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Am J Respir Crit Care Med. 2008 Sep 15;178(6):605-17. doi: 10.1164/rccm.200712-1822OC. Epub 2008 Jul 24.

Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.

Author information

1
Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.

Abstract

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-alpha, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI-associated gene modules (nuclear factor-kappaB, 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.

PMID:
18658108
PMCID:
PMC2542434
DOI:
10.1164/rccm.200712-1822OC
[Indexed for MEDLINE]
Free PMC Article

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