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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Protective effect of MOTS-c on acute lung injury induced by lipopolysaccharide in mice
Yin Xinqiang1, Chen Quan2, Jing Yuanyuan3
1School of Basic Medical Sciences, North Sichuan Medical College, Nanchong 673000, China; The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA-c), a mitochondrial-derived 16-amino acid peptide, targets the methionine-folate cycle, increases 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels, and eventually activates AMP-activated protein kinase (AMPK). AMPK activation can attenuate neutrophil pro-inflammatory activity and attenuates lipoteichoic acid (LTA) and lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. However, to our knowledge, the role of MOTS-c in LPS-induced ALI remains unclear. Hence, we investigated the potential effectiveness and underlying mechanism of MOTS-c against LPS-induced ALI in mice. The intraperitoneal administration of MOTS-c (5 mg/kg, i.p., bid, 6 days) before intratracheal LPS instillation attenuated body weight loss and pulmonary edema, inhibited neutrophilic tissue infiltration in lung tissue, downregulated the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and intercellular cell adhesion molecule-1 (ICAM-1) in lung tissues, decreased the levels of TNF-α, IL-1β, and IL-6, and increased the expression of IL-10 and SOD in serum, lung tissue, and bronchoalvelolar lavage fluid (BALF). Moreover, MOTS-c treatment significantly promoted p-AMPKα and SIRT1 expression and suppressed LPS-induced ERK, JNK, p38, p65, and STAT3 activation in the mouse lung tissues. Collectively, these findings suggest that MOTS-c plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of MOTS-c are probably orchestrated by activating AMPK and SIRT1, inhibiting ERK, JNK, p65, and STAT3 signaling pathways. Thus, MOTS-c appears to be a novel and promising candidate for the treatment of ALI.
Insights
Mitochondrial peptide MOTS-c protects against lipopolysaccharide (LPS)-induced acute lung injury (ALI) by activating AMPK and SIRT1 pathways. This peptide treatment reduces lung inflammation and injury, showing promise for ALI treatment.
Area of Science:
- Mitochondrial biology
- Immunology
- Pulmonology
Background:
- MOTS-c is a mitochondrial-derived peptide influencing cellular metabolism.
- AMP-activated protein kinase (AMPK) activation can mitigate inflammatory responses.
- The role of MOTS-c in lipopolysaccharide (LPS)-induced acute lung injury (ALI) requires clarification.
Purpose of the Study:
- To investigate the therapeutic potential of MOTS-c against LPS-induced ALI in a mouse model.
- To elucidate the underlying molecular mechanisms of MOTS-c's protective effects in ALI.
Main Methods:
- Mice were treated with MOTS-c (5 mg/kg, i.p., twice daily for 6 days) prior to intratracheal LPS instillation.
- Evaluated parameters included body weight, pulmonary edema, neutrophil infiltration, inflammatory markers (CINC-1, ICAM-1, TNF-α, IL-1β, IL-6, IL-10), oxidative stress (SOD), and key signaling pathway activation (AMPK, SIRT1, ERK, JNK, p38, p65, STAT3).
Main Results:
- MOTS-c administration attenuated LPS-induced body weight loss, pulmonary edema, and neutrophil infiltration.
- MOTS-c downregulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and upregulated IL-10 and SOD.
- MOTS-c treatment promoted p-AMPKα and SIRT1 expression while suppressing LPS-induced activation of ERK, JNK, p65, and STAT3.
Conclusions:
- MOTS-c effectively protects against LPS-induced ALI in mice, reducing lung inflammation and injury.
- The protective effects are mediated through the activation of AMPK and SIRT1 signaling pathways.
- MOTS-c inhibits inflammatory signaling cascades including ERK, JNK, p65, and STAT3, positioning it as a potential therapeutic agent for ALI.
