

Obi

Diaz

Ballard-Lipka

et al. 2014

Journal of Vascular Surgery: Venous and Lymphatic Disorders

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Background Treatment with low-molecular-weight heparin (LMWH) favorably alters the vein wall response to deep venous thrombosis (DVT), although the mechanisms remain unclear. Previous studies have suggested that LMWH alters the levels of circulating plasminogen activator inhibitor 1 (PAI-1), a known mediator of fibrosis, and may improve endogenous fibrinolysis. We hypothesized that LMWH favorably alters the vein wall response by binding of PAI-1 and acceleration of fibrinolysis. Methods Wild-type and PAI-1 −/− mice underwent treatment with LMWH after induction of occlusive DVT. Vein wall and plasma were harvested and analyzed by enzyme-linked immunosorbent assay, zymography, real-time polymerase chain reaction, and immunohistochemistry. Results Wild-type mice treated with LMWH exhibited diminished vein wall fibrosis (0.6 ± 0.6 vs 1.4 ± 0.2; P < .01; n = 5) and elevation of circulating PAI-1 (1776 ± 342 vs 567 ± 104 ρg/mL; P < .01; n = 5) compared with untreated controls after occlusive DVT. PAI-1−/− mice treated with LMWH were not similarly protected from fibrosis, despite improved thrombus resolution. Treatment with LMWH was associated with decreased intrathrombus interleukin-lβ (68.6 ± 31.0 vs 223.4 ± 28.9 ρg/mg total protein; P < .01; n = 5) but did not alter inflammatory cell recruitment to the vein wall. PAI-1 −/− mice exhibited significantly elevated intrathrombus (257.2 ± 51.5 vs 4.3 ± 3.8 ρg/mg total protein; n = 5) and vein wall interleukin-13 (187.2 ± 57.6 vs 9.9 ± 1.1 ρg/mg total protein; P < .05; n = 5) as well as vein wall F4/80 positively staining monocytes (53 ± 11 vs 16 ± 2 cells/5 high-power fields; P < .05; n = 4). Conclusions LMWH did not accelerate venous thrombosis resolution but did protect against vein wall fibrosis in a PAI-1-dependent manner in an occlusive DVT model. Lack of PAI-1 correlated with accelerated venous thrombosis resolution but no protection from fibrosis. PAI-1 inhibition as a treatment strategy for DVT is likely to accelerate clearance of the thrombus but may come at the expense of increased vein wall fibrosis. Clinical Relevance The pathophysiologic mechanism of post-thrombotic syndrome is not well understood clinically or experimentally. In this study, we evaluated the effect of the prominent fibrinolytic mechanism, plasminogen activator inhibitor 1 (PAI-1), and low-molecular-weight heparin (LMWH) on vein wall injury after thrombosis. We show here that LMWH is protective from vein wall fibrosis, but this is abrogated in PAI-1-deleted mice. This is also correlated with monocyte vein wall influx. These data support the clinical observation that LMWH may be protective from post-thrombotic vein wall injury in a PAI-1-dependent manner.

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Experimental pulmonary embolism: Effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin

Cited by 22 publications

References 27 publications

Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

Gene Expression Profiling of Pulmonary Artery in a Rabbit Model of Pulmonary Thromboembolism

Pneumonitis caused by silicone gel following breast implant rupture

Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

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