CXCR2/CXCR2 Ligand Biology during Lung Transplant Ischemia-Reperfusion Injury

• Published in: Journal of Immunology 2005-11, Vol.175 (10), p.6931-6939
• Main Authors: Belperio, John A, Keane, Michael P, Burdick, Marie D, Gomperts, Brigitte N, Xue, Ying Ying, Hong, Kurt, Mestas, Javier, Zisman, David, Ardehali, Abbas, Saggar, Rajan, Lynch, Joseph P., III, Ross, David J, Strieter, Robert M
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Case-Control Studies; Chemokines, CXC - metabolism; Disease Models, Animal; DNA - genetics; Female; Humans; Ligands; Lung - immunology; Lung - pathology; Lung Injury; Lung Transplantation - adverse effects; Lung Transplantation - immunology; Lung Transplantation - pathology; Male; Middle Aged; Neutrophils - immunology; Neutrophils - pathology; Prospective Studies; Rats; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - metabolism; Reperfusion Injury - etiology; Reperfusion Injury - immunology; Reperfusion Injury - pathology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.175.10.6931

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.