In a study published in the Journal of Clinical Investigation Insight, scientists have found
that elevated levels of chlorinated lipids are linked to sepsis, lung injury
and death. The finding may offer a way to diagnosis and treat sepsis earlier,
saving lives and avoiding serious side effects.
The key challenge in treating sepsis is to diagnosis it and
begin antibiotics quickly; as organs begin to shut down, treating sepsis
becomes a matter of beating the clock.
In 2002, David Ford, PhD, professor of biochemistry and molecular
biology at Saint Louis University, made a discovery of a type of lipid that had
not previously been identified in humans.
“My lab discovered chlorinated lipids,” Ford said.
“They are made in the body under conditions where there is
Ford’s team, together with Jane McHowat, PhD, professor of
pathology at SLU, have continued their study of chlorinated lipids and
inflammation to better understand the link between the two.
In the study described in the Journal of Clinical Investigation Insight paper, researchers
examined blood samples taken soon after admission to the hospital from patients
who were eventually diagnosed with sepsis.
They found that chlorinated lipids not only were present in
the blood but that they also predicted whether a patient would go on to suffer
acute respiratory distress symptom (ARDS) and predicted whether patients would
die within 30 days from a lung injury.
“Chlorinated lipids appear to serve as a very early
warning sign that a patient is on track for a severe lung injury that could be
fatal,” Ford said.
Investigators had learned that elevated levels of
chlorinated lipids could serve as a biomarker, a sign post that appeared when
the body became inflamed. But, they also wondered if chlorinated lipids were
the culprit causing the inflammation.
“There is another layer to this research: Are
chlorinated lipids a causative agent?
“We examined this at a basic science level,” Ford
said. “Our research suggests that they do cause injury in the
microcirculation of the lung. The data in this paper suggests chlorinated
lipids have a causative role.”
Researchers found that chlorinated lipids are generated by
enzymes in neutrophils. When the body is fighting an infection, neutrophils
kill microbes. In the process of fighting off the intruder, chlorinated lipids
are generated as a by-product. They are the collateral damage that occurs to a
patient’s own tissue by its immune system.
In a second paper, published in the Journal of Lipid Research, Ford and his collaborators explored the
mechanisms of how this process works.
Celine Hartman, a SLU graduate student, made an analogue of
a chlorinated lipid. That allowed the research team to track where the lipid
travels within the endothelial cells in the linings of blood and lymph vessels.
“What Hartman found was that the analogue goes very
specifically to a granule within an endothelial cell, called a Weibel-Palade
body,” Ford said. “That is significant because Weibel-Palade bodies
contain proteins that are responsible for inflammation at the site where blood
interfaces with the small blood vessels of an organ, the microcirculation,
which is associated with organ injury and oedema.”
The findings in these papers set the stage for two
strategies against sepsis.
First, if researchers can develop a rapid test for
chlorinated fatty acids in the clinic, they could begin treatment sooner and
buy time for patients.
“Right now, the only treatment for sepsis is
antibiotics,” Ford said. “The faster a patient is put on them, the
greater survival and fewer side effects. There have been studies showing that
the faster antibiotics are administered after hospital admission, the better
the patient’s outcome.”
Second, if chlorinated lipids are indeed causative as Ford’s
data suggests, then molecules could be developed to block their action, leading
to a potential new therapy to stop sepsis-caused organ injury and death.
NJ, et al. Myeloperoxidase-derived 2-chlorofatty acids contribute to human
sepsis mortality via acute respiratory distress syndrome. Journal of Clinical Investigation Insight. First published 7
December 2017. https://insight.jci.org/articles/view/96432