Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury.
Although the pathogenic and genetic basis of acute lung injury (ALI) remains incompletely understood, the identification of novel ALI biomarkers holds promise for unique insights. Expression profiling in animal models of ALI (canine and murine) and human ALI detected significant expression of pre-B-cell colony-enhancing factor (PBEF), a gene not previously associated with lung pathophysiology. These results were validated by real-time polymerase chain reaction and immunohistochemistry studies, with PBEF protein levels significantly increased in both bronchoalveolar lavage fluid and serum of ALI models and in cytokine- or cyclic stretch-activated lung microvascular endothelium. We genotyped two PBEF single-nucleotide polymorphisms (SNPs) in a well characterized sample of white patients with sepsis-associated ALI, patients with severe sepsis, and healthy subjects and observed that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI (95% confidence interval 3.01-19.75, p < 0.001). The T variant from the SNP C-1543T resulted in a significant decrease in the transcription rate (1.8-fold; p < 0.01) by the reporter gene assay. Together, these results strongly indicate that PBEF is a potential novel biomarker in ALI and demonstrate the successful application of robust genomic technologies in the identification of candidate genes in complex lung disease.
Ye
Shui Q
SQ
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building/Center Tower #664, Baltimore, MD 21224, USA. syq@jhmi.edu
Simon
Brett A
BA
Maloney
James P
JP
Zambelli-Weiner
April
A
Gao
Li
L
Grant
Audrey
A
Easley
R Blaine
RB
McVerry
Bryan J
BJ
Tuder
Rubin M
RM
Standiford
Theodore
T
Brower
Roy G
RG
Barnes
Kathleen C
KC
Garcia
Joe G N
JG
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D054409:Nicotinamide Phosphoribosyltransferase; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D012016:Reference Values; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D018805:Sepsis / Q000150:complications
D015415:Biomarkers; D016207:Cytokines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human