Related Experiment Video
Updated: Aug 10, 2025
Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
An engineered miRNA PS-OMe miR130 inhibits acute lung injury by targeting eCIRP in sepsis
Timothy Borjas1,2, Asha Jacob1,3,2, Molly Kobritz1,2
1Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.
Background:
Sepsis is caused by the dysregulated immune response due to an initial infection and results in significant morbidity and mortality in humans. Extracellular cold inducible RNA binding protein (eCIRP) is a novel mediator identified in sepsis. We have previously discovered that microRNA 130b-3p inhibits eCIRP mediated inflammation. As RNA mimics are very unstable in vivo, we hypothesize that an engineered miRNA 130b-3p mimic named PS-OMe miR130, improves stability of the miRNA by protection from nuclease activity. We further hypothesize that PS-OMe miR130 reduces not only eCIRP-mediated inflammation and but also acute lung injury in a murine model of polymicrobial sepsis.
Methods:
Single stranded PS-OMe miR130 was synthesized and the binding affinity to eCIRP was evaluated using surface plasmon resonance (SPR) and computational modeling. Macrophages were treated with PS-OMe miR130 with and without eCIRP and cell supernatant analyzed for cytokines. In vitro stability and the in vivo half-life of PS-OMe miR130 were also assessed. The effect of PS-Ome miR130 on eCIRP's binding to TLR4 was evaluated by SPR analysis and modeling. Finally, the effect of PS-OMe miR130 on inflammation and injury was assessed in a murine model of sepsis.
Results:
We demonstrate via SPR and computational modeling that PS-OMe miR130 has a strong binding affinity to eCIRP. This engineered miRNA decreases eCIRP induced TNF-α and IL-6 proteins, and it is highly stable in vitro and has a long in vivo half-life. We further demonstrate that PS-OMe miR130 blocks eCIRP binding to its receptor TLR4. Finally, we show that PS-OMe miR130 inhibits inflammation and lung injury, and improves survival in murine sepsis.
Conclusion:
PS-OMe miR130 can be developed as a novel therapeutic by inhibiting eCIRP-mediated inflammation and acute lung injury in sepsis.
Insights
Engineered microRNA 130b-3p (PS-OMe miR130) effectively reduces sepsis-induced inflammation and acute lung injury by inhibiting extracellular cold-inducible RNA-binding protein (eCIRP). This stable therapeutic candidate shows promise for sepsis treatment.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Sepsis, a life-threatening condition, stems from a dysregulated immune response to infection, leading to significant human morbidity and mortality.
- Extracellular cold-inducible RNA-binding protein (eCIRP) is identified as a key mediator in sepsis-induced inflammation.
- MicroRNA 130b-3p has been previously shown to inhibit eCIRP-mediated inflammation, but its in vivo instability limits therapeutic application.
Purpose of the Study:
- To investigate the therapeutic potential of an engineered, nuclease-resistant microRNA 130b-3p mimic, PS-OMe miR130.
- To evaluate PS-OMe miR130's ability to inhibit eCIRP-mediated inflammation and acute lung injury in a murine sepsis model.
Main Methods:
- PS-OMe miR130 was synthesized and characterized for binding affinity to eCIRP using surface plasmon resonance (SPR) and computational modeling.
- In vitro and in vivo stability, including half-life, were assessed.
- The impact of PS-OMe miR130 on eCIRP-induced cytokine production (TNF-α, IL-6) in macrophages and eCIRP's binding to TLR4 was evaluated.
- Efficacy was determined in a murine model of polymicrobial sepsis, assessing inflammation, lung injury, and survival.
Main Results:
- PS-OMe miR130 demonstrated strong binding affinity to eCIRP.
- The engineered miRNA significantly reduced eCIRP-induced TNF-α and IL-6 production.
- PS-OMe miR130 exhibited high stability in vitro and an extended half-life in vivo.
- It was shown to block eCIRP binding to TLR4, thereby inhibiting inflammation and acute lung injury in a murine sepsis model, leading to improved survival.
Conclusions:
- PS-OMe miR130 is a stable, engineered miRNA mimic with potent anti-inflammatory and anti-injury effects in sepsis.
- This molecule effectively targets the eCIRP pathway, offering a promising novel therapeutic strategy for sepsis and its associated acute lung injury.
Related Concept Videos
01:22MicroRNAs
02:15Experimental RNAi