CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury.

Abstract

Lung transplantation is a therapeutic option for a number of end-stage pulmonary disorders. Early lung allograft dysfunction (ischemia-reperfusion injury) continues to be the most common cause of early mortality after lung transplantation and a significant risk factor for the development of bronchiolitis obliterans syndrome. Ischemia-reperfusion injury is characterized histopathologically by lung edema and a neutrophil predominate leukocyte extravasation. The specific mechanism(s) that recruit leukocytes to the lung during post-lung transplantation ischemia-reperfusion injury have not been fully elucidated. Because the ELR+ CXC chemokines are potent neutrophil chemoattractants, we investigated their role during post-lung transplantation ischemic-reperfusion injury. We found elevated levels of multiple ELR+ CXC chemokines in human bronchoalveolar lavage fluid from patients with ischemia-reperfusion injury. Proof of concept studies using a rat orthotopic lung transplantation model of "cold" ischemic-reperfusion injury demonstrated an increase in lung graft neutrophil sequestration and injury. In addition, lung expression of CXCL1, CXCL2/3, and their shared receptor CXCR2 paralleled lung neutrophil infiltration and injury. Importantly, inhibition of CXCR2/CXCR2 ligand interactions in vivo led to a marked reduction in lung neutrophil sequestration and graft injury. Taken together these experiments support the notion that increased expression of ELR+ CXC chemokines and their interaction with CXCR2 plays an important role in the pathogenesis of post-lung transplantation cold ischemia-reperfusion injury.

• Authors: John A Belperio, Michael P Keane, Marie D Burdick, Brigitte N Gomperts, Ying Ying Xue, Kurt Hong, Javier Mestas, David Zisman, Abbas Ardehali, Rajan Saggar, Joseph P Lynch 3rd, David J Ross, Robert M Strieter
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 10 Pg. 6931-9 (Nov 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 16272353 (Publication Type: Journal Article)

Chemical References

• Chemokines, CXC
• Ligands
• Receptors, Interleukin-8B
• DNA

Topics

• Animals
• Base Sequence
• Case-Control Studies
• Chemokines, CXC (metabolism)
• DNA (genetics)
• Disease Models, Animal
• Female
• Humans
• Ligands
• Lung (immunology, pathology)
• Lung Injury
• Lung Transplantation (adverse effects, immunology, pathology)
• Male
• Middle Aged
• Neutrophils (immunology, pathology)
• Prospective Studies
• Rats
• Receptors, Interleukin-8B (genetics, metabolism)
• Reperfusion Injury (etiology, immunology, pathology)