Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.
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.
Hong
Sang-Bum
SB
Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.
Huang
Yong
Y
Moreno-Vinasco
Liliana
L
Sammani
Saad
S
Moitra
Jaideep
J
Barnard
Joseph W
JW
Ma
Shwu-Fan
SF
Mirzapoiazova
Tamara
T
Evenoski
Carrie
C
Reeves
Ryan R
RR
Chiang
Eddie T
ET
Lang
Gabriel D
GD
Husain
Aliya N
AN
Dudek
Steven M
SM
Jacobson
Jeffrey R
JR
Ye
Shui Q
SQ
Lussier
Yves A
YA
Garcia
Joe G N
JG
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
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse