Jefferson: The lungs of seven percent of all intensive care unit patients will fill up with fluid causing a 30 to 50 percent chance of death from a condition called acute respiratory distress syndrome (ARDS). This syndrome has few options for treatment, progresses quickly and is still poorly understood biologically, and being obese is an important risk factor. Using animal models of ARDS, researchers at Thomas Jefferson University in Philadelphia have uncovered a mechanism that appears to explain why obesity predisposes patients to developing ARDS, and in the process, might have discovered a novel strategy for preventing ARDS in obese individuals.
“Although our work needs to be confirmed in humans, our studies in
animals suggest that obese patients with ARDS may have a biologically
different disease than their non-obese counterparts, and our research
could point to a new therapeutic avenue for these patients,” says Ross
Summer, M.D., Associate Professor of Pulmonary and Critical Care
Medicine at Thomas Jefferson University and researcher at the Center for Translational Medicine and at the Jane and Leonard Korman Lung Center at Jefferson. The research was published online June 12th in the journal Scientific Reports, a Nature publication.
“While immune activation is usually protective and beneficial in the
body, in the case of ARDS, the immune system acts like a runaway train,
gaining speed and momentum as it goes, without the breaks that would
normally slow it down and keep it from causing too much damage in the
body,” says Dr. Summer. “Inflammation together with fluid build-up cause
the lungs lose their ability to exchange oxygen and carbon dioxide, and
can lead to death.”
Dr. Summer and colleagues looked at the bloods vessels that deliver
nutrients to the lungs of obese mice and saw that they were poised for
creating the fluid-filled, inflammatory environment seen in ARDS
patients. The junctions between cells in the blood vessels that normally
keep fluid from seeping into the airways were loosened, with fewer of
these “sealant” proteins present to support a strong barrier in obese
mice. These blood vessels were also found to express approximately 50
percent more adhesion molecules than lean mice. Adhesion molecules
function as a sort of Velcro for immune cells, capturing them from the
fast-flowing blood stream and allowing them to exit circulation and
enter tissues, where they fuel inflammation. Although obese mice had
normal fluid levels in their lung and immune cell penetration was kept
at bay in the basal state, these changes to the blood vessels suggested
they were already primed for injury.
When the researchers recreated conditions that lead to ARDS in mice,
they found that obese mice were more likely to develop respiratory
distress from fluid flooding the airspaces of the lung. Obese mice also
had approximately a 50 percent greater amount of infiltrating
neutrophils, a first-responder immune cell that often initiates an
aggressive immune response. “It’s possible that the higher quantity of
adhesion molecules in obese mice nabbed the neutrophils out of
circulation at a greater rate in obese mice than in non-obese mice,
leading to more inflammation,” says first author Dilip Shah, Ph.D., a
postdoctoral fellow in Dr. Summer’s lab.
To understand what caused the differences in adhesion molecules and
junction proteins in lung blood vessels, the researchers tested the
serum of obese mice. They incubated the obese-derived serum with normal
lung blood vessel cells and saw the same changes as observed in the
blood vessels in lungs of obese mice -- fewer gap proteins and more
immune adhesion proteins or “Velcro.” This indicated that something in
the blood of obese mice was causing changes to lung blood vessels.
Based on their earlier work, Dr. Summer and colleagues suspected the
deficiency in the hormone adiponectin might be the blood factor they
were looking for. This hormone is normally produced by fat cells but
levels are markedly reduced in the circulation of obese individuals. Dr.
Summer and colleagues had previously shown that mice lacking the
ability to produce this hormone are otherwise healthy, but have higher
likelihood of developing ARDS.
In the current study, the researchers used gene therapy techniques to
restore the decreased adiponectin levels in obese mice and found that
by replacing this hormone obese mouse were less vulnerable to developing
“It's unclear whether adiponectin acts directly on the blood vessels
of the lung,” says Dr. Summer. “It's possible that this hormone
initiates other protective and anti-inflammatory signals that prevent
the loss of junction proteins and the increase of the immune adhesion
Although drugs which can increase adiponectin levels already exist,
the first step, says Dr. Summer is to confirm that low adiponectin
levels are linked to higher rates of ARDS in humans. However, if this
association proves to be true, Dr. Summer believes adiponectin
replacement therapy may be an easy way to prevent ARDS in at-risk
Funding for this work was provided by the National Institute of
Health (NIH) R01HL105490. The authors report no conflicts of interest.