Deletion of the miR-144/451 cluster aggravates lethal sepsis-induced lung epithelial oxidative stress and apoptosis

Fan Wu; Xiaoling Yuan; Weili Liu; Lijun Meng; Xiuru Li; Xiang Gao; Shuting Zhou; Lei Fang; Duonan Yu

doi:10.21037/atm-22-1024

Deletion of the miR-144/451 cluster aggravates lethal sepsis-induced lung epithelial oxidative stress and apoptosis

Ann Transl Med. 2022 May;10(10):538. doi: 10.21037/atm-22-1024.

Authors

Fan Wu^#^{1

2}, Xiaoling Yuan^#³, Weili Liu^#^{1

4}, Lijun Meng^{1

4}, Xiuru Li¹, Xiang Gao¹, Shuting Zhou^{1

2}, Lei Fang^{1

2}, Duonan Yu^{1

2

4}

Affiliations

¹ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
² Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, China.
³ Children Rehabilitation Department, Yangzhou Maternal and Child Health Hospital, Yangzhou, China.
⁴ Intensive Care Unit, Affiliated Hospital of Yangzhou University, Yangzhou, China.

^# Contributed equally.

Abstract

Background: Sepsis is associated with a high mortality rate. A major cause of death in sepsis patients is respiratory failure, which is characterized by oxidative injury, epithelial apoptosis, and increased lung permeability. MicroRNAs (miRs) are important regulators of sepsis progression.

Methods: This study aimed to explore the role of miR-144/451 in sepsis in mice. Experimental sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP).

Results: CLP significantly induced systemic inflammation, lung permeability, and lung epithelial apoptosis with downregulated messenger RNA (mRNA) levels of antioxidant enzymes. The miR-144/451 knockout mice had a lower 48-hour survival rate, higher plasma tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, and greater pulmonary permeability compared with wild-type mice after CLP. CLP also markedly increased interstitial hemorrhage, collapsed more alveolar sacs, and increased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive and Bcl-2-associated X (Bax)-positive cells in miR-144/451 knockout lung tissues, with elevated mRNA levels of Bax and reduced activities of catalase (Cat), glutathione peroxidase 1(Gpx1). MiR-451 negatively regulated 14-3-3ζ expression evidenced in miR-144/451 knockout lungs and the A549 cell line. In lipopolysaccharide (LPS)-induced A549 cells, miR-451 overexpression remarkably suppressed the production of reactive oxygen species, inhibited cell apoptosis, and enhanced levels of FoxO3 protein and related enzymes.

Conclusions: Deletion of the miR-144/451 cluster aggravated sepsis-induced oxidative injury of lung epithelial cells.

Keywords: apoptosis; epithelial; miR-144/451; oxidative stress; sepsis.