NF-κB activation in myeloid cells mediates ventilator-induced lung injury

Yi-An Ko,Lee-Wei Chen,Hung-Tu Huang,Ming-Chieh Yang,Ching-Mei Hsu

doi:10.1186/1465-9921-14-69

Abstract

BackgroundAlthough use of the mechanical ventilator is a life-saving intervention, excessive tidal volumes will activate NF-κB in the lung with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokine/chemokine release. The roles of NF-κB and IL-6 in ventilator-induced lung injury (VILI) remain widely debated.MethodsTo study the molecular mechanisms of the pathogenesis of VILI, mice with a deletion of IкB kinase in the myeloid cells (IKKβ△mye), IL-6-/- to WT chimeric mice, and C57BL/6 mice (WT) were placed on a ventilator for 6 hr.WT mice were also given an IL-6-blocking antibody to examine the role of IL-6 in VILI.ResultsOur results revealed that high tidal volume ventilation induced pulmonary capillary permeability, neutrophil sequestration, macrophage drifting as well as increased protein in bronchoalveolar lavage fluid (BALF). IL-6 production and IL-1β, CXCR2, and MIP2 expression were also increased in WT lungs but not in those pretreated with IL-6-blocking antibodies. Further, ventilator-induced protein concentrations and total cells in BALF, as well as lung permeability, were all significantly decreased in IKKβ△mye mice as well as in IL6-/- to WT chimeric mice.ConclusionGiven that IKKβ△mye mice demonstrated a significant decrease in ventilator-induced IL-6 production, we conclude that NF-κB–IL-6 signaling pathways induce inflammation, contributing to VILI, and IкB kinase in the myeloid cells mediates ventilator-induced IL-6 production, inflammation, and lung injury.

Highlights

Use of the mechanical ventilator is a life-saving intervention, excessive tidal volumes will activate NF-κB in the lung with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokine/chemokine release
Ventilator induced lung injury in WT mice WT mice demonstrated a significant increase in pulmonary vascular permeability (Figure 1A) and MPO activity (Figure 1B) after ventilation when compared with the control group and the extent of the increase was higher in the high tidal volume group
Ventilator induced NF-κB activation and production of IL-6, IL-1β, and inter-cellular adhesion molecule (ICAM) in the lung To study the effect of ventilators on NF-κB activation and IL-6 and IL-1β levels in the lung, lung homogenates were examined

Summary

Introduction

Use of the mechanical ventilator is a life-saving intervention, excessive tidal volumes will activate NF-κB in the lung with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokine/chemokine release. Human studies suggest that the release of cytokines/chemokines and the recruitment of leukocytes causes ventilator-associated lung injury (VALI) [6]. Proteolytic degradation of IκB that has been phosphorylation by IκB kinase (IKK) liberates NF-κB to enter the nucleus and activates the NF-κB-regulated target genes This process is eventually terminated through the NF-κB-induced synthesis of IκBs and, consecutively, cytoplasmic resequestration of this transcription factor. Previous study has demonstrated that both hyperoxia and overventilation would activate NF-κB with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokines/chemokines release. The effects of NF-κB activation in the cellular level under the stimulation of ventilation remain poorly understood

Methods

Results

Discussion

Conclusion