CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.
BACKGROUND
After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process.


OBJECTIVE
Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology.


METHODS
Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates.


RESULTS
There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD.


CONCLUSIONS
DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
Michael Y
MY
Shino
S Samuel
SS
Weigt
Ning
N
Li
Vyacheslav
V
Palchevskiy
Ariss
A
Derhovanessian
Rajan
R
Saggar
David M
DM
Sayah
Aric L
AL
Gregson
Michael C
MC
Fishbein
Abbas
A
Ardehali
David J
DJ
Ross
Joseph P
JP
Lynch
Robert M
RM
Elashoff
John A
JA
Belperio
D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology*; D054371:Chemokine CXCL11 / Q000276:immunology*; D054370:Chemokine CXCL9 / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D008024:Ligands; D016014:Linear Models; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011650:Pulmonary Alveoli / Q000473:pathology*; D054367:Receptors, CXCR3 / Q000276:immunology; D012189:Retrospective Studies; D019737:Transplants / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*
C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D008024:Ligands; D054367:Receptors, CXCR3