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

Sang Bum Hong, Yong Huang, Liliana Moreno-Vinasco, Saad Sammani, Jaideep Moitra, Joseph W. Barnard, Shwu Fan Ma, Tamara Mirzapoiazova, Carrie Evenoski, Ryan R. Reeves, Eddie T. Chiang, Gabriel D. Lang, Aliya N. Husain, Steven M. Dudek, Jeffrey R. Jacobson, Shui Q. Ye, Yves A. Lussier, Joe G.N. Garcia

Research output: Contribution to journalArticle

86 Scopus citations

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 amodel of limited VILI (4 h, 30ml/kg tidal volume) and observed dramatic increases in BAL PMNs, BAL protein, and cytokine levels (IL-6, TNF-α, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI-associated genemodules (nuclear factor-κB, 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 amodel of severe VILI (4 h, 40ml/kg tidal volume) and exhibited significantly reduced expression of VILI-associated gene expression modules. Finally, strategies toreduce 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.

Original languageEnglish (US)
Pages (from-to)605-617
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume178
Issue number6
DOIs
StatePublished - Sep 15 2008

Keywords

  • Acute lung injury
  • Apoptosis
  • Chemotaxis
  • Mechanical ventilation
  • Visfatin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Hong, S. B., Huang, Y., Moreno-Vinasco, L., Sammani, S., Moitra, J., Barnard, J. W., Ma, S. F., Mirzapoiazova, T., Evenoski, C., Reeves, R. R., Chiang, E. T., Lang, G. D., Husain, A. N., Dudek, S. M., Jacobson, J. R., Ye, S. Q., Lussier, Y. A., & Garcia, J. G. N. (2008). Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury. American journal of respiratory and critical care medicine, 178(6), 605-617. https://doi.org/10.1164/rccm.200712-1822OC