Abstract
BackgroundMechanical ventilation (MV) can augment inflammatory response in lipopolysaccharide (LPS) challenged lungs. High mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury, but its mechanisms are not well defined. This study investigated the role of HMGB1 in lung inflammation in response to the combination of MV and LPS treatment.MethodsForty-eight male Sprague-Dawley rats were randomized to one of four groups: sham control; LPS treatment; mechanical ventilation; mechanical ventilation with LPS treatment. Mechanically ventilated animals received 10 ml/kg tidal volumes at a rate of 40 breaths/min for 4 h. In the HMGB1-blockade study, sixteen rats were randomly assigned to HMGB1 antibody group or control antibody group and animals were subjected to MV+LPS as described above. A549 cells were pre-incubated with different signal inhibitors before subjected to 4 h of cyclic stretch. Lung wet/dry weight (W/D) ratio, total protein and IgG concentration, number of neutrophils in bronchoalveolar lavage fluid (BALF), and lung histological changes were examined. The levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in BALF were measured using ELISA. Real-time quantitative PCR and Western blot were used to analyze mRNA and protein expression of HMGB1. Western blot were employed to analyze the activation of IκB-α, NF-κB, JNK, ERK, and p38.ResultsMV significantly augmented LPS-induced lung injury and HMGB1 expression, which was correlated with the increase in IL-1β, IL-6 and MIP-2 levels in BALF. In vivo, intratracheally administration of HMGB1 antibody significantly attenuated pulmonary inflammatory injury. In vitro experiments showed cyclic stretch induced HMGB1 expression through signaling pathways including p38 and NF-κB.ConclusionsThe findings indicated that moderate tidal volume MV augmented LPS induced lung injury by up-regulating HMGB1. The mechanism of HMGB1-mediated lung injury is likely to be signaling through p38 and NF-κB pathways.
Highlights
Despite its life-saving potential, mechanical ventilation (MV) may initiate or augment acute lung injury (ALI), which is recognized as ventilator-induced lung injury (VILI) [1,2,3,4,5]
Our recent study demonstrated that cyclic stretch significantly increased High mobility group box 1 protein (HMGB1) expression in pulmonary alveolar epithelial cells, which was correlated with the elevated levels of tumor necrosis factor-a (TNF-a), IL-1b and IL-6 [20]
There were no significant differences in Peak inspiratory pressure (PIP), PaO2/FiO2 ratio and arterial pH before the induction of Mechanical ventilation (MV) among groups
Summary
Despite its life-saving potential, mechanical ventilation (MV) may initiate or augment acute lung injury (ALI), which is recognized as ventilator-induced lung injury (VILI) [1,2,3,4,5]. High mobility group box 1 protein (HMGB1) has recently been proposed as a potent inflammatory mediator in ALI [16]. Our recent study demonstrated that cyclic stretch significantly increased HMGB1 expression in pulmonary alveolar epithelial cells, which was correlated with the elevated levels of TNF-a, IL-1b and IL-6 [20]. Mechanical ventilation (MV) can augment inflammatory response in lipopolysaccharide (LPS) challenged lungs. High mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury, but its mechanisms are not well defined. This study investigated the role of HMGB1 in lung inflammation in response to the combination of MV and LPS treatment
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.