Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury

Abstract

To test the hypothesis that IL-6 contributes to the development of ventilator-associated lung injury (VALI), IL-6-deficient (IL6−/−) and wild-type control (WT) mice received intratracheal hydrochloric acid followed by randomization to MV (MV+IT HCl) or spontaneous ventilation (IT HCl). After 4 hr, injury was assessed by estimation of lung lavage protein concentration and total and differential cell counts, wet/dry lung weight ratio, pulmonary cell death, histologic inflammation score (LIS), and parenchymal myeloperoxidase (MPO) concentration. Vascular endothelial growth factor (VEGF) concentration was measured in lung lavage and homogenate, as IL-6 and stretch both regulate expression of this potent mediator of permeability. MV-induced increases in alveolar barrier dysfunction and lavage VEGF were attenuated in IL6−/− mice as compared with WT controls, whereas tissue VEGF concentration increased. The effects of IL-6 deletion on alveolar permeability and VEGF concentration were inflammation-independent, as parenchymal MPO concentration, LIS, and lavage total and differential cell counts did not differ between WT and IL6−/− mice following IT HCl+MV. These data support a role for IL-6 in promoting VALI in this two-hit model. Strategies to interfere with IL-6 expression or signaling may represent important therapeutic targets to limit the injurious effects of MV in inflamed lungs.

Improvement of ventilation-induced lung injury in a rodent model by inhibition of inhibitory κB kinase

“…23 Moreover, it is suggested that IL-6 could be a reasonable therapeutic target for VILI not only for its antiinflammatory effect. 24 IL-6 geneYdeficient mice exhibit a markedly improved pulmonary vascular permeability when compared with a wild-type control in a rodent model of VILI, 24 and this protective effect of IL-6 is inflammation independent, 24 suggesting that IL-6 may also play a vital role on barrier dysfunction in VILI. Our data are consistent with previous studies, the elevated IL-6 production was accompanied by barrier dysfunction and lung edema.…”

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

“…IL-lβ, whether administered systemically or locally into the pulmonary parenchyma, can acutely increase pulmonary substance P (SP) and vascular permeability, possibly via stimulating PCFs [49]. Gurkan et al [50] reported that genetic deletion of IL-6 significantly attenuated alveolar-capillary barrier disruption in a two-hit model of acute lung injury. In this study, AMPK activation protected against lung barrier dysfunction induced by both high glucose and LPS stimulation.…”

Clinical and Biological Heterogeneity in Acute Respiratory Distress Syndrome

“…Several studies have investigated the role of IL-6 in lung injury 66, 72–74 . IL-6 had been previously associated with increased mortality in ARDS 75, 76 and in acute kidney injury in critically ill patients 77 .…”