OBJECTIVES: Fibrocytes are integral in the development of fibroproliferative disease after lung transplantation. Undifferentiated fibrocytes (CD45+anti-collagen 1+CXCR4+) preferentially traffic by way of the CXCR4/CXCL12 axis and differentiate into smooth muscle actin-producing (CD45+CXCR4+α-smooth muscle actin+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts. METHODS: A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. The mice were treated with either goat-anti-human CXCL12 F(ab')(2) or goat IgG F(ab')(2). Buffy coat, bone marrow, and trachea allografts were collected and analyzed using flow cytometry. Tracheal luminal obliteration was assessed using hematoxylin-eosin and Direct Red 80 collagen stain. RESULTS: Compared with the controls, the anti-CXCL12-treated mice showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days after transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In the anti-CXCL12-treated mice, there was a 35% decrease in luminal obliteration at 21 days (65% vs 100% obliterated; interquartile range, 38% vs 10%; P = .010) and decreased luminal collagen deposition at 21 and 28 days after transplantation (P = .042 and P = .012, respectively). CONCLUSIONS: Understanding the role of fibrocytes in airway fibrosis after lung transplantation could lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced the deterioration of the tracheal allografts. Thus, the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration after lung transplantation, and the quantification of fibrocyte populations could provide clinicians with a biomarker of fibrosis, allowing individualized drug therapy.
OBJECTIVES: Fibrocytes are integral in the development of fibroproliferative disease after lung transplantation. Undifferentiated fibrocytes (CD45+anti-collagen 1+CXCR4+) preferentially traffic by way of the CXCR4/CXCL12 axis and differentiate into smooth muscle actin-producing (CD45+CXCR4+α-smooth muscle actin+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts. METHODS: A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. The mice were treated with either goat-anti-humanCXCL12 F(ab')(2) or goat IgG F(ab')(2). Buffy coat, bone marrow, and trachea allografts were collected and analyzed using flow cytometry. Tracheal luminal obliteration was assessed using hematoxylin-eosin and Direct Red 80 collagen stain. RESULTS: Compared with the controls, the anti-CXCL12-treated mice showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days after transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In the anti-CXCL12-treated mice, there was a 35% decrease in luminal obliteration at 21 days (65% vs 100% obliterated; interquartile range, 38% vs 10%; P = .010) and decreased luminal collagen deposition at 21 and 28 days after transplantation (P = .042 and P = .012, respectively). CONCLUSIONS: Understanding the role of fibrocytes in airway fibrosis after lung transplantation could lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced the deterioration of the tracheal allografts. Thus, the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration after lung transplantation, and the quantification of fibrocyte populations could provide clinicians with a biomarker of fibrosis, allowing individualized drug therapy.
Authors: G I Snell; V G Valentine; P Vitulo; A R Glanville; D C McGiffin; J E Loyd; A Roman; R Aris; A Sole; A Hmissi; U Pirron Journal: Am J Transplant Date: 2006-01 Impact factor: 8.086
Authors: John M Kovarik; Gregory I Snell; Vincent Valentine; Robert Aris; Charles K N Chan; Heinz Schmidli; Ulrich Pirron Journal: J Heart Lung Transplant Date: 2006-04 Impact factor: 10.247
Authors: Jan Groetzner; Felix Kur; Fritz Spelsberg; Jurgen Behr; Lorenz Frey; Iris Bittmann; Michael Vogeser; Peter Ueberfuhr; Bruno Meiser; Rudolf Hatz; Bruno Reichart Journal: J Heart Lung Transplant Date: 2004-05 Impact factor: 10.247
Authors: Roderick J Phillips; Marie D Burdick; Kurt Hong; Marin A Lutz; Lynne A Murray; Ying Ying Xue; John A Belperio; Michael P Keane; Robert M Strieter Journal: J Clin Invest Date: 2004-08 Impact factor: 14.808
Authors: M Okazaki; A S Krupnick; C G Kornfeld; J M Lai; J H Ritter; S B Richardson; H J Huang; N A Das; G A Patterson; A E Gelman; D Kreisel Journal: Am J Transplant Date: 2007-06 Impact factor: 8.086
Authors: Melissa B King-Biggs; Jordan M Dunitz; Soon J Park; S Kay Savik; Marshall I Hertz Journal: Transplantation Date: 2003-05-15 Impact factor: 4.939
Authors: Takeshi Mimura; Natalie Walker; Yoshiro Aoki; Casey M Manning; Benjamin J Murdock; Jeffery L Myers; Amir Lagstein; John J Osterholzer; Vibha N Lama Journal: Am J Pathol Date: 2015-04-04 Impact factor: 4.307
Authors: Jacob R Gillen; Yunge Zhao; David A Harris; Damien J LaPar; Irving L Kron; Christine L Lau Journal: Ann Thorac Surg Date: 2013-06-24 Impact factor: 4.330
Authors: Hirotaka Suga; Robert C Rennert; Melanie Rodrigues; Michael Sorkin; Jason P Glotzbach; Michael Januszyk; Toshihiro Fujiwara; Michael T Longaker; Geoffrey C Gurtner Journal: Stem Cells Date: 2014-05 Impact factor: 6.277
Authors: Jacob R Gillen; Yunge Zhao; David A Harris; Damien J Lapar; Matthew L Stone; Lucas G Fernandez; Irving L Kron; Christine L Lau Journal: Ann Thorac Surg Date: 2013-04-02 Impact factor: 4.330