Ventilator-induced lung injury is alleviated by inhibiting NLRP3 inflammasome activation.
BACKGROUND
Mechanical ventilation (MV) is frequently used but can aggravate or cause lung injury, known as ventilator-induced lung injury (VILI). However, the mechanisms are unclear. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a vital component of innate immunity and is closely related to VILI.


METHODS
Mouse lung epithelial (MLE-12) cells were transfected with NLRP3 small interfering RNA (siRNA) or scramble siRNA (sc siRNA) and subjected to 20% cyclic stretch (CS). Wild-type C57BL/6 mice were injected with a liquid complex of NLRP3 siRNA/sc siRNA-Lipofectamine 2000 through the fundus venous plexus before mechanical ventilation. Western blots, immunoprecipitation, ELISAs, flow cytometry, immunofluorescence, and hematoxylin-eosin staining were used to assess the effects of the NLRP3 inflammasome on VILI and the mechanisms of those effects.


RESULTS
CS activated the NLRP3 inflammasome by activating NIMA-related kinase 7 (NEK7). NLRP3 depletion inhibited NLRP3 inflammasome activation; alleviated the degradation of cell junction proteins, including p120-catenin (p120) and occludin; ameliorated the colocalization of p120 and E-cadherin; and mitigated the decrease in mitochondrial membrane potential caused by mechanical stretch. Furthermore, after NLRP3 depletion, VILI was attenuated by decreasing IL-1β secretion and pulmonary edema.


CONCLUSIONS
Inhibiting NLRP3 inflammasome activation ameliorated VILI, suggesting a potential therapeutic target for the clinical treatment of VILI.
['Liu|Huan|H|', 'Gu|Changping|C|', 'Liu|Mengjie|M|', 'Liu|Ge|G|', 'Wang|Dong|D|', 'Liu|Xiaobin|X|', 'Wang|Yuelan|Y|']
D000818:Animals D015820:Cadherins D058847:Inflammasomes D053583:Interleukin-1beta D008168:Lung D008297:Male D053078:Membrane Potential, Mitochondrial D051379:Mice D008810:Mice, Inbred C57BL D000072379:NIMA-Related Kinases D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D034741:RNA, Small Interfering D012121:Respiration, Artificial D014157:Transcription Factors D055397:Ventilator-Induced Lung Injury
Ventilator-induced lung injury NLRP3 inflammasome Mechanical ventilation Cyclic stretch Junction proteins Inflammation