Boosting a natural cellular process could reduce damage, study suggests
Ohio State University
An unfortunate truth about the use of mechanical ventilation to save the lives of patients in respiratory distress is that the pressure used to inflate the lungs is likely to cause further lung damage.
In
a new study, scientists identified a molecule that is produced by immune cells
during mechanical ventilation to try to decrease inflammation, but isn't able
to completely prevent ventilator-induced injury to the lungs.
The
team is working on exploiting that natural process in pursuit of a therapy that
could lower the chances for lung damage in patients on ventilators. Delivering
high levels of the helpful molecule with a nanoparticle was effective at
fending off ventilator-related lung damage in mice on mechanical ventilation.
"Our data suggest that the lungs know they're not supposed to be overinflated in this way, and the immune system does its best to try to fix it, but unfortunately it's not enough," said Dr. Joshua A. Englert, assistant professor of pulmonary, critical care and sleep medicine at The Ohio State University Wexner Medical Center and co-lead author of the study. "How can we exploit this response and take what nature has done and augment that? That led to the therapeutic aims in this study."
The
work builds upon findings from the lab of co-lead author Samir Ghadiali,
professor and chair of biomedical engineering at Ohio State, who for years has
studied how the physical force generated during mechanical ventilation
activates inflammatory signaling and causes lung injury.
Efforts
in other labs to engineer ventilation systems that could reduce harm to the
lungs haven't panned out, Ghadiali said.
"We
haven't found ways to ventilate patients in a clinical setting that completely
eliminates the injurious mechanical forces," he said. "The
alternative is to use a drug that reduces the injury and inflammation caused by
mechanical stresses."
The
research is published today (Jan. 12, 2021) in Nature Communications.
Though
a therapy for humans is years away, the progress comes at a time when more
patients than ever before are requiring mechanical ventilation: Cases of acute
respiratory distress syndrome (ARDS) have skyrocketed because of the ongoing
COVID-19 pandemic. ARDS is one of the most frequent causes of respiratory
failure that leads to putting patients on a ventilator.
"Before
COVID, there were several hundred thousand cases of ARDS in the United States
each year, most of which required mechanical ventilation. But in the past year
there have been 21 million COVID-19 patients at risk," said Englert, a
physician who treats ICU patients.
The
immune response to ventilation and the inflammation that comes with it can add
to fluid build-up and low oxygen levels in the lungs of patients already so
sick that they require life support.
The
molecule that lessens inflammation in response to mechanical ventilation is
called microRNA-146a (miR-146a). MicroRNAs are small segments of RNA that
inhibit genes' protein-building functions -- in this case, turning off the
production of proteins that promote inflammation.
The
researchers found that immune cells in the lungs called alveolar macrophages --
whose job is to protect the lungs from infection -- activate miR-146a when
they're exposed to pressure that mimics mechanical ventilation. This action
makes miR-146a part of the innate, or immediate, immune response launched by
the body to begin its fight against what it is perceiving as an infection --
the mechanical ventilation.
"This
means an innate regulator of the immune system is activated by mechanical
stress. That makes me think it's there for a reason," Ghadiali said. That
reason, he said, is to help calm the inflammatory nature of the very immune
response that is producing the microRNA.
The
research team confirmed the moderate increase of miR-146a levels in alveolar
macrophages in a series of tests on cells from donor lungs that were exposed to
mechanical pressure and in mice on miniature ventilators. The lungs of
genetically modified mice that lacked the microRNA were more heavily damaged by
ventilation than lungs in normal mice -- pointing to miR-146a's protective role
in lungs during mechanical breathing assistance. Finally, the researchers
examined cells from lung fluid of ICU patients on ventilators and found
miR-146a levels in their immune cells were increased as well.
The
problem: The expression of miR-146a under normal circumstances isn't high
enough to stop lung damage from prolonged ventilation.
The
intended therapy would be introducing much higher levels of miR-146a directly
to the lungs to ward off inflammation that can lead to injury. When
overexpression of miR-146a was prompted in cells that were then exposed to
mechanical stress, inflammation was reduced.
To
test the treatment in mice on ventilators, the team delivered nanoparticles
containing miR-146a directly to mouse lungs -- which resulted in a 10,000-fold
increase in the molecule that reduced inflammation and kept oxygen levels
normal. In the lungs of ventilated mice that received "placebo"
nanoparticles, the increase in miR-146a was modest and offered little
protection.
From
here, the team is testing the effects of manipulating miR-146a levels in other
cell types -- these functions can differ dramatically, depending on each cell
type's job.
"In
my mind, the next step is demonstrating how to use this technology as a
precision tool to target the cells that need it the most," Ghadiali said.
The
collaborative work by researchers in engineering, pulmonary medicine and drug
delivery was conducted at Ohio State's Davis Heart and Lung Research Institute
(DHLRI), where Englert and Ghadiali have labs and teamed with Ohio State
graduate students and co-first authors Christopher Bobba from the MD/PhD
training program and Qinqin Fei from the College of Pharmacy to lead the
studies.
Additional
Ohio State co-authors include DHLRI investigators Vasudha Shukla, Hyunwook Lee,
Pragi Patel, Mark Wewers, John Christman and Megan Ballinger; Carleen Spitzer
and MuChun Tsai of the College of Medicine; and Robert Lee of the College of
Pharmacy. Rachel Putman of Brigham and Women's Hospital in Boston also worked
on the study.
The
research was supported by grants from the National Institutes of Health and the
Department of Defense, and an Ohio State Presidential Fellowship.
