Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.
Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment.
Belperio
John A
JA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. jbelperio@mednet.ucla.edu
Keane
Michael P
MP
Burdick
Marie D
MD
Gomperts
Brigitte
B
Xue
Ying Ying
YY
Hong
Kurt
K
Mestas
Javier
J
Ardehali
Abbas
A
Mehrad
Borna
B
Saggar
Rajan
R
Lynch
Joseph P
JP
Ross
David J
DJ
Strieter
Robert M
RM
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D013997:Time Factors; D014132:Trachea / Q000378:metabolism / Q000637:transplantation; D001620:beta-Thromboglobulin
D016209:Interleukin-8; C061615:PPBP protein, human; D010455:Peptides; D023063:Receptors, Interleukin-8B; D001620:beta-Thromboglobulin