Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 178, Issue 6, Pages 605-617Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200712-1822OC
Keywords
visfatin; acute lung injury; chemotaxis; apoptosis; mechanical ventilation
Categories
Funding
- NHLBI NIH HHS [HL 80042, HL 88144, HL 73994, HL 58064] Funding Source: Medline
- NLM NIH HHS [K22 LM008308, K22 LM008308-05] Funding Source: Medline
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Rationale: We previously demonstrated pre-B-cell colony enhancing factor (PBEF) as a biomarker in sepsis and sepsis-incluced 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-kappa B, 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.
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