Document Detail

CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.
MedLine Citation:
PMID:  24063316     Owner:  NLM     Status:  MEDLINE    
RATIONALE: 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.
OBJECTIVES: 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.
MEASUREMENTS AND MAIN 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.
Michael Y Shino; S Samuel Weigt; Ning Li; Vyacheslav Palchevskiy; Ariss Derhovanessian; Rajan Saggar; David M Sayah; Aric L Gregson; Michael C Fishbein; Abbas Ardehali; David J Ross; Joseph P Lynch; Robert M Elashoff; John A Belperio
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  188     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2013 Nov 
Date Detail:
Created Date:  2013-11-04     Completed Date:  2013-12-26     Revised Date:  2014-01-14    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1117-25     Citation Subset:  AIM; IM    
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MeSH Terms
Acute Lung Injury / immunology*,  pathology
Bronchoalveolar Lavage Fluid / immunology
Chemokine CXCL10 / immunology*
Chemokine CXCL11 / immunology*
Chemokine CXCL9 / immunology*
Graft Rejection / immunology*
Graft Survival
Kaplan-Meier Estimate
Linear Models
Lung Transplantation*
Middle Aged
Proportional Hazards Models
Pulmonary Alveoli / pathology*
Receptors, CXCR3 / immunology
Retrospective Studies
Transplants / immunology,  pathology,  physiopathology*
Grant Support
Reg. No./Substance:
0/CXCL10 protein, human; 0/CXCL11 protein, human; 0/CXCL9 protein, human; 0/CXCR3 protein, human; 0/Chemokine CXCL10; 0/Chemokine CXCL11; 0/Chemokine CXCL9; 0/Ligands; 0/Receptors, CXCR3

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