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

Background: Although use of the mechanical ventilator is a life-saving intervention, excessive tidal volumes will activate NF-kappa B in the lung with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokine/chemokine release. The roles of NF-kappa B and IL-6 in ventilator-induced lung injury (VILI) remain widely debated. Methods: To study the molecular mechanisms of the pathogenesis of VILI, mice with a deletion of I kappa B kinase in the myeloid cells (IKK beta(Delta 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. Results: Our 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-1 beta, 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 IKK beta(Delta mye) mice as well as in IL6(-/-) to WT chimeric mice. Conclusion: Given that IKK beta(Delta mye) mice demonstrated a significant decrease in ventilator-induced IL-6 production, we conclude that NF-kappa B-IL-6 signaling pathways induce inflammation, contributing to VILI, and I kappa B kinase in the myeloid cells mediates ventilator-induced IL-6 production, inflammation, and lung injury.