Pre-B-Cell Colony-enhancing Factor as a Potential Novel Biomarker in Acute Lung Injury

• Published in: American journal of respiratory and critical care medicine Vol. 171; no. 4; pp. 361 - 370
• Main Authors: Ye, Shui Q, Simon, Brett A, Maloney, James P, Zambelli-Weiner, April, Gao, Li, Grant, Audrey, Easley, R. Blaine, McVerry, Bryan J, Tuder, Rubin M, Standiford, Theodore, Brower, Roy G, Barnes, Kathleen C, Garcia, Joe G. N
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.02.2005; American Lung Association; American Thoracic Society
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Biomarkers; Biomarkers - metabolism; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Bone marrow, stem cells transplantation. Graft versus host reaction; Bronchoalveolar Lavage Fluid; Cytokines; Cytokines - genetics; Disease Models, Animal; Dogs; Endothelium; Female; Gene expression; Gene Expression Profiling - methods; Humans; Intensive care medicine; Lavage; Localization; Lung diseases; Male; Medical sciences; Mice; Middle Aged; Mortality; Neutrophils; Nicotinamide Phosphoribosyltransferase; Oligonucleotide Array Sequence Analysis - methods; Pathophysiology; Polymerase chain reaction; Polymerase Chain Reaction - methods; Polymorphism; Polymorphism, Single Nucleotide - genetics; Predictive Value of Tests; Proteins; Reference Values; Respiratory Distress Syndrome, Adult - complications; Respiratory Distress Syndrome, Adult - diagnosis; Respiratory Distress Syndrome, Adult - genetics; Sepsis; Sepsis - complications; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor necrosis factor-TNF; Ventilation; Ventilators; Lung disease; Intensive care; Respiratory disease; single nucleotide polymorphism; Gene expression; Resuscitation; Polymorphism
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200404-563OC

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.