title: Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Hong
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Barnard
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.forename: Carrie
authors.initials: C
authors.lastname: Evenoski
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Reeves
authors.forename: Eddie T
authors.initials: ET
authors.lastname: Chiang
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Lang
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Shui Q
authors.initials: SQ
authors.lastname: Ye
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D020869:Gene Expression Profiling; D015850:Interleukin-6 / Q000032:analysis; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054409:Nicotinamide Phosphoribosyltransferase / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse