When trauma spills the contents of our cell powerhouses, it can evoke a potentially deadly immune response much like a severe bacterial infection.

A drug that cleaves escaped proteins, called N-formyl peptides, appears to reduce resulting dangerous leakage from blood vessels and improve survival, report researchers at the Medical College of Georgia at Augusta University.

The research drug deformylase, or something similar, may one day be a novel treatment for patients with systemic inflammatory response syndrome, or SIRS, a body-wide inflammatory reaction to trauma or infection, as well as sepsis, a systemic infection when the cause of the infection, like a bacteria, is known.

“We are hoping our work will improve the care of trauma and other critically ill patients,” says Dr. Patricia Martinez Quinones, general surgery resident at MCG and AU Health.

Martinez Quinones is presenting the work in both animal models and human cells during the Oral Presentations by Young Investigators session on the final day of the Shock Society’s 41st Annual Conference June 9-12 in Scottsdale, Arizona.

“Once mitochondria (cell powerhouses) are damaged, they just break apart and their contents spill into the circulation,” says Martinez Quinones.

Mitochondria use N-formyl peptides to make energy for our cells, but significant volumes outside the powerhouse can quickly become a detriment. Deformylase appears to neutralize them by removing their formyl group—a combination of carbon and oxygen atoms with hydrogen.

This formyl group is part of every bacterial protein as well as all 13 proteins made by mitochondria, says Dr. Camilla Ferreira Wenceslau, research scientist in the MCG Department of Physiology and senior author of the ongoing studies.

“That is what triggers the immune system to trigger an inflammatory cascade,” says Dr. Keith O’Malley, interim chief of MCG’s Division of Trauma/Surgical Critical Care and a co-investigator on the ongoing studies.

In fact, the mitochondria themselves can similarly neuter the proteins and those benign versions are normally the only ones it releases, until there is an injury.

“The entire hypothesis behind this—and it’s called the danger theory—is that our mitochondria used to be bacteria so when their contents are released our body treats them like an infection,” Martinez Quinones says.

The results can be pretty much the same as if external bacteria entered our bodies: rapid heart rate, fever, precipitous drop in blood pressure, and swelling.

“Trauma releases fragments of mitochondria that still carry the signature from bacteria,” says Wenceslau.

If outside bacteria are the source of the immune reaction, an antibiotic should quell the resulting cascade of damage, O’Malley notes. But despite the similarities, there are no known antibiotics that target spilled mitochondrial contents, Martinez Quinones adds.

Deformylase, or something like it, on the other hand may one day be useful at both infective sepsis from an invader and this “sterile” sepsis from our own mitochondria, she notes.

In the lab of MCG physiology chair Dr. R. Clinton Webb, the investigators have looked at a mouse model of sepsis. They’ve also incubated human endothelial cells that line the aorta with N-formyl-rich plasma taken from patients with severe trauma.

Deformylase improved sepsis survival in their animal model by 28% and prevented separation of the tightly knit human endothelial cells that keep blood vessel content contained.

“What we saw is that there was a marked improvement in the vascular function of the animals that were treated with deformylase, meaning that the vessels that were leaky and couldn’t contract now could,” Martinez Quinones says. “Also, once we treated the plasma with deformylase, the endothelial cell disruption went away.”

Their findings to date have them theorizing that circulating levels of mitochondrial DNA and N-formyl peptides might one day be good biomarkers that could change both how patients are monitored and treated, Martinez Quinones says.