My name is Carolyn Calfee, and I'm an Associate Professor of Medicine and Anesthesia
here at the University of California, San Francisco.
And I’m going to talk with you today about mesenchymal stem, or stromal, cells and the
acute respiratory distress syndrome.
I'll give the first portion of the talk and then my colleague, Dr. Michael Matthay,
who's a Professor of Medicine and Anesthesia here at UCSF, also, will give the second portion.
This is a brief overview of what I'm going to cover today.
I'll start with talking about, what is ARDS, or the acute respiratory distress syndrome?
Its clinical presentation and pathophysiology.
And then I'll move on to discuss our current treatments for ARDS and why we're
in search of new ones.
And then I'll hand the pointer over to Dr. Matthay, who will talk about the work
that we and other colleagues have been doing to try to translate mesenchymal stem cells from
the preclinical side, using bench science and animal models, into human subjects.
I thought it would be useful to start with a clinical case of ARDS, to explain
what the syndrome is and give you a sense of what we're trying to treat.
So, this is a case of a patient that we took care of several years ago, a 42 year old man
who was previously in good health, until he presented to the emergency room with
fevers for five days, muscle aches and cough.
In addition, he had increasing shortness of breath for the past day.
He had no past medical history and was a nonsmoker.
This is his initial chest X-ray and, while this may look relatively normal when you compare
it to a normal chest X-ray, here you'll see that on his X-ray there are faint
interstitial opacities, as we term them, or faint whitish lines extending out from the center of
the chest out to the periphery.
Over time, as we followed his chest X-rays through his hospitalization, on the next day,
these opacities were increasing.
And increasing even further, as you can see here, progressing to what we call frank consolidation,
until the point where he required mechanical ventilator support, as you can see here.
And the diagnosis here is acute lung injury, also known as ARDS
or the acute respiratory distress syndrome,
due to H1N1, viral pneumonia.
So, this is a classic case of the acute respiratory distress syndrome.
And what this is is what we call non-cardiogenic pulmonary edema, that is, where the lungs
fill up with fluid in the alveolar space, or the air sacs of the lung, for reasons
other than heart failure.
It's diagnosed by three defining criteria, including the acute onset of bilateral opacities
on the chest X-ray, as you see here;
low oxygen levels in the blood;
and exclusion of heart failure as the primary cause of the pulmonary edema.
ARDS is a common syndrome that develops following certain clinical conditions.
These may be conditions that cause direct injury to the lungs, like pneumonia,
aspiration of gastric contents into the lungs, or near drowning.
Or conditions that cause what we call indirect lung injury, such as sepsis, which is a
severe infection in the bloodstream, severe trauma,
blood transfusion or other causes.
This is a common syndrome.
It affects about 200,000 people per year in the US alone,
and is associated with 75,000 deaths per year in the US,
more than breast cancer, colon cancer, or HIV.
And mortality -- I'll show you in the subsequent slides -- remains high, 30-40%.
Unfortunately, at this time, no specific therapies are available other than specific ventilator
and fluid management.
So, what I'm going to show you in the next couple of slides is our understanding of
the process by which normal lung, which you see here, with the alveolar air sacs nice and
filled with air, where you can imagine gas exchange occurs easily,
develops acute lung injury, which you can see here on the right,
where the air sacs of the lung are swollen,
filled with inflammatory, pink pulmonary edema fluid.
So, what I'm showing here is a schematic of what I just showed you in the previous slide.
And on the left side of your screen, you'll see a normal alveolus, or a normal air sac
in the lung.
What you see there is that the alveolus is filled with air, there's a nice thin lining
of surfactant, which helps to keep the alveolus open,
and you can see that the epithelial line -- the epithelial cell surface layer --
is thin and well... closely opposed to the capillary endothelium, here.
You can imagine that gas exchange occurs very easily across this barrier.
In contrast, this is the injured alveolus during the acute phase of acute lung injury.
And you'll notice a number of abnormalities.
So, for one, the alveolus is filled with this pink, pulmonary edema fluid, which has filled
with inflammatory cells elaborating inflammatory cytokines.
You can also see, here, that the lining of the alveolus, that epithelial barrier that's
normally very tight and helps to keep any fluid from crossing over into the alveolus,
is now necrotic, and frankly denuded in some places.
You can see that the border between the epithelial and the endothelial surface is swollen.
So, you can imagine how gas exchange is much more difficult there.
And you can see that the capillary endothelium itself is also involved.
So, the endothelial surface is abnormal and activated.
You can see that neutrophils are able to cross over from the endothelium into the interstitium.
And you can see that platelets are involved here as well, too.
So, this is a very complex process with compact... complex pathophysiology.
So, given that, what are our current treatment strategies for ARDS?
What can we do to try to treat the syndrome once it develops?
Well, I'm going to outline our current treatment strategies, which are focused primarily on
ventilation with lower tidal volumes, a fluid conservative management strategy, and then
I'll talk about the history of pharmacologic therapies and why we're in search of new therapies.
So, ventilation with lower tidal volumes is now the standard of care for ARDS patients.
These patients are placed on mechanical ventilators in the intensive care unit.
And while we initially thought, years ago, that ventilation with larger tidal volumes
was necessary to help open up the lungs and maintain normal oxygen levels,
we've now known for the past 14 years, since the publication of this landmark trial,
that ventilation with lower tidal volumes actually improves survival from this condition.
How does this work?
Well, you've seen a similar diagram to this before, just a couple of slides ago.
The injured alveolus is over here on the left.
And you can see that in the setting of high stretch or higher tidal volume ventilation,
that that actually worsens the injury, we now know.
In fact, there's more pulmonary edema, the migration of neutrophils into the
alveolar space is enhanced, and in addition alveolar fluid clearance, which is the ability of the lung
to actually remove the pulmonary edema fluid from the alveolus, is impaired.
In contrast, when lower stretch ventilation is used, alveolar fluid clearance is enhanced
and the epithelium is allowed to proliferate and heal again, thus enhancing the resolution
of ARDS.
In addition, we now know that fluid conservative therapy helps patients with ARDS to get
off the ventilator and out of the intensive care unit sooner.
This was another landmark clinical trial supported by the NIH and carried out by the ARDS Network,
which showed that patients who were treated with the fluid conservative strategy were
able to get off the ventilator sooner compared to patients
who were treated with the fluid liberal strategy.
Why does this happen?
Well, in part this goes back to what we know about the physiology of the lung.
Even under conditions of normal permeability, as pulmonary hydro... hydrostatic pressure increases,
which happens with increasing fluid in the intravascular space, the rate of lung
edema formation increases.
But under conditions of increased permeability, such as we see in ARDS,
as the pulmonary hydrostatic pressure increases,
the rate of lung edema formation increases dramatically.
And this is what we see in the case of ARDS.
And we think that by treating patients with fluid conservative therapy, that is, by decreasing
their pulmonary hydrostatic pressure,
we're actually decreasing the rate of lung edema formation.
So, these are supportive care practices.
What about specific pharmacologic therapies for ARDS?
Well, unfortunately, despite 25 years of attempts to find a successful therapy for ARDS,
none of these pharmacologic therapies have been successful.
This is just a partial list of some of the... the pharmacologic agents that have been tried
for ARDS, including, most recently, albuterol, omega-3 fatty acids, and statins,
all of which have failed to show a benefit.
During this time, ARDS mortality has improved significantly, largely as a result of ventilation
with lower tidal volumes and treatment with fluid conservative therapy,
as I've just shown you.
But as you can see from the figure, despite this improvement in mortality, mortality from
ARDS, even in randomized controlled trials, remains high, in the range of 20-25%.
And in unselected patients, mortality from ARDS remains 30-40%.
So, we still have a long way to go before we're effectively treating this condition.
And that's why we're continuing to search for novel therapies.
The therapy that we're going to focus on today is mesenchymal stem, or stromal, cells.
Why is it that we think that these cells might be beneficial for ARDS?
The original idea when mesenchymal stem cells were first studied for pulmonary disease,
now a couple of decades ago, was that the mesenchymal stem cells
would engraft in the lung and thereby facilitate repair.
However, now we know that it's very unlikely that these stem cells actually engraft in
the lung, but instead we think they act by exerting pleiotropic effects on both
lung repair and regeneration.
This is largely, though not entirely exerted through paracrine mechanisms.
The cells also have anti-inflammatory and antimicrobial properties.
And we think that it's this multiple pathway approach that may explain why mesenchymal
stem cells hold a lot of promise for potentially treating ARDS.
Now, at this point in the talk, I'm going to hand it over to Dr. Michael Matthay,
Professor of Medicine and Anesthesia at UCSF, who's going to talk about work that we and other
colleagues have been doing, both on the preclinical side and the early clinical side, to try to
translate mesenchymal stem cell therapy into clinical use.