CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury.
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.
Belperio
John A
JA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA. jbelperio@mednet.ucla.edu
Keane
Michael P
MP
Burdick
Marie D
MD
Gomperts
Brigitte N
BN
Xue
Ying Ying
YY
Hong
Kurt
K
Mestas
Javier
J
Zisman
David
D
Ardehali
Abbas
A
Saggar
Rajan
R
Lynch
Joseph P
JP
Ross
David J
DJ
Strieter
Robert M
RM
D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D019743:Chemokines, CXC / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D011446:Prospective Studies; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000209:etiology* / Q000276:immunology* / Q000473:pathology
D019743:Chemokines, CXC; D008024:Ligands; D023063:Receptors, Interleukin-8B; D004247:DNA