Liu Bo, Li Yan, Xiang Jinying, Li Yuehan, Zhou Mi, Ren Yinying, Fu Zhou, Ding Fengxia
Department of Cardiothoracic Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing Medical University, Chongqing, People's Republic of China.
J Inflamm Res. 2023 Aug 21;16:3547-3562. doi: 10.2147/JIR.S422585. eCollection 2023.
This study aimed to investigate the role of pyroptosis in alveolar macrophages regarding the immune microenvironment of acute respiratory distress syndrome (ARDS) and its prognosis.
ARDS Microarray data were downloaded from Gene Expression Omnibus (GEO). Support vector machine (SVM) and random forest (RF) models were applied to identify hub pyroptosis-related genes (PRGs) with prognostic significance in ARDS. RT-PCR was used to detect the relative expression of PRGs mRNA in alveolar macrophages of ARDS mice. Consensus clustering analysis was conducted based on the expression of the PRGs to identify pyroptosis modification patterns. Bioinformatic algorithms were used to study the immune traits and biological functions of the pyroptosis patterns. Finally, protein-protein interaction (PPI) networks were established to identify hub regulatory proteins with implications for the pyroptosis patterns.
In our study, a total of 12 PRGs with differential expression were obtained. Four hub PRGs, including GPX4, IL6, IL18 and NLRP3, were identified and proven to be predictive of ventilator-free days (VFDS) in ARDS patients. The AUC values of the 4 PRGs were 0.911 (GPX4), 0.879 (IL18), 0.851 (IL6) and 0.841 (NLRP3), respectively. In ARDS mice, GPX4 mRNA decreased significantly, while IL6, IL18, and NLRP3 mRNA increased. Functional analysis revealed that IL6 had the strongest positive correlation with the CCR pathway, while GPX4 exhibited the strongest negative correlation with the T co-inhibition pathway. Based on the expression of the 4 PRGs, three pyroptosis modification patterns representing different immune states were obtained, and pattern C might represent immune storm.
The results showed that pyroptosis plays an important regulatory role in the immune microenvironment of ARDS. This finding provides new insights into the pathogenesis, diagnosis, and treatment of ARDS.
本研究旨在探讨肺泡巨噬细胞焦亡在急性呼吸窘迫综合征（ARDS）免疫微环境及其预后中的作用。
从基因表达综合数据库（GEO）下载ARDS微阵列数据。应用支持向量机（SVM）和随机森林（RF）模型识别在ARDS中具有预后意义的关键焦亡相关基因（PRG）。采用逆转录聚合酶链反应（RT-PCR）检测ARDS小鼠肺泡巨噬细胞中PRG mRNA的相对表达。基于PRG的表达进行一致性聚类分析，以确定焦亡修饰模式。运用生物信息学算法研究焦亡模式的免疫特征和生物学功能。最后，建立蛋白质-蛋白质相互作用（PPI）网络，以识别对焦亡模式有影响的关键调节蛋白。
在本研究中，共获得12个差异表达的PRG。鉴定出4个关键PRG，包括谷胱甘肽过氧化物酶4（GPX4）、白细胞介素6（IL6）、白细胞介素18（IL18）和NLR家族含pyrin结构域蛋白3（NLRP3），并证实它们可预测ARDS患者的无呼吸机天数（VFDS）。这4个PRG的曲线下面积（AUC）值分别为0.911（GPX4）、0.879（IL18）、0.851（IL6）和0.841（NLRP3）。在ARDS小鼠中，GPX4 mRNA显著降低，而IL6、IL18和NLRP3 mRNA升高。功能分析显示，IL6与CCR通路的正相关性最强，而GPX4与T细胞共抑制通路的负相关性最强。基于这4个PRG的表达，获得了代表不同免疫状态的三种焦亡修饰模式，模式C可能代表免疫风暴。
结果表明，焦亡在ARDS免疫微环境中起重要调节作用。这一发现为ARDS的发病机制、诊断和治疗提供了新的见解。
