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Published ahead of print on July 24, 2008, doi:10.1164/rccm.200712-1822OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 6, September 2008, 605-617

A more recent version of this article appeared on September 15, 2008
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Submitted on December 13, 2007
Accepted on July 21, 2008

Essential Role of Pre-B-Cell Colony Enhancing Factor in Ventilator-induced Lung Injury

Sang-Bum Hong1, Yong Huang2, Liliana Moreno-Vinasco3, Saad Sammani3, Jaideep Moitra3, Joseph W Barnard4, Shwu-Fan Ma3, Tamara Mirzapoiazova3, Carrie Evenoski3, Ryan R Reeves3, Eddie T Chiang3, Gabriel D Lang3, Aliya N Husain5, Steven M Dudek3, Jeffrey R Jacobson3, Shui Q Ye6, Yves A Lussier2, and Joe GN Garcia3*

1 Sections of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA; University of Ulsan College of Medicine, Seoul, Korea, Republic of, 2 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA, 3 Sections of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA, 4 Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA, 5 Department of Pathology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA, 6 University of Missouri, Columbia, MO, USA

* To whom correspondence should be addressed. E-mail: jgarcia{at}medicine.bsd.uchicago.edu.

Rationale: We previously demonstrated pre-B cell colony enhancing factor (PBEF) as a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility (1). Objective: To explore mechanistic participation of PBEF in ALI and ventilator-induced lung injury (VILI). Methods and Results: Initial in vitro studies demonstrated rhPBEF as a direct rat neutrophil chemotactic factor with in vivo studies demonstrating marked increases in BAL leukocytes (PMNs) following intratracheal injection (IT) in C57BL/6J mice. These changes were accompanied by increased BAL levels of PMN chemoattractants (KC and MIP2) and modest increases in lung vascular and alveolar permeability. We next explored the potential synergism between rhPBEF challenge (IT) and a model of limited VILI (4 hours, 30 ml/kg tidal volume) and observed dramatic increases in BAL PMNs, BAL protein and cytokine levels (IL-6, TNF-{alpha}, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI- associated gene modules (NF{kappa}B, leukocyte extravasation, apoptosis, toll-receptor pathways). Heterozygous PBEF+/- mice were significantly protected (reduced BAL protein, BAL IL-6 levels, peak inspiratory pressures) when exposed to a model of severe VILI (4 hours, 40 ml/kg tidal volume) and exhibited significantly reduced expression of VILI-associated gene expression modules. Finally, strategies to reduce PBEF availability (neutralizing antibody) resulted in significant protection from VILI. Conclusion: These studies implicate PBEF as a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI.
Key words: PBEF, visfatin, ALI, chemotaxis, apoptosis






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