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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1130.)
© 2004 American Heart Association, Inc.

Thrombosis

Deep Vein Thrombosis Resolution Is Modulated by Monocyte CXCR2-Mediated Activity in a Mouse Model

Peter K. Henke; Andrea Varga; Sumit De; C. Barry Deatrick; Jonathon Eliason; Douglas A. Arenberg; Pasu Sukheepod; Porama Thanaporn; Steven L. Kunkel; Gilbert R. Upchurch, Jr; Thomas W. Wakefield

From the Section of Vascular Surgery, Jobst Vascular Research Laboratory, Department of Surgery (P.K.H., A.V., S.D., C.B.D., J.E., P.S., P.T., G.R.U., T.W.W.), the Division of Pulmonary Medicine, Department of Medicine (D.A.A.), and the Department of Pathology (S.L.K.), University of Michigan Medical School, Ann Arbor, Mich.

Correspondence to Dr Peter K. Henke, 1500 East Medical Center Drive, Room 2210 Taubman Health Care Center, Ann Arbor, MI 48109-0329. E-mail henke{at}umich.edu

Objective— 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.

Methods and Results— 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.

Conclusions— Normal DVT resolution involves CXCR2-mediated neovascularization, collagen turnover, and fibrinolysis, and it is probably primarily monocyte-dependent.

The role of CXCR2 activity on DVT resolution was determined. Thrombi in CXCR2^–/– or anti-CXCR2–treated mice had fewer PMN and monocytes and impaired early DVT resolution. PMN depletion did not affect DVT resolution to the same degree, suggesting monocytic CXCR2-mediated activity is more important for DVT resolution.

Key Words: inflammation • chemokines • neutrophils • angiogenesis

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