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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Myeloid-Specific Pyruvate-Kinase-Type-M2-Deficient Mice Are Resistant to Acute Lung Injury
Xinlei Sun1,2, Fujie Shi1, Weiran Wang1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
Abstract:
Infiltration of polymorphonuclear neutrophils (PMNs) plays a central role in acute lung injury (ALI). The mechanisms governing PMN inflammatory responses, however, remain incompletely understood. Based on our recent study showing a non-metabolic role of pyruvate kinase type M2 (PKM2) in controlling PMN degranulation of secondary and tertiary granules and consequent chemotaxis, here we tested a hypothesis that Pkm2-deficient mice may resist ALI due to impaired PMN inflammatory responses. We found that PMN aerobic glycolysis controlled the degranulation of secondary and tertiary granules induced by fMLP and PMA. Compared to WT PMNs, Pkm2-deficient (Pkm2) PMNs displayed significantly less capacity for fMLP- or PMA-induced degranulation of secondary and tertiary granules, ROS production, and transfilter migration. In line with this, myeloid-specific Pkm2 mice exhibited impaired zymosan-induced PMN infiltration in the peritoneal cavity. Employing an LPS-induced ALI mouse model, LPS-treated Pkm2 mice displayed significantly less infiltration of inflammatory PMNs in the alveolar space and a strong resistance to LPS-induced ALI. Our results thus reveal that PKM2 is required for PMN inflammatory responses and deletion of PKM2 in PMN leads to an impaired PMN function but protection against LPS-induced ALI.
Insights
Pyruvate kinase type M2 (PKM2) is crucial for polymorphonuclear neutrophil (PMN) inflammatory responses. PKM2 deficiency impairs PMN function, leading to resistance against acute lung injury (ALI) in mice.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Polymorphonuclear neutrophils (PMNs) are key players in acute lung injury (ALI).
- The precise mechanisms regulating PMN inflammatory responses are not fully understood.
- Pyruvate kinase type M2 (PKM2) has a non-metabolic role in controlling PMN degranulation and chemotaxis.
Purpose of the Study:
- To investigate the role of PKM2 in PMN inflammatory responses.
- To test the hypothesis that Pkm2-deficient mice are resistant to ALI due to impaired PMN function.
- To determine if PKM2 controls PMN aerobic glycolysis, degranulation, and migration.
Main Methods:
- Utilized Pkm2-deficient mice and myeloid-specific Pkm2 knockout mice.
- Stimulated wild-type (WT) and Pkm2-deficient PMNs with fMLP and PMA.
- Assessed PMN degranulation, reactive oxygen species (ROS) production, and transfilter migration.
- Induced ALI in mice using lipopolysaccharide (LPS).
- Evaluated PMN infiltration in the peritoneal cavity and alveolar space.
Main Results:
- PMN aerobic glycolysis regulates degranulation of secondary and tertiary granules.
- Pkm2-deficient PMNs showed reduced degranulation, ROS production, and migration compared to WT PMNs.
- Myeloid-specific Pkm2 mice exhibited impaired zymosan-induced PMN infiltration.
- Pkm2-deficient mice demonstrated significantly reduced PMN infiltration in the lungs and resistance to LPS-induced ALI.
Conclusions:
- PKM2 is essential for PMN inflammatory responses, including degranulation and migration.
- Deletion of PKM2 in PMNs impairs their function.
- PKM2 deficiency confers protection against LPS-induced acute lung injury.
