title: Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling.
abstract: OBJECTIVE
  Deep vein thrombosis (VT) can result in vein wall injury, which clinically manifests as post-thrombotic syndrome. Postinjury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7)-mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7.
  
  
  RESULTS
  CCR7(-/-) and C57BL/6 wild-type mice had inferior vena cava VT induced by nonstasis or stasis mechanisms. In both models, VT size was largest at day 1 and trended down by day 21, and CCR7(+) cells peaked at day 8 in wild-type mice. No significant differences in VT resolution were found in CCR7(-/-) as compared with wild type in either model. In the nonstasis VT model, vein wall changes consistent with fibrotic injury were evidenced by significant increases in collagen I, III, matrix metalloproteinase 2, and transforming growth factor-β gene expression, increases in α-smooth muscle actin and fibroblast specific protein-1 antigen, and total collagen at 8 days. Correspondingly, SM22α and fibroblast specific protein-1, but not DDR2(+) cells, were increased at 8 days. Early wild-type thrombus exposure inhibited profibrotic gene expression in CCR7(-/-) in ex vivo vein wall culture. Bone marrow chimera experiments further showed that circulating CCR7(+) leukocytes partially rescued midterm profibrotic changes in CCR7(-/-) mice. In human histological sections of chronic thrombosed femoral veins, CCR7(+) cells were present in the fibrotic areas.
  
  
  CONCLUSIONS
  Post-thrombotic vein wall remodeling is impaired in CCR7(-/-) mice, with a profibrotic phenotype, is dependent on the thrombotic mechanism, and is mediated by circulating CCR7(+) cells. Unlike other postinjury fibrotic responses, CCR7(+) signaling may be important for positive vein wall remodeling after VT.
authors: From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, Department of Surgery (A.L., M.E., C.L., D.S., A.S., V.S., B.D., B.M., S.K., C.H., P.K.H.) and Department of Pathology (A.L., M.E., C.L., D.S., A.S., V.S., B.D., B.M., S.K., C.H., P.K.H.), University of Michigan Medical School, Ann Arbor; and Jobst Vascular Center, Toledo, OH (C.O, A.C.).
authors: Adriana
authors: A
authors: Laser
authors: Megan
authors: M
authors: Elfline
authors: Cathy
authors: C
authors: Luke
authors: Dallas
authors: D
authors: Slack
authors: Anuj
authors: A
authors: Shah
authors: Vikram
authors: V
authors: Sood
authors: Barry
authors: B
authors: Deatrick
authors: Brendan
authors: B
authors: McEvoy
authors: Carson
authors: C
authors: Ostra
authors: Anthony
authors: A
authors: Comerota
authors: Steven
authors: S
authors: Kunkel
authors: Cory
authors: C
authors: Hogaboam
authors: Peter K
authors: PK
authors: Henke
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005838:Genotype; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010641:Phenotype; D054070:Postthrombotic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014682:Vena Cava, Inferior / Q000378:metabolism* / Q000473:pathology; D020246:Venous Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D024042:Collagen Type I; D024061:Collagen Type III; D008840:Microfilament Proteins; D009124:Muscle Proteins; D054400:Receptors, CCR7; D016212:Transforming Growth Factor beta; C051615:transgelin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: chemokines; fibrosis; inflammation; leukocytes