Asthma

want to consider the main cause of death in the UK. These are the latest figures I can get, and cardiovascular disease tells about a quarter of the age of this country. Cancer about a quarter, so they're neck and neck. The cardiovascular disease has gone down a lot in the past few decades, and more of that later on in the course of the module. The respiratory disease has killed about 10% of people, so it is quite important. Dementia has gone up a lot, about 8%, maybe more now. COVID has come down, it's not so great now. Now, one reason why respiratory disease kills so many people is because of the increase in dementia. Because the main cause of death in dementia is pneumonia, which of course is the respiratory disease. Okay, the bars are going up and down, so it's been holding fat goodness. Just to remind you, you've got your trachea going down the branch into two, one into each lung, and the airways get smaller and smaller and smaller to get to the bronchioles. So you look at the bronchioles, you've got the wall, which consists of smooth muscle cells. You've got three types of muscle cells in the body, skeletal muscle cells, cardiac muscle cells, and sleep muscle cells, which are everywhere, in blood vessels, the airways, in the gut. These are smooth muscle cells, you've got the ciliated cells on each side of the airway. This shows an alveolus there. Okay, so the cells around the airways, they're ciliated, which means they can move meatless and out of the lungs. Into the throat, and there you swallow it. Now, in blind comfort, you don't want to talk about mucus, but we're going to today, because it's important. When you breathe in microbes of death into your lungs, it's captured by the mucus, it's been sticking, and then all this cellular will beat and then move the mucus up into the top of the airways, into the throat, and then you swallow it into your stomach. And all those births will be killed by the acid in the cell. So the mucus is very important. Now, it's a certain section through the lung. You've got the terminal bronchial, then all these alveoli, this enormous certain area for gas exchange. You take the scanning electron microscope image, and we've got some of these machines over with the JJT building. That's the alveolus. This is a macrophage, which is about to protect you from any microbes you may breathe in. You'll focus on those and kill them. And these walls are very thin, so you can see the red cells squeezing through the capillaries in the walls of the alveolus. So you've got the alveolus, the epithelial cells on the inside of them, and then capillaries on the outside, where the gas exchange can take place. You can get the oxygen going into your blood. Okay, on to disease, asthma. When I was allowed a few years ago, asthma was quite rare. There's not any more. There's been a tremendous increase in asthma. I'm not sure why. Some states do have central heating, more carpets, but no one knows. Asthma is a reversible obstruction in the airways. Some diseases are a reversible obstruction, which I'll talk about later. Asthma is reversible. It comes and goes. If you've got asthma, you know, it comes and goes. Now, that contraction of the airways is due to stimuli that aren't noxious. So you breathe in the poisonous gas, and the airways contract. It makes sense. It protects you. If you're contracting the airways at response, say pollen, which wouldn't damage you, then that's abnormal. So it's an obstruction of the airways due to non- noxious stimuli. So it comes and goes. You get reason, of course. You get a cough. Sometimes in small children, if they're asthmatic, they can't tell you. But if they're coughing, you make a cycle to get an asthma attack. Just something to bear in mind for later. About 300 million people go by asthma. About 8% of people mutate it, and it can kill over 1,000 people per year. So it can be a dangerous disease. It's more common in women than men. We're not quite sure why. Some diseases are more common in women to sexes. Why ask this more common in women? We don't know. But the immune system may be different than men and women. Because women have to tolerate the existence of the foreign body inside when they're pregnant. So that immune system may be a bit different to men. We're not sure why. But we suspect that the immune system may be different in men and women. That may possibly be why it's more common in women than men. So that's going to be the innovation of the airways, because we don't understand it to know how the drugs work. So that's the inside of the airways, of course. These are smooth muscle cells. They're arranged in a circular direction. And that's important, because if they contract, what's going to happen to be damage to the airways? It wouldn't get bigger or smaller. It would get smaller. It's a circular direction. So if these contract, it becomes smaller. The airways will have a smaller diameter. So we can actually get hyper-responsiveness to things like irritant chemicals, which is fine. It's what we expect. But also cold air. So some people ask me if the exercise in winter brings something like that. Not always. Sometimes it does. So the airways are responding abnormally to the cold air. It can grow done by allergens like pollen, your petanogy, bacteria, and it's due to the jelly. Which causes the allergic reaction. And to the dust. So some people are allergic to dust. It's not the dust itself you're allergic to. It's the house mites found in the dust. And in fact it's not the house mites themselves. It's the theses you're allergic to. You're allergic to digestive enzymes and the theses of these house dust mites. Which isn't a pleasant part. So that's what we are allergic to if you are not F1s. And if you get the respiratory infection, you can get asthma as to the result of that. Now I'm used to think asthma is just due to a contraction of airways. They become smaller, their damage is less, how difficult to breathe in. But now we know that's only half of it. We have a half of that in the inflammatory disease. I'm going to digest a bit because this is quite important. Inflammation is good. If you fall over and damage yourself, you've got to heal. You get a microwave infection, you've got to fight it. So inflammation is very important in protectionists. But a lot of diseases due to increased inflammation just go too far. So think of the inflammation diseases. After these diseases, it's brought in heart attacks and thrombotic strokes, rheumatoid arthritis, asthma, colitis. These are due to excessive inflammation. Inflammation has just gone too far. Now, this is chronic inflammation. So the cute inflammation that comes and goes is good. It's protecting you. Chronic inflammation is bad because it's going an absolute lot. Cute inflammation is easy to treat. You've got patch effects on your skin. You put on some hydrocortisone cream and it goes away quickly. If it's chronic inflammation, it's difficult to treat. So a lot of major diseases due to chronic inflammation. And that is difficult to calm down. And you're going back more and more as the program goes on. Right, back to asthma. Okay, so asthma is an inflammatory disease associated with bronchial hyperresponsiveness. There are ways to contract too much. There's different phenotypes of the disease, which aren't well defined. So that's a normal bronchial. So these are the epithelial cells. The gas, of course, is in the air. These are the sweet muscle cells. So that's fine. In asthma, you see this type of thing. The sweet muscle cells contract too much and get all these mucus inside the airways. That's making it difficult to breathe. It's not just the contraction of the sweet muscle cells. It's the mucus inside the airways, which is the problem. So a bit about innovation. This is quite complex. I'll go through it slowly. So that's how sweet muscle cells are. And that's a neuron. This is the parasympathetic neuron. Now, considering the nervous system, you've got the emerging nervous, so you can move the muscle. That's due to the motor nerves. You've got all these lymphology nerves as well in the autonomic nervous system. And they're there all the time, keeping your body stable, looking after your airways, contraction, the motility of your intestines, how many blood vessels are dilated or contracting, all going on in the background all the time. You don't know about it. And there's two types of autonomic nervous system. There's a sympathetic nervous system. So you can adjust your practical practice, these lectures, run across campus. Your sympathetic nervous system is activated. If you do the reading of half marathon on Sunday, which passes past this building, your sympathetic nervous system is activated. So I'm doing the reading of half marathon up on Sunday. One of the days in the South, so maybe I'll do it in the future. Exercise is good for you. Back to asthma. You've got the parasympathetic nervous system, which is activated in your man. It's just keeping things nice and calm. You're digesting your breakfast, you've had it. The picture is being calmed. So the sympathetic nervous system activates your body. The parasympathetic nervous system calms it down. Right, now the parasympathetic nervous system, when axon cells, like smooth muscle cells, uses acetylcholine. That's a new transmitter. And that will act on the type of receptor. There's two main types. There's nicotinic and mescarinic. These are mescarinic moths. These are different types. This is an M3 type. We'll come back to this in a minute. And that will increase inositol tris phosphate. By the way, that's tris rather than tri. Just a bit of a dramatic point. And that will increase calcium, and what will the calcium do? Will the smooth muscle cell contract or relax? It'll contract. So it's keeping the airways in what should be the right state of contraction, the right habit. Now, you've got beta-2 at general receptors. Now, for the smooth muscle cells in the airways, you don't have a sympathetic innovation. In the sub-tissues you do, in the airways you build for the smooth muscle cells. They're reacting to adrenaline in the blood stream. So if you dash across campus, your adrenal glands release adrenaline. That circulates throughout the body of the blood, gets to the airways, and it will act on the type of receptor for adrenaline called the beta-2. There's armors and betas, different types of betas. This is a beta-2 receptor. You circulate adrenaline, acts on it. That will increase cyclic AMP, which you all know about. That will cause for relaxation. So the parasympathetic nervous system releases acetylcholine. That causes the contraction. Circulating adrenaline acts on beta-2 at general receptors. That causes for relaxation. So when you dash across campus, adrenaline increases in the blood, and the airways expand, it causes the smooth muscle cells to relax and get more air into your body, into your exercising, your skeletal muscle. So that's how it works. Now, this goes round in Aspen. Back to mucus. These are the goblet cells producing mucus in the airways, and they act on the parasympathetic neurons. They release acetylcholine. Again, it acts on N3, masquerading receptors. This will increase mucus production. The goblet to mucus is protecting you from microbes that you breathe in. Now, these do have a sympathetic inhibition. They've got sympathetic neurons acting on them, and they release normally. Now, these are called catecholamines, and the main one in the blood is adrenaline. You can't get three more bands. The one from neurons is not adrenaline. So it's not adrenaline. It acts on beta-2 at general receptors, and that will decrease mucus production. Because if you exercise, you don't want too much mucus. You want your airways to be nice and open and clean, so you decrease mucus production. Right, so in summary, the parasympathetic nervous system won't rest. It causes bronchoconstriction. We don't need to breathe so much. The mucus secretion. The sympathetic nerves decrease mucus secretion. The sweet muscle cells don't respond to the sympathetic nerves because they don't have a sympathetic inhibition. But they respond to some neurotransmitters. That can cause bronchodilation, adrenaline in the blood, and maybe nitric oxide. You come across nitric oxide. Nitric oxide isn't just a chemical, or just a chemical that is firstly imported. It's a single molecule in the body. And you come across more of this as you go through the degree. So the circuit adrenaline will act on the airways, causing bronchodilation. The damage of the bronchioles and airways will get larger. Okay, let me come on to prostaglandins. Okay, this is a membrane bilayer, your cluster membrane. The bilayer is a phospholipid with proteins embedded in it, or surface. And these phospholipids have two fatty acids on them, as you know. And one of these can be removed by a phospholipase A2, which acts on the fatty acid of the second position of the phospholipid. And some of these fatty acids are arachidonic acid, as you know many of them. One is arachidonic acid, and that's important. Okay, so it's got the carboxyl group, four double bonds. And this can be act on by any signs, including cyclooxygenase, to form prostaglandins. There's a number of prostaglandins.

This is one of them. They've got these weird and wonderful structures. And they're important, the same as the molecules in the body. They contain a control of mucous veins. They've also got leukotrins. These are formed arachidonic acid by an enzyme called thiolipoxygenase. Several of them, this is one of them, leukotrine C4.

Those are the four double bonds. And these are amino acids attached to it. They're weird and wonderful, but important, the same as the molecules. Okay, now in asthma, you've got two phases, an early phase and a late phase. If you've got asthma, these two tend to merge together, and you never notice. In fact, there's two phases. Okay, so you've got your allergen, what exactly it is. This will activate cells in the airways, mainly the mast cells, which are derived from basophils in the blood. But they also act on the acinophils and the mantrophils. The mantrophils protect us against microbes, the phagocytose microbes. And these release histamine, so the mast cells release histamine, which of course is hay fever. Also, all these other things as well, like the platelets activate in the factor. Just in case it activates platelets, that's how it was discovered. Just numerous other things as well. You get across the glands and leukotrines. I've put leukotrines in a pool because they're the most important in asthma. And vehicles from the spasm. So the smooth mast cells contract, the airways become constricted. You've got an asthma attack. It becomes, we say, it's difficult to breathe, mainly due to leukotrines. So inflammation has gone too far. Okay, so we've got these leukotrines and chemokines. Now the chemokines are protein molecules, and they attract leukocytes to a site of inflammation. So the chemotactic, where the name comes from. And this will cause the late phase, which is more inflammation. So in this inflammatory phase, we've got the leukotrines and chemokines. These will attract T-cells from the blood. Here's cinophils and utrophils and monocytes. And when the monocytes get blood into the tissue, they differentiate into a macrophage. So monocytes and macrophages are the same cell type. The monocyte and blood, and it's quiescent, calm. The macrophages and tissues can be quite aggressive. So you've got all these cells involved. So it is complex. Now these cells normally fall to protect us from microbes. But in terms of evolution, that's the main factor. A lot of people die from microbial diseases. So in terms of evolution, there's a great pressure to protect us from microbes. And the reason why we get chronic inflammatory diseases is because there's a spill over, and it's causing disease because it's going to bark. But in terms of evolution, it's very important. Right, so all these cells will produce inflammatory mediators, like leukotrines played back to the fact that chemokines, cytokines, cytokines cause inflammation, or some can calm it down, that most cause inflammation. There's numerous ones, but the main monocyte and asthma are interleukin-4 and 13. This is all very complex. And it's called inflammation, mucus production, and bronchospasic. The sweet muscle cells contract. The eosinophils, these release a protein called eosinophil, major basic protein. It's called eosinophils, it comes from eosinophils. It's a major protein and that's basic, which means it's got a strong positive charge. So this protein can cause damage to the epithelium. You can damage the epithelium for airways that become hyperresponsive. Because they see things they shouldn't normally see. So things in the air that you breathe in, these are normally see the epithelial cells, but not the sweet muscle cells. If epithelial cells are damaged, they can get the sweet muscle cells and then cause them to contract. So it's all very complex, it's just an complex disease. I hope that makes some kind of sense. Okay, on to treatments. We've got asthma, if you know what the treatments are. This is the bronchodilators. We've got asthma, this is the blue inhaler. This is anti-inflammatory drugs, brown inhaler. Okay, the bronchodilators. Now these are beta-2 adrenergic agonists, which means they act on beta-2 receptors for adrenaline in this case. And they do what the body normally does. It's increasing the response that normally gets with adrenaline. So a lot of drugs, they do it by magic. What they do is they control a normal physiological control system. As a matter of fact, make it work a bit faster or by a carbonic dad. That's how drugs work. They normally work on normal control methods. So the beta-attendergic agonists, between what adrenaline in the blood normally does, they're widening the airways. It's first-line drugs. So the balance of these beta-2 adreno-septins of sweet muscle cells increase cyclic Np, like I showed you a minute ago, and cause relaxation, so the airways look larger and increase diameter. These should inhale, they can be taken by a mouth. When Sothea has something, they can be ejected. They're shot after my salbutamol, which has a maximum effect of about half an hour. It lasts about five hours. All big bidor actin, like some metrol, lasts about 12 hours. Some of you may know about these. From personal experience, a bit of pharmacology. That is salbutamol. That's adrenaline. You can see they're quite similar. So normally, your sweet muscle cells will relax in the airways to adrenaline when you exercise from airways to the tongue. Larger. They do seem salbutamol. But salbutamol is tertiary butyl groupone. And that's important. It was first discovered in this country, and it was a great breakthrough. Because of all time of treatment, asthma was adrenaline. And that's how the major problem. Because adrenaline speeds at the heart. And that sometimes led to fatal effects. It caused the heart to beat too fast. Now, salbutamol does affect the heart much. Because salbutamol affects beta-2, the adrenoceptors. And the heart is mainly beta-1 adrenoceptors. Now, beta-1s and beta-2s both respond to adrenaline. But beta-2s, there responds to salbutamol that the beta-1s don't. So salbutamol widens the airways, but has little effect on the heart. So it's a much safer drug. This tertiary butyl group is very important. What it does is this tertiary butyl group makes the molecule bigger. So it can't bind to beta-1-receptors in the heart. It's just two beta-3s. They can bind to beta-2s in the airways, because they'll accept a large amount of the binding to them. So the details can be quite important. So salbutamol selects the beta-2s, adrenaline binds to both, but salbutamol selects the beta-2s throughout the beta-1s. Any questions about that? Okay, on to centipene drugs. Thethelin is found in tea. People drink tea because of the issue of booze, thus due partly to caffeine, also to thethelin. Now, thethelin is a treatment for asthma. We've got an asthma attack. We don't have to drink from tea. There's far too little thethelin there to have an effect. It can be taken as a drug. I've been awfully... They're less effective than the beta-2s, so they don't tend to be used alone, but they can be used together with the beta-2 athletes. The beta-2s aren't effective by themselves. You can take one of these drugs. We don't know how it works. It's true for a number of drugs, but we do know how salbutamol works. It's given by mouth. Okay, so concentrated on salbutamol. They can also have drugs that work on parasympathetic side. So the sympathetic nervous system and parasympathetic nervous system tend to work against each other. If you find control of whatever it is, treat asthma as a drug called epitrochemical bromide. And this is a muscarin antagonist. So it's antagonizing the effect of acetylcholine in contracting the smooth muscle cells. Also, bronchial contraction. So it widens the airways. Okay, so it binds to M3, muscarin receptors, or the smooth muscle cells, and stops acetylcholine binding to them. So it stops, in fact, acetylcholine, making the airways become smaller, giving back inhalation. It's not normally given by itself, as the salbutamol says, but enough, it can be given along with salbutamol to make it better. Or together with glucosapides, which brings to the opposite of anti-inflammatory drugs. Now, if you ask me to take a drug that's salbutamol, it works within minutes. You've got asthma, you know that. The trouble is, we just take salbutamol. Asthma can come back the next day. So to try to get that in code, you can take your salbutamol and anti-inflammatory drugs. These anti-inflammatory drugs treat the next day asthma, if you like. If you've got an asthma attack and you take anti-inflammatory drugs, you won't do anything straight away, but you can work the following days. They slow out, and they're glucocorticoids. They're not run to the dilators, but they'll dam down the inclination. And in the long term, they can dam down the early phase, and they can even treat exercise-induced asthma. There's a number of, there's Beklam metasone, which is a brown inhaler. It's got more fruiticosone being held. And you need several days for the fun fact. And there's a big push to get these models of the asthma treatment regimes. Okay, these were, because they decreased the formation of inflammatory cytokines, proteins called alpha-inflammatory. They did in a number of ways. Quite a few drugs act in more than one way, and the glucocorticoids are a good example. They can turn on the gene for a protein called lipopoietin. Now, this protein can have its phospholipase A2. Now, think back to what phospholipase A2 does, which is to cause the synthesis of four compounds, the glucotrines and prostaglandins, mediators of inflammation in asthma. Okay, so you get less nucleotrines and prostaglandins, an activating factor that reduces mediator release from the acinophils, and it increases the beta-2 in the trevus actus. These can respond to circulating and generally more. It's to work in all these ways to down down inflammation. We've also got the leukotrine receptor antagonists. It's at least got the leukotrines to make the inflammation worse. Montilla castes one of them, state-reducing inflammatory effects of the leukotrines. But they're also bronchodilators, taken by mouth. And they are effective. Okay, we'll take a break in a few minutes. Just let me tell you about this because there's some object lesson here as well. If you've got asthma, some people with asthma, not all. If they take aspirin or ibuprofen, make the asthma worse. Asthma is something inflammatory disease. Aspirin and ibuprofen are anti-inflammatory drugs. So would you expect aspirin to make asthma better or worse? Asthma is to add inflammatory disease. Aspirin is anti-inflammatory. Would it make asthma better or worse? It should make it better. It can make it worse. Asthma and ibuprofen, perhaps by inhibiting the cycle of oxygenates. To get less prostaglandins formed, include prostaglandin E2. Now, prostaglandin E2 inhibits the formation of leukotrines to get increased leukotrine production, therefore more asthma. Okay, let me go through that again. You take aspirin, inhibit cycle oxygenates, less prostaglandin E2. Prostaglandin E2 inhibits leukotrine synthesis. So you've got less prostaglandin E2. This is less efficient, more leukotrines. These are the main inflammatory fraction asthma. So more leukotrines, more asthma. So once you understand it, it makes sense. But at first it doesn't. It's the exact opposite of what we expect. And I mentioned this, just not the cost of asthma. For some, aspirin and ibuprofen can make it worse. But it's important to understand that science is not improved. A lot of people think it is.

It is not. Because you can say, well, if I do this experiment, it will go wrong way. It could go the exact opposite way. And my research career has noticed that numerous times. So if we do this, it will go that way. It's going the exact opposite way. And that's because we don't understand everything about the body. It is far more complex than we understand. It is discovering new, completely unexpected claims all the time. So until you do the experiment, you just don't know. If you can do something, you get an unexpected consequence. And if you do that, it's going away. How should you discover something new? All you've got to do there is to find out what's going on. So it's not intuitive. Unless you do the experiment or the claim trial, you just do not know. It's a little bit of a great deal to discover about the body. There's lots of exciting, unexpected things we're discovering all the time. Any questions about that? Okay, we'll take a terminate break and start again at 5 to 10, shall we? Right.

Right. Okay. Chronic obstructive pulmonary disease, COPD. There's two main types. They're related both, as you'll see in a minute. There's chronic bronchitis and enphysema. Okay, right. Asthma is reversible. COPD is one. It's pretty reversible. One should go to the product for life. It affects about 2% of people in the UK. It's just about 30,000 people per year. It's getting worse worldwide. Again, it's an inflammatory disease. It's chronic. It means that when a patient has got it for life, it's truly chronic. Accused when it comes and goes. Chronic process. Two false neutrophils, macrophages, and teal lymphocytes. Again, it's complex. And all you get, the more likely you are to get it. This is true for many diseases. It affects more men than women. And the reason for that is because more men are really smoked. That's such a big difference now. It used to be a big difference. How do you diagnose it? We do a quarterly function test. See a breathing tube as hard as you can. And it matters how fast you can excel there from your lungs. And if your lungs aren't working too well, watch from the next spell. Yeah, less well. That can be measured. You can do it by taking arterial blood gases, not feeling as blood. That doesn't work. So taking arterial blood isn't a trivial thing. I can do a chest x-ray. Okay, chronic bronchitis is an inflammation. Bronchial tubes are, of course, inflammation. See the bronchitis can't be inflamed. You get too much mucus produced. And the cilia, when you're active for your cells, stop eating. So you can actually remove this from your lungs into the back of the throat and swallow it. So it accumulates in the lungs. Which isn't good. Try and cough it up. Have difficulty in breathing. Not at all pleasant. What causes it? The main cause. Smoking. It can be caused by bacteria or viruses. Or the occupation of dust or chemicals. Or the indoor or outdoor air pollution. Maybe due to the cars. The indoor pollution is mainly in developing countries. Because they don't have tumors. They have a fire, an open fire inside where they live. And the smurly chemists in the house. They can cause chronic bronchitis to be produced. Okay, how does it work? We've got the cigarette smurly or test for terminitis. And this attracts the monocytes from the blood into the lungs. They become macrophages. They release chemo-captive factors to attract other leukocytes from the blood into the lungs. For instance, interleukin 8. In this case, neutrophils start attracting the blood. They secrete an enzyme called elastase. Now, elastase breaks down, elastin. Just a protein that makes certain organs. Elastase, hence the name. For instance, in the airways or blood vessels. So when the airways or blood vessels, they expand. They can relax again in the presence of elastin. It makes them elastic. Now, this elastase can cause too much mucous secretion. The cilia don't beat as much, the cilia have chronic bronchitis. It can also degrade elastin and collagen and cause anphysema. So there are two types of chronic obstructive pulmonary disease, chronic bronchitis and anphysema. They're different. The chronic bronchitis occurs further up in the lungs. Anphysema is right down in the lungs. It's more furovine, but the cause is similar. It just depends if it's at the top of the lungs or the bottom of the lungs. Now, a sad fact of life is that I should get older. You can't breathe in so much air. So if you measure the force exponentially volume of air as you breathe in as much as you can, then breathe out as fast as you can. When you're young, you can breathe out quite fast. When you get older, then you can breathe out less. It's not that any nervous effect that is there. So the ability to exercise goes down, you should get older. But if you smoke, it goes down faster. Now, if you're a smoker and susceptible to the effects of smoke, your first respiratory volume goes down a lot. It's not an off-smoker that's getting set. It can be a big effect. The good news is, if you stop smoking, then it doesn't go down like that. It goes down like that at the same rate as the net of smoking. The bad news is that we start off from a lower level. So you never capture the lungs to a netherwork as well as they would if you never smoked. So good news is there. How do you treat chronic bronchitis? Stop smoking in a pretty office. You can use antibiotics if there's an infection because you can't get the mucus expelled. Use a bronchodilator we talked about before. Or mucolytic drugs. For instance, Epastoscysteine. Now, these drugs contain a phial group, SH, and they can break down mucus, make it more ready so the cell can accelerate out of the lungs. We've now got a fairly new drug that's been around about, what, eight years? Here are three of the last. And this inhibits phosphogesterase 4. Now, phosphogesterase 4 breaks down the site of Np. I have a number of these breaking down the site of Np. The site of Np is anti-inflammatory. So you can stop this anti-inflammatory breaking down the site of Np. The site of Np will increase and it will be anti-inflammatory. So it damages down into the nation of bronchioles. If you get started about, you may have to use phantelators to try and make oxygen into your body. Any questions about chronic bronchitis? Okay, M5C. Now, further down from the lungs. Again, it's an inflammatory disease. When the terminal bronchioles are destroyed and the elastic fibers in the walls of the alveoli, they're degraded by the elastase, which isn't good. And the structural cells in the alveoli, they may die by apoptosis, they can make suicide. Now, you have more difficulty exhaling and inhaling. And the reason why is when you inhale, you decrease the pressure inside the chest and then air comes into the lungs. When you breathe out, the muscles contract, you increase the pressure inside the chest and the air comes out. If your terminal bronchioles and alveoli are damaged, then when the pressure in the chest increases, these will collapse. It makes it more difficult to get the air out. So, M5C makes multi reports of breathe. And when this is to breathe in, it can certainly become short of oxygen. Okay, these are what the alveoli's genomic look like and the normal cells of the gas exchange. In M5C, these walls are destroyed by elastase from neutrophils. So, you have these large holes there. And of course, the surface area of the gas exchange is reduced to grey fields. What causes M5C, I think you can guess, is smoking. The energy to smoking doesn't come in straight away. They may come on by age 50. It can also be caused by academic disease, because some people don't have this enzyme. Well, not enzyme protein called alpha-1 antitrypsin. Now, we've got all these protease in the body doing things that we need. But they can cause damage. So, the body has a lot of protease inhibitors. So, down-down activity with these proteases. Keeping them under control and alpha-1 antitrypsin will inhibit elastase. But some people don't have this protein. About 0.2% equal. They can get M5C in their 30s and 40s. The treatment, of course, is to stop smelting, take the bronchodilated drug it may be, take an antibiotic with this bacterial infraction. If you've got alpha-1 antitrypsin deficiency, they can take what's called alpha-1 protease inhibitor. It's just the same thing. It can be elastase. They may need to go up on a ventilator to become spare. Okay, any questions about chronic obstructive pulmonary disease? Let's move on to infections of the respiratory tract. The common cold. We all know about the common cold. I'll talk about all this. I'll go through them one by one. Okay, so it's coming up. Okay, it's caused by a thousand cause. I saw the upper respiratory tract. Not the vertebrate respiratory tract. Of course, it's common. Unless you only get massive secretions with no surrounds. The meatless mangroves have been flayed. And it can be caused by a number of things, like rhinopharsis, planar median dose, paracid pharasis, mesoprotis, and cetylpharas, cronypharas. It's not just cronypharasis. It's just cause. It's a common cause as well. It's a family of proteins and denopharsis. Now, it's a well-established fact that all people get less cold. So you're more susceptible to getting a cold than me. That's well known, but we don't know why. What we do know is that the immune system changes a great deal with age. It's not a subtle change, but a large change. And that may be why all the people get less cold. It may be because we don't respond to the pharas so much. We don't know about that. It's one of the rare advantages of getting old. Rhinopharasitis, we can figure out what this means. Rhinopharasitis, the whole of the inside of your skull. It adds this inflammation. So nasal and perinatal sinuses become inflamed. Show you the picture notice. So in your skull you've got these pores, these sinuses. And these are connected to the inside of the nose. So these narrow openings called ostea. And if these become inflamed, then mucus will accumulate in the sinuses. The mucus can't drain up into the nose. This can be caused by bacterial or pharas infections. If you're on the verge of something. So these ostea become obstructed, so the mucus can't pass through these sinuses in your skull. They enter your nose. Which means it is by mucologic agents like N-acetyl cysteine to break down mucus. Make it more running so it can drain more easily. By an antebiotic, there's some infection by bacteria. Decongestant to produce so much mucus. Or by a glucocorticoid. Like kidney or plantar inflammatory drug. Any questions about one? Okay, influenza flu. Now, if you're wondering if you've got a cold or flu, you've probably got the cold. Because flu is a serious disease. Why are you out? It's really almost impossible to get out of bed. It's much worse than a cold. Okay, this is an acute upper risk of tract infection. Trachon changes, of course, as we all know. And it's caused by influenza viruses, which is ferrous types. And they are RNA viruses. They are DNA viruses. Now, the problem is, it's pretty bad if it's stretched from the upper lungs into the lower lungs. It can be really serious. Because it means that we can share the cells from the arm. From the bronchioles and the alveoli. And that will need to be known yet. We shall come on to it in a minute. And it can cause death within a few days. So, flu is quite a serious disease. And test mammoths appear and must belong at the wedding of a man. Again, we don't know why. You can see the effect in male and female mice. So, it may well be true. The treatment is anti-firal drugs. If you can get a flu jab, do you get it? It tends to be all the people that get it. Or those with the goal. Also, the male and compromised people. Now, the problem is with the flu jab. It's that the pharmacy changes each year. And the drug companies make these vaccines. They try and guess what the virus will be in the winter. So, start in the summer, doing their research, making the vaccine. In this country, we normally look at what happened in Australia in their winter. We see what type of virus is causing the disease. And then we make a vaccine that will treat the virus that's present in Australia. And sometimes they get it right, sometimes they don't. Because the virus may change, it may mutate. So, some years the virus, the vaccination is quite effective. In other years, there's certainly a tiny protective effect. So, guesswork to a certain extent, in full guesswork, sometimes works well, sometimes doesn't. So, getting the flu jab decreases your chance of getting flu. It doesn't eliminate it. And it fells a lot from year to year. You can get it. Do get it. Just like that. Any questions about flu? Pneumonia. There was a British physician called Ostler, who was very eminent. And he said that pneumonia is the captain of the man of death. Now, think back to your grandparents or great-grandparents. Today, what diseases do you care about? Dementia, heart attacks, strokes, Covid. It wasn't always so. Back in time, around the 1920s, it was mostly infectious diseases. They killed far more people than cancer or cardiovascular disease. This is what really scared people, getting an infection, because they didn't have antibiotics. So, a lot of people died from infections. They were the main cause of death. Not cancer and cardiovascular disease, like it is now. One of these was pneumonia. It was a single main cause of death in the West until the 1930s. So, it's changed a lot now. There's still about 25,000 deaths per year due to pneumonia. The summation, which is the main cause of death in Pneumonia. So, it's going on. Okay, this is quite important. It kills ten times as many people. It's all that other infectious diseases put together in the UK, except for Covid. And Covid has now gone down a lot of costs. Certainly, it's important. And the incidence is higher in the fairly young and the elderly. And worldwide, it kills about, it's responsible for about 50% of the deaths of children under five. So, worldwide, it's as far worse than in this country. And it kills more children than any other single disease. Okay, it's a serious infection and inflammation of the lungs. And in it, the alveoli filled with pus. So, you get an infection, the white cells treat the infection, the white cells die, and you get pus. So, you're drowning in your own pus, and you burn an alveoli. It's not the pleasant thought, but that's why it's so dangerous. You get all this pus in the alveoli, and the gas exchange goes down. You've got W pneumonia, like the Pope, and you've got pneumonia in both lungs. What causes it?

What causes it? Bacteria. The bacteria in the fairly young, the alveoli. They must come on the streptococcus pneumoniae. Now, some people carry this bacteria, and they get no effects. They're asymptomatic. So, they're nose and throat, and they're tolerated. No problems, but they can pass it on to other people that may get pneumonia. They may get flu, caused by virus, and then later on, the lungs are damaged. So, the bacteria can invade, and then you get bacterial pneumonia. Now, in pneumonia, we have this toxin called pneumolysine. Now, this is found in the bacteria, and it binds to cholesterol in the plasma membrane. Most cholesterol in the cells is in the plasma membrane. So, this toxin will bind to the cholesterol for pause in the plasma membrane. And, of course, that's damaging. So, it's damaging the cells in the lungs. It can also activate complement, which is involved in inflammation. So, you get inflammation, and then more perswish damages than alveoli. The treatments are, I just felt it in the moxicelline, but it's become a resistance to the moxicelline. I'll digress a minute here, because bacterial resistance antibiotics is a major problem. We have seen some bacteria that are completely resistant to all known antibiotics, and that's true in this culture as well. So, some bacteria just cannot kill them with anything. And this is getting worse, and it is a major problem. And part of this is due to the way the pharmaceutical companies work, because the pharmaceutical companies want a drug they've got to take every day to treat a chronic disease. They've got a lot of profit in it. If you make an antibiotic, you take it. The time to cure it doesn't make much profit out of that. It's not every day, it's just a few days. And it's difficult to find a new antibiotic. It's the authority of the server in decades. So, the pharmaceutical companies don't put a lot of effort into this. So, we desperately need more antibiotics, and we're not getting them. There had been a new one to discover a while ago. It's been fairly few. So, it's difficult to overestimate how important this subject is. Okay, back to the spiritual disease. There is going to be a routine fascination in the UK against pneumonia. Some adults, the elderly, and those with certain diseases will get the vaccination. You need one vaccination to last a lifetime. So, all people in this country offer this vaccination, just once. It can be caused by viruses, flu viruses, or COVID-19. It's gone to COVID-19 for a long time now. Okay, we all know about this. It's the first identified in China in 2019. Now, we still don't know where it came from. It could have come from some animal, maybe a bat, and it evolved in respect to humans, but it could come out of a lab in China. In Ruan, we don't know. It's very uncertain where this virus came from. But we all know what it did. You can get symptoms one day after the infection that could be two weeks. About a third get COVID and have no symptoms. We can pass it on to others. About 200% get severe and unknown symptoms. In Facebook, I have a lower respiratory tract. And it binds to a protein in the body called ACE2. Angiotensin converting enzyme 2. Now, this is an enzyme. Angiotensin 1 into angiotensin 2. And this is involved in regulating the blood pressure. Now, pharmacists are quite clever. What they do is they evolve to bind to the normal protein in the body. For example, if there's something wrong in the body, they're dying to it. They can get access to cells by dying to it. And in this case, COVID-19 evolved to bind to ACE2. And I feel like right down in the lungs, which isn't good. It causes pneumonia. It's not the virus that actually kills you. It's your response to it. Because it produces what's called a cytokine storm, you overreact to the virus, produce all these inflammatory proteins, and they damage the alveoli. And they fill it with fluid, so the gas exchange isn't efficient. So it's not the virus that kills you. It's the over response virus, which goes over the top. You can also get a microthrombi in the blood vessels of the lung, which is something we've worked on here in the Health and Life Sciences Building. And the treatment is oxygen thoracic and dexamethasone. This is a very old drug. It's an anti-inflammatory drug that's discovered in this country. And if you get this old drug, you decrease the deaths by about a quarter. So it's definitely got the inflammation. The inflammation which is killing you. The anti-diagnostic, best placed by PCR. So you take a swab from the nose, open with all the pharynx, convert the RNA from the phallus and RNA phallus into DNA, blended PCR. But we all know about the lateral flow test. And this detects not the RNA, but the viral protein. It's quicker, there's a lot of false negatives. So the lateral flow test can say you haven't got the disease, it's negative, but you do. The PCR test is a lot more reliable. So you take your swab, add it to the plethora. This affects the virus so that individual proteins can run along an absorbed pad. So you should only put it into this hole that runs along an absorbed pad. That's why it's called the lateral flow test. You should put it on when it runs in a lateral direction along this pad. Then you detect the protein with antibodies. And you see it at the bound of your postum. Any questions about COVID? Don't go as it's died down. Okay, pneumonia. This can be caused by microappressment, certain type of microorganism. Biphobia. Biochemicals. For instance, chlorine, which is used in the first world war, or lighter fuel. Sometimes people use this to get high. Okay, moving on to tuberculosis. Okay, this is caused by a bacterium, mycobacterium, which is the closest. A quarter of the world's population is infected by this bacterium, which is not uncommon. And it causes over a million deaths a year, especially in sub-Saharan Africa. And if you've got HIV, you're more susceptible to TB, tuberculosis. And it's the largest single cause of death in the world due to the single bacterium. There's quite a lot of TB in this country compared to Western Europe, quite a bit in London. And if you go about in history, it's killing more people than any other infectious disease. Just really did terrify people some time ago. It can affect any part of the body, usually the lungs. Just while I'm talking about it, it's transmitted by aerosol like COVID. And it can go to the lungs. It can remain there late and cause no damage. But it can be reactivated. It can get old or by HIV at the time. Now, normally, a microfarad is called phagocytols bacteria. If you go to phabosome and then to a lysosome, then the lysosome anxiety will digest the bacteria and kill it. The bacteria can fight back. The phagocytols, in a way, are what they can do. So these bacteria, phagocytols bacteria, like macrophages, go into phagosome. Instead of going to the lysosome execution chamber, they stay in the phagosome. We've got a very nice home, thank you. And the reason they can do that is that they produce a protein called protein kinase G. And this goes through phagosome or mandray into the cytosol of the macrophage. And it prevents diffusion of the phagosome with a lysosome. So instead of being tied to the lysosome and being degraded, they stay in the phagosome. So you've got a very nice home inside the macrophage. Now we do have a phagosome against it. ECG, still has to come back. We're on. This isn't new. It was made over 100 years ago. That's not a tie for this. That's not 2021. That's 1921. And it comes from a type of sugar-closet that infects cattle. So this was altered in the lab to make it non-infectious to attenuate it. So it wasn't dangerous. It doesn't matter where the birth is. This culture, for many years, became non-infectious. Then it could be used as a vaccine to inject it and then form antibodies against it. And they protect you from the human fault of the bacteria causing sugar-closets. Now unfortunately, it's not very good. It's partially affected in children, but not very effective in adults. So we need a new vaccine to get it to you. It's about time that we got one over 100 years ago. This one was made. Just said that. It's not the treatment of these antibiotics. For instance, rhythmisin, acidisin. For at least six months. This is the case where it's not just for a few days. Because this bacteria is high in the cytoplasm. It's difficult to get out. So you have to take these antibiotics, a number of them, not just the number. For six months. If you're living in a developing country, you don't have much money. You can't afford the drugs. So you may buy the drug for a short time. The disease may die down. Then you stop taking it. Then it comes back and that spreads to the people. This is the real problem with TB. Because you need to take the antibiotics for so long. And people can't afford it in developing countries. So multiple resistance is developing. So some of these bacteria, they're not killed by any antibiotic. So that is really thrive. Any questions about TB? Okay, we'll come on to fungi. Fungi. Fungi are useful. The cost pay, decay, dead matter, animal or plant. The worth of fungi will be knee deep in dead matter by now. So like bacteria, some bacteria, the fungi will break down, dead organisms. But they can infect us. But they're free in nature or in soil. Normally, there's only minor damage afterwards, photovolta and so on. They sometimes can be serious, even theta. Now the fungi, they don't want to kill us. We don't produce any toxin that we often react to. And our reaction to the fungi actually causes a serious problem in the big microbe. This is heartless sensitivity, which is the problem. I think the immune system goes too far. The HIV, this can be a problem. You've got drugs against it. It's a connoisseur. It's one of them. That's just a patch of fungi on the skin. Let me come on to cystic fibrosis. Now this is the commonest leaf of recessive disease in Caucasians. There's recessive in two fat alleles, one from the mother and one from the father to get it. This is also recessive. It's just about one in two and a half thousand people, so it's not all that uncommon. One in 25 that carries just one fat allele. This one's working well, you're okay. And that one in 25 has one fat allele. So probably some of you are carried. No problems. They couldn't pass it on to your children, if you marry someone who's also got one fat allele. There's a screening program for it in the UK, and you've got babies. And it's due to a mutation, what's called CFTR gene cystic fibrosis transmembrane conductance regulator, which is a bit of a mouthful. It transports chloride ions across the plasma membrane. And there's been a lot of mutations described in it, about 2,000 of them, maybe more. So it causes chloride channels. And it's in the epithelium of the airways, not elsewhere, not just in the lungs, elsewhere. And this is activated by cyclic AMP. So what happens is that in cystic fibrosis, you've got the two bad alleles, and this chloride channel can't work. You can't transport chloride ions from the cytosol into the mucus, the inside of the airways. Now, when you do that, transport out the chloride, water goes with it by the samosas. So the mucus becomes more thin. It's easier to move, less fiscus. So the silicon, trying to out the lungs, into the throat to be swallowed. In cystic fibrosis, there's two little chlorides, two little water, and it's just too thick, two fiscus. So the mucus accuments in the lungs. And that can cause bacteria to stick to the mucus and get infections. Just set that. So get these chronic infections of inflammation. It's very first of all, of course. And the key thing is your dietary respiratory failure. Now, the life expects the use to be about 30 years. It can now be over 50 years. Just set it up. The most horrible thing to die from is spiritual failure. But the chloride channel's seen at the organs as well, like the liver. It can cause liver cirrhosis, collagen being laid down in the liver. Sulfur in the intestines and pancreas. The treatment is physiotherapy to try and get the mucus out of the lungs, which is time consuming. Nucleitics. To make the mucus less fiscus, like in acetyl cysteine, the S-H group. Dr.

Ryberg's. Because when the cells die, they lose their DNA, which actually is a fairly large molecule. And it can make the mucus more fiscus. So you can break that with DNA. The mucus can come some more away. There has been a major breakthrough in the past six years. These drugs have been developed. Lumicaftor. Iforcaftor. Now, lumicaftor refers to misfolding of this chloride channel. But it's synthesized. Of course, this is one of the major mutations. The protein is made that misfolds. Guess the plus membrane doesn't work. But this drug will protect this misfolding. So guess the plus membrane can work. Notice other drugs can open the channel with the plus membrane. Guess where it should be. The base opened up, and it can transfer chloride out. But it's only effective in people with a certain mutation. It's about half the people with cystic fibrosis benefit greatly from this drug. They only transform their lives. The other half, they get in a better place. Because they've got different mutations. This has been a major breakthrough. The treatment of antibiotics. Because it's found that the tissues, the panorhism works so well. So you may get the panorhism enzymes. Lum transplantation is not a possibility. It's a good target for gene therapy. I've seen that now as well too. You only need about five to ten percent of the channel activity to be okay. So you need to get all the normal proteins back. All the normal genes. The lifetime is about four months. So you don't need to get the gene therapy about three or four times a year. You can use adenophalases to do it. But clearly it didn't work. So you see adenophalases to get the gene into cells. It didn't work because the actual virus caused inflammation. It only got a small amount in any way. Adeno-associated virus was dried. There was less inflammation.

It didn't work. You can use light service on the DNA to try and get the gene in. They caused fusion of the plasma membrane and the DNA go the same. Got the gene into the airways. It gave influence-like symptoms, something to work. So gene therapy for cystic fibrosis has been disappointing so far. This works for a few other diseases. But not in cystic fibrosis. This is the final thing. Ambulism is common. There's fellow men in people in hospital in bed not moving about. Also long-haul flights. It's the most common cause. Preferable hospital. Jeff's. Jeff's caused by being in hospital, I should say. What happens is that we get a thrombosis blood clotting from the deep veins of the leg. The thrombosis swept away from the legs into the right part of the heart, then into the lungs. And lots of problem in archery, which isn't good. Too little short of oxygen. Sometimes symptoms of silence, more difficult breathing, dyspnea, chest pain. You can confirm that it's called the deep down of blood test, which detects thrombosis and ultrasound blood. CT scan. That's a CT scan, that's a formulae. Archery, which is blocked by an embolus. The treatment is by hetring, or the prevention is by hetring, to try and stop the blood from thrombosing. More of them will do the same, more of these, they're shown in the degree. That's prevention for the treatment, use of psychometric therapy. Use of a drug called tissue type, that's known as an activator, or multiplex. And this will do what the plasmidic activator normally does. Because this will convert plasmidicin into plasmid. And the plasmid will degrade the thrombin in the embolus and dissolve it. Again, more of this wrote in the module. And those are the references, and I finished just in time. So you're free to go to your