Abstract 18331: Microvascular Thrombosis Increases Pro-inflammatory Gr-1(+) Cd11b(+) Myeloid Cells Activation and Promotes Endothelial Barrier Disruption
Vascular thrombosis triggered by accumulation of fibrin results in regional ischemia and blood vessel pathology. Growing evidence demonstrates a strong correlation between thrombogenesis, cardiovascular thrombotic diseases and inflammation. However, the mechanisms that could explain this link are still warranted. Addressing this question, we studied the association between microvascular thrombosis, vascular integrity and pro-inflammatory CD11b+ cells response using plasminogen-deficient mice (Pg-/-; B6.129P2-Plgtm1Jld/J) whose fibrinolytic system is impaired in the microcirculation.
Methods: Pg-/- mice (25±5 weeks old) were compared to heterozygote (Pg+/-) and wild type (Pg+/+) littermates. The total blood cell count, flow-cytometry analysis of leukocytes, and cytokine mRNA levels in lung tissue were assessed. The endothelial barrier permeability of lung microvasculature was also analyzed.
Results: Adult Pg-/- mice developed systemic microvascular thrombosis affecting lung tissue as well. Pathological fibrin deposition in microcirculation induced significant increase in platelets (1.4-fold, p<0.001), monocytes (1.7-fold, p<0.01) and granulocytes (3.5-fold, p<0.001) levels in the blood compared to Pg+/- and Pg+/+ controls. Moreover, pro-thrombotic Pg-/- mice had microcytic anemia due to low red blood cell volume (36.7 fl versus 41.6 fl, p<0.001) and reduced level of hemoglobin (12.4 g/dl versus 14.6 g/dl, p<0.001). Analysis of leukocytes obtained from the blood and lungs of Pg-/- mice showed the significant expansion of activated CD11b+ cell type. Further characterization of these CD11b+ cells by flow cytometry revealed a population with a phenotype of CD11b(+)Gr-1(+). The CD11b+ associated level of VCAM-1 was also significantly elevated (2.0-fold, p<0.05). Moreover, lung micro-thrombosis in Pg-/- mice was associated with increased endothelial permeability (1.3-fold, p<0.05) and up-regulation of TNF-α mRNA expression.
Conclusion: In a mouse model, microvascular thrombosis promotes the increase of pro-inflammatory GR-1(+)CD11b(+) myeloid cells and endothelial barrier disruption. Our data suggest that Pg-/- mice may be an adequate model for further study of therapeutic approaches against vascular leakage.
- © 2011 by American Heart Association, Inc.