by Roni Dengler, Thomas Jefferson University

Graphical abstract. Credit: Molecular Therapy—Nucleic Acids (2024). DOI: 10.1016/j.omtn.2024.102285

Chronic obstructive pulmonary disease (COPD) affects nearly 12 million people in the U.S. alone and is the third leading cause of death worldwide. High levels of immune molecules known as cytokines, which can damage the lungs, are a hallmark of COPD.

Now, molecular biologist Yohei Kirino, Ph.D. and lung disease expert Deepak Deshpande, Ph.D. have teamed up in a new study to discover a molecular smoking gun behind the rise of cytokines in COPD. The findings are published in the journal Molecular Therapy—Nucleic Acids.

The link seems to be another class of small molecules known as short non-coding RNAs, or simply sncRNAs, whose levels can change in response to infection or environmental pollutants.

Dr. Kirino and researchers in his laboratory have developed a “very simple trick” to detect all the sncRNAs in a sample. Standard sequencing methods rely on two chemical features on sncRNA molecules (known as 5′ phosphate and 3′ hydroxyl ends), which many sncRNAs do not have.

So, the researchers first treated the samples with an enzyme that equipped every RNA molecule with these features. Dr. Kirino and colleagues were then able to sequence all the sncRNAs in people with COPD and compare them with those in healthy people.

The researchers had previously shown that one type of scRNA, called 5′-tRNAValCAC half, is a potent activator of the immune system in general, causing increased levels of cytokines. The current study, spearheaded by first-author Megumi Shigematsu, Ph.D., looked specifically at people with COPD and found they have high levels of the scRNA 5′-tRNAValCAC half. The findings suggest that this scRNA might be responsible for the rise of cytokines in COPD, driving lung damage and inflammation.

“The results illuminate this possibility for the first time,” says Dr. Kirino.

Altogether, the research paves the way for potential new diagnostics and therapies. The sncRNA, 5′-tRNAValCAC half, could be a biomarker for COPD, for example. “COPD is often underdiagnosed because of a lack of sensitive and reliable diagnostic markers, despite its high prevalence,” says Dr. Deshpande.

“If we can suppress the activity of 5′-tRNAValCAC half and it mitigates the effects of COPD,” adds Dr. Kirino, “that suggests it can be a therapeutic target.”

More information: Megumi Shigematsu et al, Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease, Molecular Therapy—Nucleic Acids (2024). DOI: 10.1016/j.omtn.2024.102285

Provided by Thomas Jefferson University

---

Explore further

Small RNAs found to boost immune response to tuberculosis