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

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

Correspondence and requests for reprints should be addressed to Joe G. N. Garcia, M.D., Lowell T. Coggeshall Professor of Medicine, Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637. 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.

Objectives: To explore mechanistic participation of PBEF in ALI and ventilator-induced lung injury (VILI).

Methods: Two models of VILI were utilized to explore the role of PBEF using either recombinant PBEF or PBEF^+/– mice.

Measurements and Main Results: Initial in vitro studies demonstrated recombinant human PBEF (rhPBEF) as a direct rat neutrophil chemotactic factor with in vivo studies demonstrating marked increases in bronchoalveolar lavage (BAL) leukocytes (PMNs) after intratracheal injection in C57BL/6J mice. These changes were accompanied by increased BAL levels of PMN chemoattractants (KC and MIP-2) and modest increases in lung vascular and alveolar permeability. We next explored the potential synergism between rhPBEF challenge (intratracheal) and a model of limited VILI (4 h, 30 ml/kg tidal volume) and observed dramatic increases in BAL PMNs, BAL protein, and cytokine levels (IL-6, TNF-, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI-associated gene modules (nuclear factor-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 h, 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.

Conclusions: These studies implicate PBEF as a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI.

Key Words: visfatin • acute lung injury • chemotaxis • apoptosis • mechanical ventilation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Pre–B-cell colony enhancing factor (PBEF), whose gene variants are associated with ventilator-induced lung injury (VILI) susceptibility, has been identified as a potential VILI candidate gene and biomarker and has been localized to animal and human lung epithelium in acute lung injury. The mechanism of this association remains unknown. What This Study Adds to the Field This study implicates PBEF as a key inflammatory mediator in the development and severity of VILI in murine models of VILI. PBEF may be a molecular target for amelioration of VILI in critically ill patients.