Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA.
Department of Surgery, The Warren Alpert Medical School of Brown University and Lifespan-Rhode Island Hospital, Providence, RI, USA.
Redox Biol. 2022 Nov;57:102467. doi: 10.1016/j.redox.2022.102467. Epub 2022 Sep 15.
It is increasingly recognized that cigarette smoke (CS) exposure increases the incidence and severity of acute respiratory distress syndrome (ARDS) in critical ill humans and animals. However, the mechanism(s) is not well understood. This study aims to investigate mechanism underlying the priming effect of CS on Pseudomonas aeruginosa-triggered acute lung injury, by using pre-clinic animal models and genetically modified mice. We demonstrated that CS impaired P. aeruginosa-induced mitophagy flux, promoted p62 accumulation, and exacerbated P. aeruginosa-triggered mitochondrial damage and NLRP3 inflammasome activation in alveolar macrophages; an effect associated with increased acute lung injury and mortality. Pharmacological inhibition of caspase-1, a component of inflammasome, attenuated CS primed P. aeruginosa-triggered acute lung injury and improved animal survival. Global or myeloid-specific knockout of IL-1β, a downstream component of inflammasome activation, also attenuated CS primed P. aeruginosa-triggered acute lung injury. Our results suggest that NLRP3 inflammasome activation is an important mechanism for CS primed P. aeruginosa-triggered acute lung injury. (total words: 155).
越来越多的研究表明，香烟烟雾（CS）暴露会增加重症患者急性呼吸窘迫综合征（ARDS）的发生率和严重程度。然而，其具体机制尚不清楚。本研究旨在通过临床前动物模型和基因修饰小鼠，探讨 CS 对铜绿假单胞菌引发的急性肺损伤的致敏作用的机制。我们发现 CS 可损害铜绿假单胞菌诱导的自噬通量，促进 p62 积聚，并加重肺泡巨噬细胞中铜绿假单胞菌引发的线粒体损伤和 NLRP3 炎性体激活；这一作用与急性肺损伤和死亡率增加有关。炎性体的组成部分之一半胱氨酸天冬氨酸蛋白酶-1（caspase-1）的药理学抑制作用，可减轻 CS 预致敏的铜绿假单胞菌引发的急性肺损伤并提高动物存活率。炎性体激活的下游成分白细胞介素-1β（IL-1β）的全身性或髓样特异性敲除，也可减轻 CS 预致敏的铜绿假单胞菌引发的急性肺损伤。我们的研究结果表明，NLRP3 炎性体激活是 CS 预致敏的铜绿假单胞菌引发的急性肺损伤的一个重要机制。（总字数：155）
