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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
IP3R-1 aggravates endotoxin-induced acute lung injury in mice by regulating MAM formation and mitochondrial function
Shuan Dong1, Ya Wu1, Yuan Zhang1
1Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
Abstract:
Acute lung injury (ALI) caused by endotoxin represents one of the common clinical emergencies. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as a critical link between mitochondria and endoplasmic reticulum (ER), which has an essential effect on maintaining intracellular homeostasis. As an important component of MAM, type-1 inositol-1,4,5-trisphosphate receptor (IP3R-1) mediates the ER-to-mitochondrial transport of Ca2+. This study explored the role of IP3R-1 and MAM in ALI. Besides the levels of inflammasome-associated components interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malonyldialdehyde (MDA) were increased in both bronchoalveolar lavage fluid (BALF) and serum, increased cross-sectional area of mitochondria, elevated MAM formation, and decreased respiratory control ratio (RCR) were observed within lung tissues collected in lipopolysaccharide (LPS)-treated mice, accompanied by upregulation of IP3R-1 in total lung lysates and MAM. Ca2+ uptake level in the mitochondria, production of reactive oxygen species (ROS) in the mitochondria, and the formation of MAM were elevated within LPS-treated MLE-12 cells, and all those changes in response to LPS were partly inhibited by knocking down of IP3R-1 expression in MLE-12 cells. Collectively, IP3R-1 has a critical effect on MAM formation and mitochondrial dysfunction, which could be innovative therapeutic targets for ALI caused by endotoxin.
Insights
Endotoxin-induced acute lung injury (ALI) involves mitochondrial dysfunction. The study reveals that inositol-1,4,5-trisphosphate receptor type 1 (IP3R-1) critically impacts mitochondria-associated endoplasmic reticulum membranes (MAM) formation and cellular damage in ALI.
Area of Science:
- Cellular Biology
- Mitochondrial Biology
- Respiratory Medicine
Background:
- Acute lung injury (ALI) from endotoxins is a critical clinical issue.
- Mitochondria-associated endoplasmic reticulum membranes (MAM) are vital for cellular homeostasis.
- Type-1 inositol-1,4,5-trisphosphate receptor (IP3R-1) regulates calcium (Ca2+) transport at MAM.
Purpose of the Study:
- To investigate the role of IP3R-1 and MAM in endotoxin-induced ALI.
- To understand the mechanisms linking IP3R-1, MAM, and mitochondrial dysfunction in ALI.
Main Methods:
- Lipopolysaccharide (LPS) administration in mice and MLE-12 cells.
- Analysis of inflammasome components (IL-6, TNF-α, MDA) in BALF and serum.
- Assessment of mitochondrial morphology, MAM formation, and respiratory control ratio (RCR) in lung tissues.
- Measurement of mitochondrial Ca2+ uptake, reactive oxygen species (ROS) production, and MAM formation in MLE-12 cells.
- IP3R-1 knockdown in MLE-12 cells.
Main Results:
- LPS treatment increased IL-6, TNF-α, and MDA levels.
- Mice exposed to LPS showed increased mitochondrial size, elevated MAM formation, and reduced RCR.
- IP3R-1 expression was upregulated in lung tissues and MAM of LPS-treated mice.
- In LPS-treated MLE-12 cells, mitochondrial Ca2+ uptake, ROS production, and MAM formation were elevated.
- Knocking down IP3R-1 partially reversed these LPS-induced changes in MLE-12 cells.
Conclusions:
- IP3R-1 plays a crucial role in MAM formation and mitochondrial dysfunction during ALI.
- Targeting IP3R-1 could offer a novel therapeutic strategy for endotoxin-induced ALI.
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