PDF(Pubmed)
Abstract：
Acute respiratory distress syndrome (ARDS) remains a significant cause of morbidity and mortality in critically ill patients. Oxidative stress and inflammation play a crucial role in the pathogenesis of ARDS. Extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is an important enzymatic defense against superoxide. Human single-nucleotide polymorphism in matrix binding region of EC-SOD leads to the substitution of arginine to glycine at position 213 (R213G) and results in release of EC-SOD into alveolar fluid, without affecting enzyme activity. We hypothesized that R213G EC-SOD variant protects against lung injury and inflammation via the blockade of neutrophil recruitment in infectious model of methicillin-resistant S. aureus (MRSA) pneumonia. After inoculation with MRSA, wild-type (WT) mice had impaired integrity of alveolar-capillary barrier and increased levels of IL-1β, IL-6, and TNF-α in the broncho-alveolar lavage fluid (BALF), while infected mice expressing R213G EC-SOD variant maintained the integrity of alveolar-capillary interface and had attenuated levels of proinflammatory cytokines. MRSA-infected mice expressing R213G EC-SOD variant also had attenuated neutrophil numbers in BALF and decreased expression of neutrophil chemoattractant CXCL1 by the alveolar epithelial ATII cells, compared with the infected WT group. The decreased neutrophil numbers in R213G mice were not due to increased rate of apoptosis. Mice expressing R213G variant had a differential effect on neutrophil functionality-the generation of neutrophil extracellular traps (NETs) but not myeloperoxidase (MPO) levels were attenuated in comparison with WT controls. Despite having the same bacterial load in the lung as WT controls, mice expressing R213G EC-SOD variant were protected from extrapulmonary dissemination of bacteria.
摘要：
急性呼吸窘迫综合征（ARDS）仍然是重症患者发病和死亡的重要原因。氧化应激和炎症在ARDS的发病机制中起着至关重要的作用。细胞外超氧化物歧化酶（EC-SOD）在肺中含量丰富，是针对超氧化物的重要酶防御。EC-SOD基质结合区的人类单核苷酸多态性导致精氨酸在位置213（R213G）被甘氨酸取代，并导致EC-SOD释放到肺泡液中。不影响酶活性。我们假设在耐甲氧西林金黄色葡萄球菌（MRSA）肺炎的感染模型中，R213GEC-SOD变体通过阻断中性粒细胞募集来抵抗肺损伤和炎症。接种MRSA后，WT小鼠肺泡毛细血管屏障完整性受损，IL-1β水平升高，支气管肺泡灌洗液（BALF）中的IL-6和TNF-α，而表达R213GEC-SOD变体的感染小鼠维持了肺泡-毛细血管界面的完整性，并降低了促炎细胞因子的水平。表达R213GEC-SOD变体的MRSA感染的小鼠BALF中的中性粒细胞数量也减弱，肺泡上皮ATII细胞对中性粒细胞趋化因子CXCL1的表达降低，与感染的WT组相比。R213G小鼠中性粒细胞数量的减少不是由于细胞凋亡率的增加。表达R213G变体的小鼠对中性粒细胞功能有不同的影响，-与WT对照相比,嗜中性粒细胞胞外陷阱(NETs)而非髓过氧化物酶(MPO)水平的产生减弱。尽管肺部细菌负荷与WT对照相同，保护表达R213GEC-SOD变体的小鼠免受肺外细菌传播。
