Erin Spain: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, executive editor of the Breakthroughs newsletter. Air pollution is shortening the lifespans of people around the world, and it's not just lung diseases. Scientists have discovered ties between air pollution and heart attacks and stroke. In a new study, Northwestern scientists have found that metformin, a drug used to treat type 2 diabetes shows promise as a potential therapy to prevent premature cardiovascular deaths related to air pollution. Dr. Scott Budinger, chief of the division of Pulmonary and Critical Care Medicine at Feinberg led this study and he's here with the details. Thanks for joining me.
Scott Budinger: Thank you.
Erin Spain: So your lab, one of the focuses of your lab is on what's called particulate matter air pollution. What does that mean exactly and how serious of a health concern is it?
Scott Budinger: So when people talk about air pollution, they're usually talking about one of a few things. One of the components of air pollution that people are familiar with is ozone. And another one is something that's called nitrogen dioxide. And the third component is this particulate matter air pollution. All of these things are formed when we burn fossil fuels, primarily, epidemiologists have carefully studied these different components of air pollution and they've shown that they are associated with different kinds of health problems. The one that actually is most associated with death is particulate matter air pollution, and that's the one that we study in our laboratories.
Erin Spain: What are, what is the matter you're talking about? Can you explain it to me?
Scott Budinger: So, when, when fossil fuel burns in a combustion chamber it actually leaves behind a little core of ash. And that core is actually really, really small. It's about 30 nanometers when it is first formed, but it doesn't like to be alone. And so these little 30 nanometer particles tend to aggregate very, very quickly within the combustion chamber. And as they do so, they sort of pick up the organic constituents from the unburned fuel and they also pick up the metals and the vanadium that are in the engine or the catalytic converter. And those things condense on the surface of those particles and then are released through the exhaust pipe and once they get out into the atmosphere, they still like to stick together and so they get bigger and bigger. And what we're looking at is the particulate matter fraction, that little tiny particles that are less than 2.5 microns in size, so much bigger than when they're formed, but still not as large as they get in the environment. And we look at that 2.5 micron form because that size is the right size to get all the way down deeply into your lungs. So when the drug companies make things like a inhalers for people with asthma, they actually designed the particles to be right in that range so they can get them far down into the lung. So that's why we look at those, those particular particles.
Erin Spain: So you're walking down the street, you're breathing the air, you're jogging that exhausts. It's coming from the buses and the cars. That's where the particulate matter is coming in through your mouth, into your lungs.
Scott Budinger: Correct. And your body is actually very well suited to actually take care of particles that are in the environment. You know, we grew up, we evolved, in dusty environments, and so we have developed really robust mechanisms to both filter the particles through our nose and through the back of our throats, and to actually get rid of them. We have cells that are within our lungs that we study in particular called alveolar macrophages, and these cells avidly take up any particles that you inhale. Those cells promptly commit suicide, they die and they come up through your lungs into your mouth and you swallow them. So we have really efficient mechanisms to live in dusty environments. The problem that we have with particles that form from a combustion engines like in cars or from power plants or other urban sources, is that they contain these, components on their surface that I talked about, either those organic constituents or the iron and those things can react with those cells and cause them to react in an inflammatory way as opposed to just eating them up and getting rid of them.
Erin Spain: And that's where we have discovered that this can lead to stroke. It can lead to heart attack.
Scott Budinger: Correct. So, the, what we have found is that those angry macrophages that have taken in the urban particles, they release inflammatory mediators that get into the body, and those inflammatory mediators we know are very, very tightly linked to heart attacks and strokes. And what we've found is that just a very short exposure to particles is sufficient to induce enough of these inflammatory mediators to increase the risk of forming a clot after you injure an artery. And this might happen in a heart attack or stroke where you have a plaque that's there already, and a thrombus then forms in that plaque and that causes the heart attack or stroke.
Erin Spain: You're referring to some research that was about what, five, 10 years ago?
Scott Budinger: My colleague and I, who's at the University of Chicago, Gökhan M. Mutlu, discovered that the alveolar macrophages release this cytokine called IL-6, into the circulation and increase the susceptibility to heart attacks and strokes.
Erin Spain: But it was back in the 1970s when we first found out that there was a connection between this particulate matter and a heart attack and stroke. Tell me about those first findings or as a set of studies. And it actually led to a lot of the legislation we have today around clean air.
Scott Budinger: That's exactly correct. So there were really a few very large landmark epidemiologic studies that were done in the 70s, both in Europe and the United States. And what the epidemiologists were looking at in those studies was they were looking at the levels of particulate matter air pollution, and the association of those levels with all-cause mortality. So if there were higher levels of pollution, did more people die? And what they found was that there was a direct relationship between the levels of particles and death from primarily heart attacks or strokes, and that was the surprising finding in those studies was that we're inhaling a particle into the lung and somehow that's increasing the risk of death from heart attacks or strokes, but that recognition that those particles were associated with death was really what drove legislation like the Clean Air Act in the United States that led to the founding of the EPA, that we all hear about now. And that legislation has been enormously successful. So, it's very, very clear that particle level, since the late 70s when the clean air act was approved, was approved have dropped significantly in the United States and in Europe where similar legislation was put in place. And with that, we've actually seen a reduction in all-cause mortality associated with heart attacks or strokes. And we've seen a reduction in the risk associated with particulate matter air pollution. It hasn't gone away, however. So a study that was done as late as last year, actually showed that exposure to particles in the most polluted compared to the least polluted American cities was associated with a seven percent increase in mortality in the medicare population in the United States. So it's still a big problem, but much less of a problem than we used to have in the late 70s.
Erin Spain: And in other places around the world, pollution, air pollution, it's almost unimaginable in places like China and India.
Scott Budinger: So the levels of particle exposure in places like China and India are tenfold higher than what we experience here in the United States. And in fact, in our studies, we used an animal model of particle exposure where we concentrated the particles tenfold higher than they are here in Chicago. And that's what we used for our study. So that would be like a bad day in Beijing.
Erin Spain: Let's talk about this most recent study. Metformin is emerging as a bit of a wonder drug to be used beyond diabetes. Why did you use it in this latest study?
Scott Budinger: So that's a great question. My colleague Navdeep Chandel, who's a cancer researcher here at Northwestern, was looking at the way that metformin works to protect against cancer. So there's an observation that people that are on metformin have a lower risk of cancer and perhaps have a lower risk of cancer death. And there are now clinical trials that are ongoing to look at metformin or a related drug phenformin or some other compounds that have spun off that as drugs for cancer. When we were looking at cancer with Nav, we found that metformin works by inhibiting an organelle, this tiny little piece of the cell that's called the mitochondria. And the mitochondria are sort of powerhouses of the cell. What Nav found was that metformin is a really weak inhibitor of the mitochondria. And by inhibiting the mitochondria, it was inhibiting the growth of the cancer cells. And so we had noticed in our work in pollution that a lot of the toxic molecules that were coming in response to the particles were coming from these mitochondria. And we thought that by inhibiting the mitochondria with metformin, we might be able to attenuate some of those effects.
Erin Spain: Is this the first study that's used metformin in this way with air pollution study?
Scott Budinger: It is. Part of the reason this study is novel, is that, it's obviously potentially impactful, if our studies are confirmed in humans, but also because it suggests that metformin might also work as an molecule to inhibit inflammation. So the molecule that we're looking at, IL-6, has also been studied in the context of cardiovascular disease, independent of air pollution exposure. So there was a recently a study that was published, it's a very high profile paper in the New England Journal of Medicine, that showed that if you give a drug that inhibits IL-6, it actually inhibits it by inhibiting a molecule that's upstream of it called IL-1 beta, that you could reduce the risk of heart attacks and strokes in all people. So this was just unselected patients at risk for developing heart attacks or strokes. And so we think that our findings might have implications for the use of metformin beyond just pollution, and to the broader group of people that have hearts that are at risk for heart attacks and strokes.
Erin Spain: Let's talk about those findings, your study used mice as well as human cells. How did the experiment work and how did the drug work in your experiment?
Scott Budinger: So what we did was we fed mice metformin, and as you know, metformin is a diabetes drug and unfortunately there is a pediatric formulation of metformin that's available. So we gave mice the same drugs that kids with diabetes are taking, in their drinking water. And then we exposed them to levels of pollution that, like I said, are similar to what you would have and a bad day in Beijing. And after exposure for three days, eight hours a day, we actually took the mice and we've looked at how much, how susceptible they were to developing a clot in their carotid artery, which will be a model of stroke. And what we found was that if you exposed mice to pollution, they made clots much, much faster than mice that weren't exposed to pollution. And the metformin treated animals were protected against that effect. So they behave just like mice that were not exposed to pollution.
Erin Spain: Protected?
Scott Budinger: Totally protected in that model.
Erin Spain: And you also use some human cells.
Scott Budinger: So what we took human cells from normal human lungs, and we isolated these cells, the macrophages that I talked about, and we looked at their response to particles when we put the particles directly on the cells and we found, just like in the mice, they made IL-6 and that we could predict, prevent that generation of IL-6 by giving the cells metformin.
Erin Spain: Are there side effects to consider with metformin?
Scott Budinger: Sure. you know, the metformin is not for everybody. And that's certainly not the message that I would be promoting here. Metformin is a drug that does have side effects. The side effect profile is quite good, but there is a rare risk that inhibition of the mitochondria that I talked about, can cause sort of a power crisis in the body and actually can lead to the buildup of acid in the blood because your mitochondria aren't doing what they're supposed to do in terms of consuming oxygen. That's very rare, but it can happen. And so it's something that we certainly would want to exercise caution.
Erin Spain: But it is overall a fairly safe drug?
Scott Budinger: It's a very safe drug and you know, metformin is one of a handful of drugs, that has been shown to extend lifespan in animals. So when investigators at the NIH gave mice metformin throughout their life, they actually found that the mice lived longer, and perhaps were slightly healthier, although there's some controversy about that, but certainly they lived longer than mice that did not receive metformin. And really those studies are the foundation for trial that's actually planned in people. This is a trial called the TAME trial, which is "targeting metformin in aging." And in that trial the plan is to give metformin to older people with a primary outcome of a age related adverse events. So something like a heart attack or stroke or hip fracture or anything else that's associated with aging.
Erin Spain: So what's the next step now, since you have discovered this works in mice, it seems to have an effect on these human cells. Are clinical trials next?
Scott Budinger: So part of the reason that we're so excited by these findings is that a couple years ago, a group in China actually looked at our model. The model that we had published back in the mid 2000s and instead of actually exposing people to higher levels of particles like we do here, would they did, was they took people in China that were actually always exposed to higher levels of particles and they had them where filters for 10 days, face mask filter. So they were actually not being exposed to the particles over that 10 day period that they would normally be exposed to in their daily lives in China. What they found was that IL-6, some of the transcriptional targets of IL-6 molecules called crp and fibrinogen as well as catacholamines, other things that we had observed in the mice, were reduced in people who are wearing the face masks for those 10 days, sort of validating the model. So I think the next step would be to actually go to an environment like that, and see if metformin was able to similarly reduce some of those risk molecules that we know are elevated in people that are exposed to pollution.
Erin Spain: What about here in the U.S., I know you said that China and India, it's tenfold what we have here with air pollution, but how at risk are Americans with health issues related to air pollution?
Scott Budinger: It's a really good, yeah question. We know, from the study that was done last year, that there's still a big risk of air pollution induced death here in the United States. So again, in the medicare population alone, we know that it causes about seven percent increase in all cause mortality in the most polluted compared to the least polluted American cities. But it's not actually affecting probably everyone. So the people that are at risk for pollution exposure are people that certainly have a history of heart attacks or strokes. And that's what our model would suggest that those people are at risk. Older people just because they have a higher risk of developing those events, probably are also at risk for the health effects of pollution. We know that even though it doesn't cause excess death, we know that pollution exposure can cause asthma exacerbations. And in patients that have chronic obstructive pulmonary disease, it can cause exacerbations of chronic obstructive pulmonary disease. So people that have chronic respiratory disorders, are at risk for pollution related effects, and the other population that we know is particularly susceptible, is a young children. So we know that higher levels of pollution exposure over the first 18 years of life is associated with reduced lung function, peak lung function in your early twenties. So if you're exposed to higher levels of pollution, you're never going to get your lungs to grow all the way to where they could grow to.
Erin Spain: What can we do to help eliminate our exposure to environmental pollution?
Scott Budinger: But that again, is a really good question. And there's two parts to that question. one part of that question is on a personal level, what can you do? On a personal level, you can watch for a pollution alerts. So the levels of particulate matter air pollution are actually what drive sort of the air quality alerts that you'll see on the weather reports and on TV, when those levels are high, particularly if you're somebody that's at high risk, you're better off staying indoors. That's not to say you shouldn't exercise or do activity, but you should do it indoors. If you're inside the levels of political exposure about tenfold lower than they are outside, irrespective of where you are. And so that is a good strategy on a personal level. On a more global level, recognizing that pollution is a problem for you and your family is important and you know, supporting legislation and projects that actually are designed like the Clean Air Act that are designed to lower a particle levels, exposures in the population or something that we should all be thinking about supporting.
Erin Spain: You mentioned the facemask filters that were used in the experiment and China. What about in home air filtration systems and those types things you see on the market to those really work? Do they help, especially if you have a young child?
Scott Budinger: We don't have, again, a good question. We don't have really good data on that so we just don't have enough science behind that. But it's a good question. We do know, you know, there are studies that are currently being conducted where children and adults are being volunteering to wear particle monitors for some of their day. And so we're actually looking at, there are investigators that are looking at whether their personal exposure to particles can be reduced, in different environmental settings, and whether that translates into improved health outcomes.
Erin Spain: Do you get excited when you hear about the future of electric cars and things like that? As a scientist, as a physician that maybe soon in the future we won't be experiencing so many of these, particular matters in our lungs.
Scott Budinger: Yes, I would, I would love to see the day where my research becomes obsolete because we're no longer exposed. In the meantime, sort of our goal is to look for things that we can do in people that are exposed, like metformin, or other drugs that might be effective and actually reducing some of the risks and people that are inevitably exposed.
Erin Spain: Read more about this research and other new.feinberg.northwestern.edu