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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid
  • Chemokine CXCL1 / metabolism
  • Chemokine CXCL2 / metabolism
  • Chemotaxis, Leukocyte / physiology
  • Cytokines / physiology*
  • Gene Expression Profiling
  • Interleukin-6 / analysis
  • Macrophages, Alveolar / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nicotinamide Phosphoribosyltransferase / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / physiopathology*
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventilators, Mechanical* / adverse effects


  • Chemokine CXCL1
  • Chemokine CXCL2
  • Cytokines
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse