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

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.