Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 20080, China.
Inflamm Res. 2021 Jan;70(1):89-98. doi: 10.1007/s00011-020-01420-3. Epub 2020 Nov 13.
The dysfunction of pulmonary microvascular endothelial cells (PMVECs) is one of the critical characteristics of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by severe infection. PIM1 is a constitutively active serine/threonine kinase that is involved in multiple biological processes. However, the underlying correlation between PIM1 and PMVECs injury remains unclear. The main purpose of this study was to reveal roles of PIM1 and explore the potential mechanisms during the development of endotoxin-induced ALI induced by intraperitoneal LPS administration.
PIM1 level in the lung tissues of endotoxin-induced ALI mice or plasma derived from cardiopulmonary bypass (CPB)-induced ALI patients were measured. The protective roles of PIM1 specific inhibitor SMI-4a on endotoxin-induced lung injuries were evaluated through histological, permeability, neutrophil infiltration and survival assessment. The relationship between PIM1 and ELK3/ICAM-1 axis was validated in vivo and vitro. The correlation between plasma PIM1 and indicative vascular endothelium injury biomarkers (PaO/FiO ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed.
PIM1 expression in the lung tissues was increased in the mice of endotoxin-induced ALI. The PIM1 specific inhibitor SMI-4a administration relieved the severity of endotoxin-induced ALI. More importantly, PIM1 modulates ICAM1 expression through regulating transcription factor ELK3 expression in vitro. Eventually, plasma PIM1 level was positively correlated with Ang-II and PAI-1 levels but negatively correlated with SpO/FiO ratio among CPB induced ALI patients.
Our results indicated that PIM1 inhibition carried a protective role against endotoxin-induced ALI by modulating the ELK3/ICAM1 axis on PMVECs. PIM1 may be a potential therapeutic target for endotoxin-induced ALI.
肺微血管内皮细胞（PMVEC）功能障碍是严重感染引起的急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）的关键特征之一。PIM1 是一种组成性激活的丝氨酸/苏氨酸激酶，参与多种生物学过程。然而，PIM1 与 PMVEC 损伤之间的潜在相关性尚不清楚。本研究的主要目的是揭示 PIM1 的作用，并探讨其在腹腔内 LPS 给药诱导的内毒素性 ALI 发展过程中的潜在机制。
测量内毒素性 ALI 小鼠肺组织或体外循环（CPB）诱导的 ALI 患者血浆中的 PIM1 水平。通过组织学、通透性、中性粒细胞浸润和生存评估评估 PIM1 特异性抑制剂 SMI-4a 对内毒素性肺损伤的保护作用。验证了 PIM1 与 ELK3/ICAM-1 轴之间的关系。分析了 CPB 诱导的 ALI 患者血浆中 PIM1 与指示血管内皮损伤生物标志物（PaO/FiO 比值、Ang-II、E-选择素和 PAI-1）水平之间的相关性。
内毒素性 ALI 小鼠肺组织中 PIM1 表达增加。PIM1 特异性抑制剂 SMI-4a 给药减轻了内毒素性 ALI 的严重程度。更重要的是，PIM1 通过调节转录因子 ELK3 的表达来调节体外 ICAM1 的表达。最终，CPB 诱导的 ALI 患者的血浆 PIM1 水平与 Ang-II 和 PAI-1 水平呈正相关，与 SpO/FiO 比值呈负相关。
我们的结果表明，PIM1 抑制通过调节 PMVECs 上的 ELK3/ICAM1 轴对内毒素性 ALI 具有保护作用。PIM1 可能是内毒素性 ALI 的潜在治疗靶点。
