Lungs, Gut, and Skin: Biological Interfaces with the Outside World

Speaker 1 (00:00:05):
Good evening everyone. Um, I must admit, I'm pleasantly surprised that we have so many people who are interested in biological barriers and toxicology. It's like the lecture I don't give at university. So look, this is the third lecture that I've given in a series which have really dealt with the way in which our environment impacts on our health. In the first lecture I talked about the exposome, which is everything everywhere at all times. And how that totality of the stuff which happens in our daily life impacts on our health. And in the second lecture, I kind of narrowed it down, you can only narrow it down from everything everywhere at all times. Yes, to focus on the impact of air pollution on health. And I used the 70th anniversary of London smog to do that. What I really want to do now is to bring those two things together to start thinking about how we as an organism interface with our environment and how we have evolved to actually deal with a chemical environment in which we live. 

Speaker 1 (00:01:14):
And theoretically it sounds as though we've got quite a lot to be concerned about. Um, if you pick up the newspaper, look at the internet, look, I mean there are microplastics everywhere aren't there within our rivers, in our sea, in our food, in our milk, in our blood. Other body fluids are available. People are finding them absolutely everywhere. And look, we have, um, people are always banging on about how bad air pollution is for your health. And I'm probably partially responsible for that. But nevertheless, you know it, this stuff in the air that we breathe, the diesel fumes and Nu and dioxide, all of that stuff is really very, very topical. Then we are worried about all these per and poly fluoride alco, forever chemicals and we can keep on going burnt toast, acrylamide roast potatoes. That's pretty bad for you. It turns out. Then we've got all our cleaning products, which now it turns out are much more toxic than we ever thought they were. We can keep on going because we, you know, we know cigarette smoking's pretty, pretty bad. But now we can worry about e-cigarettes. So clearly, um, it's a miracle. You are all looking quite as healthy as you're looking this evening <laugh>. It's a miracle we even get outta bed in the morning if you think about it. 

Speaker 1 (00:02:35):
And actually the chemical landscape is much worse than that. Just let's get, let's get all the cheerful noise outta the way. Yes, I showed this slide very rapidly during my first lecture and it's worth revisiting just for this middle compound here. And it says the total inventory of licensed chemicals to use currently within Europe, it's around 360,000. Not including the other chemicals which may arise from those chemicals during atmospheric transformation transformation in our ecosystem within our bodies. And we don't know very much about the toxicology and the safety of most of those chemicals. And do you know what we are never going to know cuz there's no way we can keep up. We make more compounds and newer compounds more quickly than we can test them. So if we were worried about our chemical landscape and it's impact on our health, then it's actually disappearing into the distance. We are not really sitting on top of all of this. 

Speaker 1 (00:03:41):
So there we are, sad old human race, declining, choking in its haze of chemicals, no hope. And yet here we are. We prevail, we live, we have children, we grow old. So clearly we need to understand something more about this. We have to understand how we interact, how we cope, how we accommodate these stresses to try to understand how we actually defend ourselves. To understand how we can improve our protections and potentially as well to understand the bits of our system which might not work terribly well against the new chemicals that have been formed in the last a hundred years, which we never had a chance to evolve to deal with. So let's think about this. How do we interact with our world? For me, this is quite straightforward. Yes, okay. We are physically enmeshed in the world via our skin, our gut and our lungs. 

Speaker 1 (00:04:52):
Those are the bits of us. Yes. Which are in contact with our external environment. And we can put some data on this. All the average human, yes. Whatever the average human is. So skin on average, all of you in this room have about two square meters of skin. Yes. Clearly not all of it is available for chemicals at all time. Thankfully I, our gastrointestinal tract, well this is all over the place. If you go in the literature, I can find figures up to 300 meters squared. So I actually was quite careful, went to a really good reference where they'd done some good pathology and biopsies to actually work at the area. They came out at about 30 meters square of intesine stomach, esophagus. Yeah. And then we have our lungs. And again there's a big range. It doesn't help if you go online and it says how big is the lung? 

Speaker 1 (00:05:53):
The surface area of the lung. All it tells you is it's the size of a tennis court, the most meaningless statistic ever. It's somewhere between this range 50 to 130 meters squared. So, okay, let's total all of that up roughly and work out how much of us is in contact with our chemical environment. And let's say that's about 200 square meters of us directly interfacing with our environment. That's where we are going to start this presentation focusing on those interfaces only. Of course that's not even right, is it two meters of skin assumes we are shiny mannequins? Yes. If you begin to follow each of our pores, each of our hair follicles in and out, grieving in to get the total surface area, the surface area where we have our microbiome plus our skin, it goes up to 25 meters. And actually if we did finer measurements down here of every individual affiliated cell in the body, those numbers would increase even further. There's a lot of us in contact with the outside world. 

Speaker 1 (00:07:17):
Now how do we work out therefore whether we have anything to worry about. And this is where I think we have to take a step aside and I put on my toxicology health hat because one of the reasons I think people get so concerned about the stories in the newspapers is that humans don't have really good statistical brains. We are really bad at evaluating risk. In fact, most people don't know the difference between a hazard and a risk. You can think of hazard as being like how potentially toxic or harmful so is Yes risk is whether it actually has an impact. So I've got these two extreme scenarios, yes. To make the point. Both of these are hazards of different types and risks of different types. This is very hazardous. The risk effect of this individual beneath the piano falling is very high. But the impact that will have on the rest of society is quite low. 

Speaker 1 (00:08:24):
<laugh>, this individual is just eating a burger, lots of processed meat. So he's definitely gonna get bowel cancer. Let's phase that. We know what the press says. Yes. Okay. But actually individually that's a very low hazard. But so many people eat fast food. So many people have unhealthy diets that actually the risk at the population level is much higher because here you'll have a low hazard multiplied up to a large risk because of the actual numbers of people eating a harmful diet. So we can begin to think about hazard and risk thus, so we have our hazard and we have our kind of toxicity is something really bad, but we have to understand something about exposure. Yes. Okay. Traffic related pollution would be not very bad for you if you didn't live near a road, would it? Yeah. It stands to reason, yes. Plutonium isn't very hazardous if it's 2000 miles away, but it is dangerous intrinsically. So we have to try to understand that to think about how risk manifests at an individual level. But also once you scale it up to think about populations in general. Now other things are important. They modify the risk. The age of an individual, you know, we are not completely defenseless. We have mechanisms for detoxifying chemicals, for eliminating chemicals from our body. We have mechanisms to repair injury. We have mechanisms to regulate inflammation. 

Speaker 1 (00:10:16):
But we don't always have those optimally when we are young, many of those systems are immature and not effective. And as we age, they begin to degrade. Yes. So we begin to be less good at dealing with toxicants. We begin to be less good at mounting appropriate inflammatory responses. We begin less good at repairing tissue damage, less good at repairing DNA damage as we age. And so at any one point in the population, we have some people who are normal, but we have these tales of people who are extremely sensitive and people who have very low sensitivity. And for this, I always think about cigarette smoking. I mean you couldn't really design something which would cause more harm to a population if you sat out to try to design it. Yes. But everybody will know a 95 year old grandmother who lives in their village. Yes. Who smoked 40 cigarettes a day. She's, she's really very low sensitivity. Yes. And everybody will use that individual as a patron's patron saint to justify why smoking isn't bad for you without asking the most sensible question. Which is why is she the only 95 year old woman living in the village? 

Speaker 1 (00:11:38):
That's not the end. So we have to think about exposure. We also have to think about underlying genetics. Many of these individuals who have low sensitivity are super metabolizers of toxic compounds and specifically within pathways. Again, and I've mentioned this and I've mentioned it a lot today. Defenses, xenobiotic, metabolism, the metabolism of xeno foreign stuff in the body, how we regulate inflammation, how we repair and remodel damage. Then the other thing is this, and this gets back to my slightly contrived piano falling on your head versus eating a beef burger type hazard and risk scenario. The other thing which matters is how many people are affected. And this is one of those things which makes the media presentation of risks difficult to understand. For most people, something might have an incredibly high hazard. Think of somebody who works occupationally in a factory where there are occupational exposures to very toxic fumes. 

Speaker 1 (00:12:45):
Yes. The individual who's going to be affected is the factory worker. Yes. The person who's exposed in his workplace. I can think of scenarios, asbestos would be a good example where maybe the person who lives with the individual who's exposed to asbestos has some risk. There's lots of evidence of people washing the workloads of people who worked on asbestos developing mesothelioma for example. But it's a risk experience by those group within that setting. But certain things, if it's a common food, if it's in the air that everybody breathes is experienced by everybody. And that multiplier matters and it confuses everybody ever so much when people talk about it. Because something which is relatively low toxicity may produce huge effects at the population level simply by multiplying a low risk by everybody versus a large risk by a smaller group of the population. 

Speaker 1 (00:13:45):
Now so far we've said there's lots of us in contact with the environment and we've talked about hazard and risk and how we think about that and different things. But actually, you know, I'm, I'm a toxicologist apparently somewhere in my past and toxicology is a word which we're not actually allowed to say. It's a word which is phased out. In fact, there are very few toxicologists left in the United Kingdom. We have to call ourselves things like drug safety. Yes. Or has a and risk, you know, the word shall not be spoken, you can dress it up as long as you study mechanisms. It's fine. Just not mechanisms of harm and death. But some of the core principles of toxicology are again absolutely essential in terms of understanding how we interact with chemicals in our environment and how we understand how they impact on our health. 

Speaker 1 (00:14:38):
So if we think about the barriers, the skin, the GI tracted, the lung, the key issue, the first thing which has to happen is we have to absorb the damn stuff. Whatever the damn stuff is, yes it has to enter our body in order for it to affect us. But that's only the beginning. We really then have to begin looking at these other domains. How the compound which has entered the body, distributes through the body, how it is metabolized. You know the body has evolved mechanisms to detoxify chemicals in our body to make them safe, to make them more water soluble, to promote their exclusion from the body. And if we hadn't evolved, if those mechanisms, yes we wouldn't even be able to sit down and have a meal at home because many of the things we eat on a daily basis without the enzymes which do this detoxification task would be toxic to begin with. 

Speaker 1 (00:15:37):
But it's not perfect. So if we imagine here we have our exposure to a toxin and toxic content. If you are to a toxicologist, this really matters. Okay? Toxin is a biological thing. Toxic can't is something which is antibiotic. Yes. That matters. Here we are, we either breathe it or we eat it or it comes into contact with our skin and then it distributes. And metabolism should be good but it's not always good. We have some design errors and those design errors stem from the fact that we evolved to transform other chemicals and now we have new chemicals which should look like them, but we don't necessarily handle them in the same way. Then once we have these metabolites and there are lots of examples where the metabolites, for example, are more harmful than the thing which you absorbed. We can think of some can be, we could think of methanol, yes. 

Speaker 1 (00:16:33):
Becoming folic acid and causing acidosis. We could think of antifreeze, uh, again becoming oxalic acid after it's been metabolized in the liver. But ultimately what we're interested in is whether the compound or the metabolite causes a harmful effect. Now I can't do skin, gut and lung in detail and I'm a long person. Yes. So I'm gonna use little young as a prototypical organ because it's the best organ. Um, other people may have interest in enough organ systems, but it's my favorite. Look how beautiful it is. Okay. Look how beautifully engineered this is as a moment of evolution, this is a resin cast of a human lung. It's a work of art. Yes. Here we can see all of our airways from the track here down into the bronchials. Here we can see all the gas exchange regions and rather beautifully here they've actually used different colored resins to show the Venus and material supply in the lung. 

Speaker 1 (00:17:40):
That's for me absolutely beautiful. To give you an idea after how wonderful this mold is, you can blow it up and you can go right through to the gas exchange regions which look a bit like cauliflowers. Yeah. That's what they look like. And we can begin to see in the structures how the capillary beds into digitate around the gas exchange reasons. So few things to take from this. I'm gonna go back one the lungs an interesting organism. Cause we breathe in, we breathe out, it's a branching structure. Not all the things which go in, come back out again. Yes. So they gotta go somewhere <laugh>. Okay. So it's almost potentially a trap for certain compounds. So it will accumulate things. And the other thing we have to bear in mind is it's got very clearly different regional areas which do slightly different tasks. And this is where I'm gonna just take you through them. 

Speaker 1 (00:18:34):
This is what I would teach an undergraduate group. Yes. About the, so we have our conducting airways. Yes. We have our upper airways, the first 12 generations of this bifurcating structure supported by Richard cartilage to keep the airway caliber open to enable us to breathe. And then as we go down and it keeps on branching, we get down to 13th, 24th generations. And here you're then not supported by cartilage anymore. They're supported by the tissue. They are embedded within. And I can give you an illustration of that in a second to assure you how that works. 

Speaker 1 (00:19:11):
What is the barrier? Like histology, pictures take a little while to get your eyes into Yes. Mostly they look like pink and purple blobs. If that's all you're seeing, that's all anybody sees for about two and a half years. Okay. <laugh>. But there are some key things here. We have the bronchial epithelium. In the conducting airways we have these elongated colom epithelial cells. That's important. We have these little celia sitting at the top which are waving, they're beating. So they're rotting mucus which sits on the top of this blanket from the distal to the proximal lung. Yes. Almost as a sanitation mechanism to keep the surface of the airway clean. Here we have the progenitor cells. If these cells die, these cells will de differentiate to re replicate this tissue sitting on a basement membrane. And down here we have the submucosa tear egg cognito, lots of stuffing the stuffing which all your cells stick to cause it's not just epithelium and endothelium, they're stuffing and things have to be glued together. 

Speaker 1 (00:20:24):
Yes. People forget that. So here we have our structure and in between you can see that these is all purple dark sections and those are mucus secreting cells. So we have this relatively thick barrier and it's got the Celia wafting in this direction and it produces mucus because this is absolutely the beginning of our protective barriers in the airway. So again, schematic, it's the same thing here we have our sort of rectangular colom epithelial cells on their basement membrane. The genitor cells at the bottom here we have a lovely siia. You can see the golet cells in the mucus cells look much more lovely. And here we have our layer of mucus known as the gel layer. Now if we only produce mucus, this wouldn't work. Yes. Mucus is super sticky. Yeah. So actually this liquid layer comes in two, two sort of varieties. There's a watery S layer which sits at the bottom, which is low viscosity. And that allows the siia to beat and to create sort of like force which drags the mucus. And the mucus sits on the top. You breathe something of a particular size. If it were deposited in the area and it lands in the mucus, yes it's gonna be removed from the lung taken up to this office and you're gonna swallow it. Yes. So it's not in the lung, it's now the problem for the gi. Yeah. Different issue entirely. We, as far as I'm concerned, it no longer exists. I'm a long person <laugh>. 

Speaker 1 (00:21:55):
Then we begin to go down into the lower airways. And I said, you know, as we got small and we didn't have the cartilage, the airways were supported by the paran chima. And this is kind of a lovely scanning electron micrograph showing that. And you can see the airways coming down. But we can actually see they're supported within the body of the actual structure of the power of the lung. And these are the little airspace within it. And over here, if we look at these airspaces, we can see they're wrapped around sort of like the capillary network to enable gas exchange. But we can begin to look more closely into this, blow it up a bit. We can begin to see the individual alviolas, our gas exchange regions blow it up even more. 

Speaker 1 (00:22:46):
And we can actually look at it in cross section. So whenever you see pictures of this, I don't think, and people say your cells in the airway in the alvioli, they're really thin because you have to have gas exchange. Yes. You gotta get oxygen in, gotta get CO2 out that straightforward. And they say it's very thin. This is how thin it is. Yes. You can see here the cilla is, these are red blood cells in the tissues, the actual airway epithelial cells. And these are type one cells. So if you look, there's a little line here, if I follow it around here, da da da da, that's one cell. They're almost vacuum wrapped around the capillary network. It's that intimate but equally that delicate and that vulnerable to damage. 

Speaker 1 (00:23:33):
And this is just looking it in a different way. Here we have, and this again illustrates just how thin this barrier is. This line at the top here, that is the epithelial cell, the bit in the middle terra incognito. That's a bit of connective tissue. And then here we have the endothelial cell of the blood vessel. Super thin. Yes. And then you have this monster <laugh>. Okay. And this is the other cell you get in the alveola compartment. Yes. Almost as numerous. But they take up much less surface area. And this is basically the powerhouse, the metabolic part of the actual lung. So these have small little microvilli on the surface. It doesn't show parti behavior. You can see a few little imaginations and have these big dark granules. And these are granules of surfactants which are released onto the surface of the airway to reduce the surface tension. Which means we breathe in and out, our lungs just don't collapse, which would be a bad thing. So a very good evolutionary advantage. Yes, they do a whole host of other stuff as well. They release inflammatory proteins and anti-inflammatory proteins to regulate the immune status. And if there is damage to the deep lung, it's these cells which will de differentiate into type one cells to repopulate that tissue. So they are critically important. But that is our landscape. We've now seen the barrier in the upper airways. We've seen the barrier in the lower airways. 

Speaker 1 (00:25:04):
Now in the upper airway we had the, that sort of SS phase of liquid and then we had the mure sitting on the top of it. And that liquid phase, the S cirrus phase continues all the way down into the deep lung. This is a beautiful electron micrograph. It's incredibly difficult to do this because here again, capillary endothelial cell basement membrane, this is our type one alveola cell or pneumococci. This is an extracellular layer of fluid sitting on the surface of the airway. Okay. And it's striated with Laila bodies because it has surfactant structures within it. But if we breathe something, a gas, a vapor, a chemical, a particle, a bacteria, the first bit of us, the first interface that interacts with is not the cells, it is this extracellular liquid. Everything has to pass through this first before it interacts with the US in our airway. 

Speaker 1 (00:26:12):
Now here's the good news for a scientist. We can get at it. Yes. And we can get at it and we can study it and we can see what it is. And we can do that in a variety of different ways. Which go from quite pleasant to not something you would want to do without a significant financial incentive. <laugh>. Okay. Nasal lava. I haven't talked about the nose. The nose. I could, I could wax difficult about the nose for two hours. It's a fantastic organ. Yes. Um, really wonderful. But, so you can wash that and you can get samples. You can get saline in the nose, wash it out, collect the cells, take the cells out, count them, do whatever you wanna do with the cells. Use the supernatant, measure the molecules within it. If you wanna get to the deep lung, you probably have to do uh, lavage procedure. 

Speaker 1 (00:27:01):
So you're gonna have to put a bronco alveoli lava into the lung washout areas of the airways. And you can do that just by instilling small or large volumes to take samples of the conducting airways. Or you can basically flood an entire lobe of an airway and get a sample which incorporates most of the alveolis. And because if you do that, there's more alviolas than there is airway in terms of absolute area. You get a sample which is mostly off that airway. So we know quite a lot about this compartment and these are some of the things that I found <laugh>. Okay. We, I've done some work, it's um, and but actually it's a kind of a clue. Yeah. The stuff which is there is not there by accident. Yes, it's there by design. It has very high concentrations of antioxidants within it, but specifically low molecular rate antioxidants such as a score bait or vitamin C or glutathione, which is probably the, the most abundant antioxidant biological systems. 

Speaker 1 (00:28:06):
Your rate a bit of Alpha Q associated with the lipid phase. And it's there because this extracellular compartment has quite a potential to generate free radicals and reactive oxygen species. So we have evolved to make sure there's a huge antioxidant buffer on the surface of our airway to mitigate against that issue. I mean normally in the body, oxygen tensions are quite low in this interface it's quite high. So the chemistry to make free radicals is quite high. What else do we have? Um, we have surfactant, lipids. Some of those are involved in a native immunity. We have a whole host of anti-inflammatory cytokines and antimicrobial peptides to try to keep the airway sterile. Sterile and in a reducing environment. But we also have a whole range of proteins associated with metal binding. So if metals deposit in the airway, they're sequestered into metal binding proteins taken up into cells to remove them from the surface of the airway where they would otherwise promote damaging oxidation reactions. 

Speaker 1 (00:29:14):
See when I say dam damaging oxidation reactions, I always used to think I have to explain it, but everybody's heard that statement on a pharmaceutical, you know, sort of like face wash advert on the television, damaging oxidation reactions. They're bad. We all know that now. So we have this liquid layer and it's very important. And I told you that the cells were different throughout the airway. And guess what, the composition of that liquid is different throughout the airway reflecting differences in the underlying cells and the pH more than anything else. So when you get down into the deep lung, I always like this diagram cuz it kind of illustrates that this liquid layer is like one lesser, one micron thick. Yes. So if you have a a, a macrophage in that cell, it's, it's kind of like just coated with it. It's moving around in the coating. 

Speaker 1 (00:30:04):
It's not in a swimming pool. It's damp is a better way to put it. If we move up the area, we can begin to see the structures, we can begin to see the mucus up here, different cell types. So the composition varies. Why does that matter? Because different things when we breathe them go to different places. Therefore they see different cells and they see different extracellular liquids. Then I had to put this in. For those of you who don't do science, this is what immunology looks like. Yes. Only usually there are many more arrows going in both directions simultaneously. To confuse you, all I want to put out is all I've talked about at the moment to structural cells, the epithelial cells, we've got lots of innate immune cells within this compartment. We have alveola macrophages which are basically there acting as a mechanism for capturing biological and a biological material to eliminate it. 

Speaker 1 (00:30:59):
We have specialized cells known as dendritic cells which have kind of like periscopes. They push through the epithelium to s sense and grab material which they then present in antigens. And then we have cells which are recruited from the bloodstream drawing inflammation such as neutrophils, ceils, basophils, lymphocytes, a whole host of interstitium, similar lymphocytes. There's a lot going on. Yes. But essentially this complement of cells is there to regulate and to control inflammation, repair and regeneration of a tissue under stress. So they should be seen within the context of the barrier, the barriers not just the structural components, it's the dynamic immune cells which contribute to maintaining that structural environment. Now deposition depends on size and something else which has disappeared. I think it says shape <laugh>. Okay, I just wanted to say this, that there's a very fundamental thing people say in in in inhalation toxicology. 

Speaker 1 (00:32:02):
Um, and it's only partially wrong. Yes. This is how it goes. Small stuff goes deep. The smaller it is, the deeper it gets into your airway. Yes. Ish. Yes. The things we breathe deposit with our airway based on the principles of chemistry and physics. How soluble are they? Yes. If it's very soluble, it's likely to be absorbed in the upper AirWave. It's not very soluble, it's gonna get deeper in the airway. S So two at the top N oh two and ozone deeper down in the airways, big heavy particles enter the airstream like cannonballs when they hit something they hit. They have momentum, they have inertia. Yes. Small particles are kind of dancing around with brownie in motion. Yes. And because of that they can go deeper into the airways. And if you look at this general pattern, what this is telling us is the different particles, the different sizes have different deposition frequencies. 

Speaker 1 (00:33:02):
So the big ones in the nasal cavity, but actually bizarrely the small ones get stuck in the nasal cavity as well because the structure sort of traps them. And then in the alveolis we have certain populations which are actually able to get deeper into the airway. So particles go where they go depending on size, quite a lot of them go in and go straight out. If they're particularly small and nobody mentions those fibers are interesting fibers deposit based on their aerodynamic diameter. So it doesn't matter how long they are, they will deposit according to this based on their cross-sectional area. So if it's a long and a rigid fiber, it will align with your airstream and it will go in like a javelin. Yes. And you see that with sort of asbestos particles. 

Speaker 1 (00:33:54):
The other thing which is important again in terms of understanding this is that in toxicology not only do you have to get there, you've gotta have enough of a dose of something to trigger something to happen. Yes. And in my field people don't really spend enough time thinking about the dose of the things which are depositing. And it matters cuz whilst it's the case that the alveolis may receive a very large proportion of small particles, it's also the case that it's a massive area. And so if you actually look at the deposition dose for different particle sizes and at this end we are looking at the upper airways and this end we are looking at the low airways. You will see the, actually the dose is always low in the alveolis in the deep lung. Not because stuff isn't getting there. It's just stuff is getting there. And it's huge as an area relative to the bronchial airways. 

Speaker 1 (00:34:55):
Now we've got an iron in. Yes the airways has some problems, different barriers. You know what we basically have is we've got an epithelium, we've got lots of air being breathed. It can trap particles. We've got lots of immune cells, all of which could be triggered to cause harm. I mean one of the things you see in the airway very often in terms of its toxicology is the immune cells get ar get erroneously activated. And the damage you see is very often almost like a friendly fire scenario. The immune system actually damages the epithelium. So I had to pick something to talk about which is a toxing in the airway. And I, it's the elephant in the room and the elephant in the room is smoking. Do you see it's a reference. I thought that was quite clever. Anyway, we spend a lot of time talking about air pollution and I think it is incredibly important for the reasons I said earlier because lots of people breathe and we kind of forget that this is still probably our, our major toxic burden in most people. 

Speaker 1 (00:36:00):
Uh, cigarette smoke in the United Kingdom has fallen yes dramatically since the 1950s because of regulation, taxation and public education. But 13.5% of adults over the age of 18 still smoke. That's 6.6 million people within the United Kingdom. That is a big enough group for me to be concerned about not remembering to talk about cigarette smoking as a significant inhaled toxic challenge. Okay. That's the downward shift. I've just extended it to 2023. What does smoking do? Are people, again, this is one of those things. Every cigarette you smoke causes injury. Yes. You don't feel it. Yes. Every cigarette you smoke triggers damage to epithelial cells and the immune cells and the damage it causes triggers inflammation. And that inflammation, while there are lots of species here, it doesn't really matter, but it does two things. It releases theoreticals and it releases proteases into the tissue to degrade the tissue. 

Speaker 1 (00:37:12):
So the cigarette smoke arms, the immune system and the immune system begins to attack the tissue and it's happening subc clinically in individuals who smoke the whole time without them noticing. And the reason they don't notice is because of a number of reasons. Number one, our cells just don't sit there and take it. Yeah. They adapt. So this is a really simple paradigm. Yes. If you imagine we've got cigarette smoke here and it's bearing down on the epithelium, the cigarette smoke, the first thing the tissue does is it doesn't throw its hands up and go, I'm gonna die. I've had enough cigarette smoke's. Terrible. It adapts. Yes it adapts to tolerate the stress. And it can do that in a different number of ways. If that fails, then you move to inflammation. If that fails, then cells begin to die and you begin to get injury. 

Speaker 1 (00:38:10):
But those stages under the regulation of different mechanisms. But these are just in, in science. We have these things, lots of letters all over the place. Over here we have two transcription factors and what they do is when there's a stress, they switch on antioxidant genes, xbo genes to detoxify compounds and repair genes. And then when they're overwhelmed we begin to move into genes which trigger cellular proliferation, inflammation, cell death. And some of these things cause structural changes and some of these things are really cryptic. This is a really interesting one. Another transcription factor. The AOL hydro AOL hydrocarbon receptor. Yeah. This, if it sees p PAHs, poly sophic aromatic hydrocarbons, they bind to this little protein. All these other proteins fall off. It goes to the nucleus binds to the DNA upregulates, an enzyme known as P four 50 s sip one alpha one that then metabolizes the pah. 

Speaker 1 (00:39:17):
And it should be less toxic but it's not. It makes it more toxic. It sounds insane, doesn't it? But actually it's only been the last 10 years we've discovered what that evolved to do. And it evolved to deal with bacterial ligons and liggins from triptan metabolism. And when it's doing its job properly, it actually helps our immune system and it keeps barriers tight. So it's a failure of our system. Uh, an error. The AAL hydrocarbon receptor is doing bad stuff by mistake. The other thing I wanted to point out is, again, it's not just you have all this molecular stuff going on when you have this injury, cells adapt. One of the things cells do is they adapt, they undergo, they they, they undergo division hyperplasia, they get bigger hypertrophy. Sometimes they actually divide and change from one type of cell to another type of type of cell because it is more protective for the tissue than was under the stress. And I can illustrate that here. 

Speaker 1 (00:40:24):
In somebody who smokes as a step towards developing chronic obstructive form of disease or the bronchitic presentation, you see the formation instead of those long rectangular cells, it suddenly given becomes what's known as a ter squamous epithelium or metaplasia. It changes into a couple stoning thicker membrane. More resistant to damage. Yes. The other thing which happens is more of the cells change into mucus secreting cells. Cause one way you can protect the underlying environment is to actually throw lots of mucus onto the surface of the airway. Both of these things sound great, don't they? More protective barrier. Lots of mucus downsides. Can't get rid of infected mucus. Lots of mucus. You generate persistent inflammation in the tissue. Short term benefit for long term harm, the message of all tissue adaptions in the body. And I can actually show you this here. This is a normal lung, lovely colom cells. This is from somebody with C O P D. We can see, look at that. These are all goblet cells down here. This is staining for mucus in that section. And here you can see this kind of metaplasia. The tissue has changed the barrier physically changes within you. Yes. As a preliminary step towards disease. 

Speaker 1 (00:41:49):
And it's not just cigarette smoking, I have to talk about air pollution. This is a nasal biopsy from an immigrant who arrived in Mexico City about 20 years ago. Here we have normal solidated epithelium and then we have the next four weeks as he gets used to breathing the air in Mexico City. After one week the structure's gone. The sillier have gone. Cobal stoning is already happening, the tissue is adapting, it gets worse, it gets worse, it gets worse clinically no symptoms. But the tissue is changing. You can see the barrier is incredibly vulnerable. What does this do? It means that lung function begins to deteriorate. This is a very famous graph which is actually following lung function from individuals who smoke. These functional changes reflect changes in the actual lung structure itself. So if this is somebody aging from 25 to 75 and this is an individual not smoking lung functions going down, this is an individual who smokes, da da da. You can see lung function loss is accelerated. The damage, persistent inflammation, remodeling of the airway results an accelerated loss of lung function. Good news is if you stop at 45 or 60, you fall off this trajectory and you go back to the normal trajectory. But you never get back what you lost, what you've lost has gone 

Speaker 1 (00:43:28):
Again. Some big studies again, cigarette smoking. How much years do you, how many years of life do you lose? 10 years on average because you smoke. What happens if you quit smoking almost goes back to normal. This is mine, this is my quit smoking talk. Okay, here's a toxin. It's really bad. It actually does bad stuff to you. Stop. Now you get the benefits back. And then this is interesting because of course we didn't know very much about women cuz women didn't actually start smoking until the 1960s and the seventies as much as men. Yeah. Men used to smoke more. And this is the million women study, um, with Richard Petto. And again, this is just looking at the increased risk of heart disease, stroke, lung cancer, emphysema form of chronic obstructive pulmonary disease based on 0 5, 10, 15, 20 cigarettes a day. And these numbers in terms of increased risk are eye wateringly large? Yes. I often again think about women and smoking and also then just put a toxicologist head in or head on. If a woman smokes as much as a man with the same smoking behavior as a man, their dose of toxins will be greater than the man because they have smaller lungs. 

Speaker 1 (00:44:52):
Very simple. Now I talked about the six city study before in my first lecture this was about air pollution. But really I would wanted just illustrated again, we've known this fer in the six city study. They looked at the most in the least polluted city. And for all course mortality, lung cancer, cardio pulmonary disease, look 26% increase, 37% increase, 37% increase relative to if you just smoke. Twofold increase, eightfold increase 2.53 fold increase. Just emphasizing that it doesn't make a huge amount of sense to be very anxious about air pollution and your health if you are smoking 40 cigarettes a day. It seemed logical. <laugh>. Now this is where I'm gonna wrap up and I, I kind of wanted to end with what I always regard as truth. Truth is always for me. Pathology, yes. What you can actually physically see within the body. I do lots of work where I correlate A with B and show associations. 

Speaker 1 (00:45:59):
I do lots of mechanisms but pathology really means a lot to me. And we've been talking about barriers. Yes. And so the question becomes what happens on a barrier fails? Does the barrier fail? And there's a kind of statement in lung research, especially in the people who develop inhaled drugs, that the lung is a bit like a leaky bucket. It's not really like a leaky bucket. Actually the barriers are quite tight though not always. When you're young it's a bit leaky as you get older it leaks a bit more when you are ill and have infections, it's pretty leaky as well. And you can actually measure that because you can see proteins on the surface of the airway moving into the plasma pool as a marker of permeability. But the reason I wanted to just point this out was to show you that actually you can show things leaking into the system. So these are AutoID lungs, a study from San Paul in Brazil. And what you're looking at is the surface of the lung. And this is a smoker. And so you can see these, these sort of like black carbonation accumulations on the surface of the airway. Not a surprise he smokes. This is a non-smoker. This is the air pollution in Sao Paulo. So the particles you breathe aren't just abstract. You can actually see them accumulating within the tissues. 

Speaker 1 (00:47:29):
This is one of the lavas that my colleagues did. I do lots of studies up with colleagues in Sweden. This is a lava from a healthy individual. This is a lava farmer person who smokes it comes out black and if you spin out the cells and look at them normal alveola macrophages and neutrophil there and over here look at these absolutely packed full of carbon particles. And actually what's really interesting is if you get somebody and they've quit smoking for years, you can still lavage out of them these macrophages. It's as though they've become senescent. They sort of become immortal within the tissue in the lung just sitting there slowly smoldering, releasing inflammatory mediators which may explain why when people quit smoking you still get this accelerated lung function decline. And then finally this, this is quite new. This is published only last year out of Cornell University, uh, by Donna Farber's group. 

Speaker 1 (00:48:35):
And you know I showed you that picture of the airway and in the tissue there were those dentritic cells reaching out to grab stuff. Yes. What they're trying to do is grab the stuff and then it'll go on a trip into the lymphatic system to the lymph nodes to talk to other aspects of the immune system to try to make, to mount a normal, an informed, let's say an informed immune response. These are human lymph nodes, again from autopsy samples, from people of different ages living in an urban area. None of these individuals are smokers. All of these individuals have only accumulated these black carbonation particles as a function of living in the area. So these are like accumulations accumulating over time. What's really interesting about this study is they're able to show that the accumulations had a functional consequence in the capacity of those immune cells within the lymphatic system to actually mount appropriate responses so that the carbon wasn't just there as a biomarker of what you have briefed. 

Speaker 1 (00:49:40):
It was actually saying something about how well your immune system was going to respond to subsequent stresses. For me this, and I'm so jealous because I wanted to get lymph nodes for years and then this came out. You know how it is. You know, somebody always beats you to the lymph node paper. But for me it's really important because again it takes you beyond associations. We move towards causation. We begin to see that the chemicals and the entities people talk about in the outdoor air are accumulating within tissues and have functional consequences. I think that's incredibly powerful And the reason I think it's powerful is because you know what we can't do very much about our biology. Yes. Our evolution, we've it yes we, we've got our repertoire of defensive mechanisms. The only way we can actually deal with this is to regulate emissions. The challenge for us is to identify which emissions are the ones which are really important and which of them are the sort of daily scare stories which appear in our popular press. Which probably should have lots of caveats and be introduced for a little bit more care. And that's it. 

Speaker 1 (00:51:02):
Any questions from the 

Speaker 2 (00:51:03):
Floor? Let's have one from the very back then please. Have you got the microphone? Microphone? 

Speaker 3 (00:51:10):
Just taking your last point about what, what would, what should we be worried about and what should we be less worried about at a, either as an individual or a population level? 

Speaker 1 (00:51:21):
I, this is as soon as you ask me a question that I've gotta come in and say I have opinions. Yes. And, and people will disagree with me about the opinions. I think that we've got quite enough problems <laugh> at the moment dealing with air pollution and cigarette smoking. Yes. For people to be tremendously upset about microplastics in the air. And I'll tell you why. Cause it sounds insane cuz it's red hot. Yes. Okay. So there is probably in the air, cuz I'm only thinking about the lung because I'm a very narrow person. So in the air probably you at most you get 2000 plastic potentially particles per cubic meter by the side of the road. Outside this building on chancery lane it will be between 35,000 to 50,000 particles of exhaust, road wear, tire wear. Not all of its plastic, believe it or not. 

Speaker 1 (00:52:22):
Brake wear per cubic centimeter do the masks. The, to me it seems as though we are chasing something when it's a minority. And actually when and because we're doing that, we're not being sensible, I don't think, it's not an important question. I think that if I was thinking about microplastics, I would say why, what is unique about them that I would be concerned about? And the thing which is unique about them is there biologically persistent in tissues. But once you identify that that's what you are concerned about, then you should be specifically looking for certain diseases and certain pathways which would be linked to it. And that's not happening at the moment and people are just going around measuring it in any, and it sounds wrong to say this, in the age of hta, any tissue we happen to have from a human hanging around, let's have a look for microplastic. And it's, it's very difficult to measure them because we live in a plastic cloud. Yes. Most of the time. And they're measuring one or two or three plastic particles in a tissue discussed. So that would be my, my be careful about the microplastics. It certainly needs to be dealt with but wouldn't put it at the top of the list when we've got things which are much more pressing. 

Speaker 4 (00:53:32):
Uh, thank you very much. That was, uh, very entertaining. Um, would you breathe in through your nose or your mouth? 

Speaker 1 (00:53:42):
I also answer, caveat that by saying one or the other. <laugh>, um, 

Speaker 2 (00:53:45):
Always 

Speaker 1 (00:53:49):
The nose is a fantastic filter. Yes. So definitely I would, the nose is a really good filter. Yes. But I, I'll give you an illustration that you know, we are a bit cavalier about it. Yes. So one of the things which you can definitely see in urban populations is they lose their sense of smell. Yeah. Over periods of time. You can see differences in Snell ability compared to people who live in countryside. And that reflects damage. Yes. It reflects those underlying morphometric changes which are occurring to the epithelium of the nose. It's still better I think, than the alternative is breathing for your mouth, but just breathe 

Speaker 2 (00:54:26):
<laugh>. 

Speaker 1 (00:54:27):
I mean I always have to say, you know, let's put into context, you know, toxic, everything's poisonous. Oxygen is a toxin. Yes. It's just a highly convenient toxin that we just happen to breathe at the right concentration. 

Speaker 2 (00:54:40):
So we, we've had a, a question online which is very relevant and you talked about plastics. What about vaping? Because um, there's obviously such a massive increase in young people vaping. What? Tell us about that. 

Speaker 1 (00:54:55):
Well, vaping's an interesting one. So I mean I, again, this is my personal view. If vaping is a medical strategy to take people off something which is really, really bad Yes. Then it should be prescribed, not commercialized. Yes. Simple as, as far as I'm concerned, as soon as you start making money from it, you start promoting it. You see what we are seeing, which is it's become a gateway mechanism. So children are vaping and after they vape, they move into smoking. Yes. So it's not acting as a cessation aid because it's actually being used as part as the pathway to dangerous behavior, maybe not nicotine. Yeah. 

Speaker 2 (00:55:40):
The the and so on that are, that are within the vapor that they're, 

Speaker 1 (00:55:44):
I think it's, I think it's just too open because you have your PE and your pg but then you heat it up. Yes. So it's py then you have all the flavorings which may or may not be safe. Yes. Which we don't know. And then there was a story in the United States where they added to cough oil acetate and they linked to cough oil acetate within the actual liquor to fibrotic presentations in certain individuals. But that was only in the states. It wasn't over here. I think we're in a really strange situation and I hate to say this but I am gonna say it, that for, for e-cigarettes, we are now in a position we can do the epidemiological study. We don't actually have to do the detailed, pull it apart toxicology on, on e-cigarettes because, and vaping because so many people now do it in the real world. We can track them longitudinally and if you track them longitudinally, we see what's actually happening to their health. Yes. That then will begin to sharpen our focus. 

Speaker 5 (00:56:41):
Certain parts of the world and certainly, um, few generations ago and still prevalent. They smoked the Hubble bubble or the hookah and that is smoke, which is filtered through the water. Is that, uh, a safe way of smoking? 

Speaker 1 (00:57:02):
So I don't know, but I know one thing. Yes. Fin, which has combustion involved in it in any sense. <laugh>. Yes. Um, and you inhale it probably, I would not call it safe. It's shades of risk. Yes. Shades of hazard. And I don't think I've seen a really good comparative study and I've not seen a study like those epidemiological studies myself. But that's cause I haven't looked, I'd have to check. 

Speaker 6 (00:57:32):
And um, uh, you spoke about these um, lavage to uh, take out some samples from different parts of the body. I wonder if that can have therapeutical use, like if you use it to get out toxicant out of 

Speaker 1 (00:57:51):
The lung, it's, it's used in certain conditions to clear airways. If there's lots of mucus, yes you can use it. I don't think it's ever, I look I've had it done to me Yes. To see what it was like. Um, I found it quite relaxing to be quite honest. <laugh>, um, you get to lie down, it was, it was much, it was much nice and I had biopsies taken. So what I haven't told you is that you can actually take a little sort of fenestrated claw into the thing and you can pull out a little section of the lung to analyze. Yet it's such fun because you have no pain receptors in your lung. Yes. But you have motion sensors so you can feel your lung shifting ever. They've taken it, but I don't think it's the solution to the toxins. I think by the time you go to wash out the toxins, they've probably been taken up into the cells already. Yes. Plus the fact if you do a lavage, it causes inflammation itself. Yes. Lower level of inflammation. But it does cause some injury. It's not without, it's not completely benign. 

Speaker 7 (00:58:52):
Thanks for the talk. Um, the uh, lymph nodes that you put there, did they then investigate what the primary, um, chemicals were in them? You know, the, the, especially the older ones that were 

Speaker 1 (00:59:05):
Not yet. Not yet. But I'm sure on your, I mean yes. I mean I still, it's on my list cuz you, I'm, I'm quite interested in metals for example, just uh, and we have the technology now if I get a lymph node, I can use laser ablation and actually go across all of them in sections and identify all of the elements in there, in all of the particles at a resolution. Yes. It's more difficult with other chemical species it could be done but it's gonna be pretty messy in there. You can imagine. Yeah. In terms of all the chemicals. But it's definitely the next thing to do. And again, once you've identified what's there, you can actually start doing experiments to try to work out which components could be causally driving some of the behaviors you see in those cells. 

Speaker 8 (00:59:55):
Uh, thank you for the talk. Um, I guess from the premise of what you're saying is that smoking cause irreversible damages, damages in the body. But I was also wondering um, during the, the survey, was there any like study looking into like the kidney functions or the eliminative systems? Like do they suddenly reduce so that in that case there's a struggle to even remove any of the toxins that are store from, you know, the smoking? 

Speaker 1 (01:00:24):
It's an interesting question to which I don't actually know the answer. Yes. Because the lung and cardiovascular pathology is so well established. Yes. Um, 

Speaker 1 (01:00:36):
But one of the big issues about this whole field in gases and particles is um, what causes the extra pulmonary effects? Yeah. Is it caused because the chemical on the metabolite enters the circulation and goes to a peripheral organ? Is it because a particle gets in there and goes to the peripheral organ? Or is it simply because you get inflammation within the airway and that inflammation effectively the mediators themselves enter the circulation? These are very inflamed lungs. Yes. Especially in C O P D. It's unlikely you won't have other organ systems being impacted by the higher level of systemic inflammation. But again, I dunno the answer to your question, but as always in these events I go away and I check. 

Speaker 2 (01:01:26):
Thank you. Well, um, very sadly, uh, this is in Ian's final lecture of his series as visiting professor of environmental health. And I wanted to say a few word of thanks on behalf of the college, uh, for the excellent series. I mean the dangers of, uh, all forms of pollution have may been made very clear in this last three series. Who smokes by the way? Is there anybody in the audience who smokes <laugh>? I hope you've learned your lesson. <laugh>. Um, he, um, the research way that Ian's been doing it, Imperial and with the RC is clearly important, self-evident. And we feel a bit privileged to have had him to agree to speak here and share that experience and his learning with us. It fits him with his personal commitment to communicating with the public and um, to teaching complex things to ordinary people like us. And he has done a fantastic job so far in this series and, um, we hope to welcome him back in the future if I can persuade him to do so and come back and give some talks. In the meantime, thank you very much for everything you've done for the college and with your lectures and I hope you'll join me in thanking in Wei once more. Thank you.