Molecular Mechanism of Ventilator-associated Lung Injury Based on Keap1/Nfr2/ARE Signaling Pathway
Abstract
To explore the molecular mechanism of ventilation induced lung injury (VILI) formation based on Keap1/Nfr2/ARE signaling pathway. Methods The VILI model was established by excessive mechanical ventilation in SD rats. HE staining was used to detect the pathological changes of lung tissue in the control group, normal tidal volume (VT) group and large VT group (VT 40 mL/kg). The wet weight of lung tissue was detected in each group. Dry weight (W/D) ratio change; BCA method was used to detect the changes of total protein in bronchoalveolar lavage fluid (BALF) of each group; ELISA was used to detect interleukin-1β (IL-1β) and leukocyte in BALF and serum of each group. The content of 8-OHdG in the lung tissue was detected by IL-8 and the content of malondialdehyde (MDA) in the lung tissue was detected by TBA method. The NLRP3, ASC and caspase-1 proteins in macrophages were detected by Western blotting. The changes of Keap1 and Nrf2 proteins in lung tissues were detected by RT-PCR. The expressions of SOD mRNA and HO-1 mRNA in lung tissues of each group were detected by RT-PCR. Results Excessive mechanical ventilation could damage lung tissue, leading to alveolar rupture, inflammatory cell infiltration and erythrocytosis. Compared with the control group and normal VT group, the W/D value, 8-OHdG and MDA content in the large VT group, and total BALF, the contents of IL-1β and IL-18 in protein, IL-1β, IL-18 in serum increased significantly (P<0.05). Compared with the control group and normal VT group, NLRP3, ASC, in macrophage of large VT group, the content of Keap1 protein in caspase-1 protein and lung tissue increased significantly (P<0.05). The expression of Nrf2 protein, SOD mRNA and HO-1 mRNA in lung tissue decreased significantly. Conclusions Large VT ventilation can cause acute inflammatory injury in lung tissue and lead to the occurrence of VILI. Inflammatory bodies of NLRP3 in alveolar macrophages are involved in this process, and the mechanism of NLRP3 inflammatory bodies is caused by hyperventilation in addition to mechanical injury. Decreased Keap1/Nrf2-ARE pathway inhibition and ROS clearance may also cause macrophage production of NLRP3 inflammatory bodies.
Keywords: Ventilator-associated lung injury, Reactive oxygen, Keap1/Nfr2/ARE signaling pathway, Mechanism
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FAN E， VILLAR J， SLUTSKY AS. Novel approaches to minimize ventilator-induced lung injury. Bmc Medicine，2014，11(1): 1–9.
CURLEY GF， LAFFEY JG， ZHANG H， et al. Biotrauma and Ventilator Induced Lung Injury: Clinical implications. Chest，2016，150(5): 1109–11017.
ALBAICETA GM， BLANCH L. Beyond volutrauma in ARDS: the critical role of lung tissue deformation. Critical Care，2011，15(2): 304.
FUKUMOTO J， FUKUMOTO I， PARTHASARATHY PT， et al. NLRP3 deletion protects from hyperoxia-induced acute lung injury. American Journal of Physiology Cell Physiology，2013，305(2): 182–189.
DAVIDOVICH N， DIPAOLO BC， LAWRENCE GG， et al. Cyclic Stretch–Induced Oxidative Stress Increases Pulmonary Alveolar Epithelial Permeability. Am J Respir Cell Mol Biol，2013，49(1): 156–164.
LEE PJ， CHOI AM. Pathways of cell signaling in hyperoxia. Free Rad Biol Med，2003，35(4): 341–350.
SEITZ DH， PALMER A， NIESLER U， et al. Altered expression of fas receptor on alveolar macrophages and inflammatory effects of soluble fas ligand following blunt chest trauma. Shock，2011，35(6): 610–617.
OECKLER RA， LEE WY， PARK MG， et al. Determinants of plasma membrane wounding by deforming stress. American Journal of Physiology Lung Cellular & Molecular Physiology，2010，299(6): 826–833.
PAF ME， PADILHA GA， MORAES L， et al. Effects of pressure support ventilation on ventilator-induced lung injury in mild acute respiratory distress syndrome depend on level of positive end-expiratory pressure. Eur J Anaesthesiol，2018，35(4): 298–306.
LI H， WU Z， FENG D， et al. BML-111, a lipoxin receptor agonist, attenuates ventilator-induced lung injury in rats. Shock，2014，41(4): 311–316.
Hoegl S， Boost KA， Czerwonka H， et al. Inhaled IL-10 reduces biotrauma and mortality in a model of ventilator-induced lung injury. Respiratory Medicine，2009，103(3): 463–470
OHNSTON LK， RIMS CR， GILL SE， et al. Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. Am J Respir Cell Mol Biol，2012，47(4): 417–426.
XIANG M， SHI X， LI Y， et al. Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells. J Immunol，2011，187(9): 4809–4817.
JULIANA C， FERNANDES ATJ， DATTA P， et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem，2010，285(13): 9792–9802.
VAK R， CHAN FK. Inflammasome, Inflammation, and Tissue Homeostasis. Trends Mol Med，2018，24(3): 304–318.
AWAD F， ASSRAWI E， LOUVRIER C， et al. Inflammasome biology, molecular pathology and therapeutic implications. Pharmacol Ther， 2018，187: 133–149.
JIANG D， CHEN S， SUN R， et al. The NLRP3 inflammasome: Role in metabolic disorders and regulation by metabolic pathways. Cancer Letters，2018，419: 8–19.
LUNOV O， SYROVETS T， LOOS C， et al. Amino-functionalized polystyrene nanoparticles activate the NLRP3 inflammasome in human macrophages. Acs Nano，2011，5(12): 9648–9657.
ZHOU R， YAZDI AS， MENU P， et al. A role for mitochondria in NLRP3 inflammasome activation. Nature，2011，469(7329): 221–225.
SCHRODER K， ZHOU R， TSCHOPP J. The NLRP3 inflammasome: a sensor for metabolic danger?. Science，2010，327(5963): 296–300.
KA C， JW S， KH L， et al. IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1β by keratinocytes via the ROS-NLRP3- caspase-1 pathway. Int Immunol，2012，24(3): 147–158
HU LY， CUI JB， XU XM， et al. Expression of Nrf2-Keap1-ARE signal pathway in traumatic lung injury and functional study. Eur Rev Med Pharmacol Sci，2018，22(5): 1402–1408.
XIAO ZT， SU WW， LI PB. Research progress in epigenetic regulation of Keap1-Nrf2 signal pathway. Central South Pharmacy，2018(1): 76–81.
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