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Updated: Nov 30, 2025
Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
PIM1 inhibition attenuated endotoxin-induced acute lung injury through modulating ELK3/ICAM1 axis on pulmonary
Yumeng Cao1, Xia Chen1, Yuqi Liu1
1Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 20080, China.
Objective:
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.
Materials And Methods:
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 (PaO2/FiO2 ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed.
Results:
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 SpO2/FiO2 ratio among CPB induced ALI patients.
Conclusion:
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.
Insights
PIM1 inhibition protects against acute lung injury (ALI) by modulating the ELK3/ICAM1 pathway in pulmonary microvascular endothelial cells (PMVECs). This finding suggests PIM1 as a potential therapeutic target for ALI.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Cellular Biology
Background:
- Pulmonary microvascular endothelial cell (PMVEC) dysfunction is central to acute lung injury/acute respiratory distress syndrome (ALI/ARDS).
- The role of PIM1 kinase in PMVEC injury during ALI remains largely uncharacterized.
- Severe infections can trigger ALI/ARDS, highlighting the need to understand underlying cellular mechanisms.
Purpose of the Study:
- To investigate the role of PIM1 in endotoxin-induced ALI.
- To explore the molecular mechanisms by which PIM1 influences PMVEC injury.
- To assess PIM1 as a potential therapeutic target for ALI.
Main Methods:
- Measured PIM1 levels in lung tissues of ALI mice and plasma from ALI patients.
- Evaluated the protective effects of PIM1 inhibitor SMI-4a on ALI using histological and functional assessments.
- Validated the PIM1-ELK3-ICAM-1 axis in vitro and in vivo.
- Correlated plasma PIM1 levels with ALI biomarkers in patients.
Main Results:
- PIM1 expression was elevated in endotoxin-induced ALI mouse lungs.
- PIM1 inhibition with SMI-4a ameliorated ALI severity, improving lung histology, permeability, and survival.
- PIM1 was found to regulate ICAM-1 expression via the transcription factor ELK3 in PMVECs.
- Plasma PIM1 levels correlated positively with Ang-II and PAI-1, and negatively with the PaO2/FiO2 ratio in ALI patients.
Conclusions:
- PIM1 inhibition demonstrates a protective effect against endotoxin-induced ALI.
- The protective mechanism involves modulating the ELK3/ICAM-1 axis in PMVECs.
- PIM1 represents a promising therapeutic target for managing ALI.
