When hospital patients need assistance breathing and are placed on a mechanical ventilator for days at a time, their lungs react to the pressure generated by the ventilator with an out-of-control immune response that can lead to excessive inflammation, new research suggests.

While learning that lungs perceive the ventilation as an infection, researchers also discovered potential drug targets that might reduce the resulting inflammation - a tiny piece of RNA and two proteins that have roles in the immune response.

Using human cell cultures, Ohio State University researchers determined that mechanical pressures trigger an innate immune response - the same immune response that the body launches to begin its fight against any kind of infection.

The rhythmic pressure of ventilation stimulated the production of pro-inflammatory chemicals by activating proteins called toll-like receptors (TLRs) in lung cells, the research showed.

"We showed that these cells respond to a mechanical force, pressure, as if it were an inflammatory stimulus. They almost perceive it as a bacterial toxin - and they don't like it," said Samir Ghadiali, associate professor of biomedical engineering at Ohio State and co-lead author of the study. "We didn't know until this study how we could possibly turn off that type of mechanically induced inflammation. Essentially what we found are two things that may help: microRNAs and two TLRs in the innate immunity pathway."

The job of TLRs is to recognize distinctive characteristics of pathogens and send out signals to activate other players in the immune system. This response persists during ventilation even with no pathogen present, and the prolonged inflammation can lead to organ failure. Acute lung injuries requiring mechanical ventilation lead to more deaths annually than do breast cancer and prostate cancer combined.

The study also suggested that at least one tiny piece of RNA - called a microRNA - is influential in this immune response because its behavior regulates the activation of the toll-like receptor proteins. The findings suggest that manipulating levels of either the microRNA or TLRs could be the basis for potential new treatment options for acute lung injury that requires ventilation.

This study appears online and is scheduled for future print publication in the Journal of the Federation of American Societies for Experimental Biology (FASEB Journal).

The study has clinical relevance as well as an influence on the big picture of the field of mechanotransduction - the study of how a mechanical force gets changed into a chemical stimulus inside the body. Mechanics play a role in many disease processes, including hardening of the arteries, other cardiac disorders, kidney problems, emphysema and chronic obstructive pulmonary disease, and cancer.

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