fibrin and Neutropenia

To determine the role of CXCR2, the receptor for cysteine-X-cysteine (CXC) chemokines, and its primary effector cell, the neutrophil (PMN), on deep venous thrombosis (DVT) resolution.. DVT in BALB/c, anti-CXCR2 antibody-treated, and BALB/c CXCR2(-/-) mice were created by infrarenal inferior vena cava (IVC) ligation and the thrombus harvested at various time points over 21 days. The CXCR2(-/-) mice had significantly larger thrombi at early time points (days 2 to 8), and significantly decreased intrathrombus PMNs, monocytes, and neovascularization as compared with controls. Thrombus KC/CXCL1 was significantly higher at 2 days in CXCR2-/- thrombi as measured by enzyme-linked immunosorbent assay. Fibrin content was significantly higher, with less uPA gene expression at 4 days in CXCR2-/- thrombi. Late fibrotic maturation of the thrombus was delayed in the CXCR2-/- mice, with significantly decreased 8 day MMP-2 activity, whereas MMP-9 activity was elevated as compared with controls. Similar impairment in DVT resolution was found at 8 days with anti-CXCR2 inhibition. However, systemic neutropenia, unlike CXCR2 deletion, did not increase the thrombus size as compared with controls.. Normal DVT resolution involves CXCR2-mediated neovascularization, collagen turnover, and fibrinolysis, and it is probably primarily monocyte-dependent.

Topics: Animals; Cells, Cultured; Chemokine CXCL1; Chemokines, CXC; Chemotaxis; Collagen; Endothelial Cells; Fibrin; Fibroblast Growth Factor 2; Humans; Intercellular Signaling Peptides and Proteins; Laminin; Ligation; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Knockout; Models, Animal; Monocytes; Neovascularization, Pathologic; Neutropenia; Neutrophils; Receptors, Interleukin-8B; Vascular Endothelial Growth Factor A; Vena Cava, Inferior; Venous Thrombosis

This study examines the role of neutrophils (PMN) in the pathogenesis of endotoxin-induced microclot formation. It is intended to clarify whether granulocytes are involved in endotoxin-induced activation of intravascular coagulation (generation of soluble fibrin) and/or in endotoxin-induced precipitation of soluble fibrin. Precipitation of soluble fibrin was achieved by injection of endotoxin into ancrod-infused rabbits with circulating soluble fibrin (first model). Activation of intravascular coagulation was elicited by two intravenous injections of endotoxin into rabbits (second model). Seventy-two and ninety-six hours after injection of nitrogen mustard, leukopenic rabbits had PMN counts between 0 and 50 cells per mul. Neutropenia did not prevent the occurrence of glomerular microclots after infusion of ancrod and injection of endotoxin (first model). Neutropenia influenced neither the decrease in mean fibrinogen concentrations nor the drop in mean platelet counts after ancrod and endotoxin administration. In contrast to the first model, neutropenia prevented the occurrence of glomerular microclots and of circulating soluble fibrin after two injections of endotoxin (second model). It did not, however, protect rabbits from the decrease in mean platelet counts after endotoxin administration. These data indicate that granulocytes are involved in endotoxin-induced activation of intravascular coagulation and the production of soluble fibrin but are not essential to endotoxin-induced precipitation of soluble fibrin.

Topics: Animals; Blood Cell Count; Blood Platelets; Disseminated Intravascular Coagulation; Endotoxins; Female; Fibrin; Fibrinogen; Granulocytes; Hematocrit; Kidney Glomerulus; Leukocyte Count; Leukocytes; Male; Neutropenia; Neutrophils; Nitrogen Mustard Compounds; Rabbits; Salmonella enteritidis; Solubility; Tryptophan; Venoms