“Stop and think about the fundamental question,” Jason Christie is saying. “A hundred people get pneumonia, or major trauma—hit by a car or something—or a severe bloodstream infection. About 30 to 40 of them get ARDS. The others don’t. Why? Why do they have susceptibility for a given insult?”
That question is at the heart of Penn’s research efforts in the field. But—apart from certain known behavioral risk factors such as chronic alcohol abuse—it’s a damnably difficult one to answer.
“It’s difficult because it’s a very complicated set of events that lead to the Shock Lung picture, where your lung fills up with fluid and inflammatory cells and makes it so you can’t breathe without a ventilator,” says Christie, whose many titles include senior scholar in the Center for Clinical Epidemiology and Biostatistics and director of clinical research in the pulmonary division. “So we spend a lot of time thinking about Why?”
Part of that question involves “whether there’s an inter-individual genetic variation to this,” since over the centuries, our ability to survive events such as bleeding, severe infection, and plagues may have “conferred a survival advantage in the setting of those environmental insults.”
But in recent years, medicine has evolved a lot faster than our bodies. “Now, when faced with a severe insult—such as trauma that people wouldn’t have survived 50 years ago, severe pneumonias that people wouldn’t have survived a hundred years ago when we didn’t even have oxygen to give to them, other bloodstream infections that would have claimed people’s lives—now that we’re good at treating some of those, why then do some of these people go and have this severe Shock Lung?”
The biological causes of acute lung injury (ALI) and ARDS “are not perfectly understood,” Christie notes. “There’s one theory that you have an over-exuberant inflammatory response, either on the basis of your own immune system or on the basis of how you respond to some of the pressures such as clotting, which can cause inflammation, or fibrin deposition—how your blood vessels handle acute inflammation—which may have been selected for based on how you would heal a cut.”
The tragic irony is that for some people, a strong, evolutionarily honed immune response to infections “may tip over to an over-exuberant inflammatory response that might actually end up causing the disease,” says Christie. The numerous “checks and balances in the modulation of the immune system” were developed in a different era. “I mean, there’s no evolutionary pressure on surviving an intensive care unit, right? Because we’ve only had them for 30 or 40 years. There’s no evolutionary pressure on surviving severe major trauma, because [in the past] you just died! Now that we can handle the early phases of the critical illness, these organ failures that occur are good targets for thinking about how we can approach susceptibility to them.”
For Nuala Meyer, an assistant professor of medicine whose research focuses on identifying genetic and molecular risk factors for ALI/ARDS and organ dysfunction, the balance between “pro-inflammation and anti-inflammatories” is one of the critical unsolved puzzles. “On the one hand, [ARDS] looks like an over-exuberant inflammatory response, and maybe those pro-inflammatory molecules are what break down your lungs’ vascular barrier, and that’s why you leak,” says Meyer. “On the other hand, you actually need functional immune cells, monocytes and T cells, to get better. So it may be that if you’re immunosuppressed, and sepsis can incite a type of immunosuppression, maybe that’s suppressing your body’s ability to heal from ARDS.
“So we certainly haven’t quite figured out the timing and the balance of pro- and anti-inflammatory molecules in ARDS. Maybe some patients, their problem is that they have too much pro-inflammatory, and others it may be that they don’t have the type of immune cells that resolve inflammation.”
Much of Meyer’s research involves looking at “both the genetics and the proteins in tandem.”
“Can we identify proteins, either in the blood or in the lung-lavage fluid, that might help distinguish between people with a good prognosis or a poor prognosis, or can we learn something about why that individual developed ALI based on the pattern of proteins that we see?” she asks. “If I find what seems to be a genetic risk factor, I can look at the protein product of that gene and try to determine if there’s something different about the protein for the people carrying the genetic variant or the polymorphism. And by doing that, maybe we’re going to identify a subgroup of people whose ARDS is somehow related to this protein.”
One intriguing finding concerns a protein called angiopoietin-2, “which seems to contribute to making the vessels leaky,” Meyer adds. What happens, she posits, is that the “barrier at the endothelial side and the epithelial side—the cell that lines the air sacs in the lungs—breaks down and lets fluid leave the blood vessel and enter the air space. So maybe there’s a subgroup of patients whose ARDS somehow is related to irregular handling of this protein, for lack of a better term. We’re trying to figure out if there’s something different about the protein they secrete. Is it in a higher amount? Is it a slightly different isoform of the protein? And, if so, does that different isoform have a stronger effect disrupting the endothelium?”
Other researchers around the country are looking at “molecular markers, biomarkers in general, to see if we can see things in the blood, the plasma of patients that might mark somebody as being a high risk to develop ARDS,” Meyer adds. If one of these markers were discovered in the emergency room, “maybe you’d be more likely to admit [a patient] to the ICU or to take the ventilator from over-stretching the patient’s lungs.”
While one goal of much of this research is to identify drug therapies, “those therapies may not apply to the whole population of ARDS patients but [just] to the patients who have a molecular subtype.” The other goal is thus to develop a personalized therapy that follows the contours of an individual’s risk profile. Patients often have “different molecular reasons for flooding their lungs,” she adds, and “we’re going to need to be testing therapy only in the patients whom you might predict it will have an effect on in order to show a benefit.”
“We have an active and productive program in molecular epidemiology, genetics, or ARDS risk-factors prevention,” says Paul Lanken. “The ultimate goal is this personalized, molecular medicine. And it’s really taking everything to the next step. And that’s what a place like Penn should do—do the basic science, and then do the translational, and then do the clinical. We have it all here, potentially. And we’re part of an international group trying to move things forward.”—S.H.
Mar|Apr 2012 Contents
Download this article (PDF)
feature pages 1 | 2 | 3 | 4 | 5