Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.

Abstract

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.

• Authors: John A Belperio, Michael P Keane, Marie D Burdick, Brigitte Gomperts, Ying Ying Xue, Kurt Hong, Javier Mestas, Abbas Ardehali, Borna Mehrad, Rajan Saggar, Joseph P Lynch, David J Ross, Robert M Strieter
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 5 Pg. 1150-62 (May 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15864347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-8
• PPBP protein, human
• Peptides
• Receptors, Interleukin-8B
• beta-Thromboglobulin

Topics

• Animals
• Bronchiolitis Obliterans (metabolism)
• Humans
• Interleukin-8 (metabolism)
• Mice
• Neovascularization, Pathologic (metabolism)
• Peptides (metabolism)
• Receptors, Interleukin-8B (metabolism)
• Time Factors
• Trachea (metabolism, transplantation)
• beta-Thromboglobulin