Cellular Injury Mechanisms PDF

[00:00:01] >> Let's take a look at some of the mechanisms behind cellular injury and how the cells respond to this. I've mentioned the term injurious stimulus or cellular injury on a few different occasions, and there's lots of different types of mechanisms that will cause a cellular injury. So that...

[00:00:01] >> Let's take a look at some of the mechanisms behind cellular injury and how the cells respond to this. I've mentioned the term injurious stimulus or cellular injury on a few different occasions, and there's lots of different types of mechanisms that will cause a cellular injury. So that's what we're going to talk about here. [00:00:24] And it's important to recognize that some of these don't necessarily occur in isolation, a lot of them can all occur at the same time. What we'll start with here is the one that I gave in the earlier example of cell membrane damage. So as an example right here, here's our cell membrane damage. [00:00:45] This might be something that we actually get from weight training. So as you're doing weight training and you're lifting heavy weights and you're lowering them, the cell membrane actually might be getting damaged a little bit with each lift. It might be like a little microscopic damage. And again if it's pretty minor, it might be more of a stressor than an injury. [00:01:07] But if I take that baseball bat and hit the cell again, you're hit a muscle again just as that example, that's going to cause membrane damage. And so the point here is that, plasma membrane has an important function to it. It's going to help regulate what's going in and out of the cell. [00:01:28] And if we damage that membrane somehow, that's going to mean we're not going to be able to regulate what's going in and out of the cell as well. And stuff is going to start leaking out, and stuff that shouldn't be going in might come in. And so that's going to be one potential injurious mechanism. [00:01:46] And so what you could see here is, if we've got the loss of cell components, some stuff might leak out of cells. We might start digesting some stuff in the cells. And again, this is one mechanism of injury is cell membrane damage. So just as as one example, we'll see another type that can happen, and this is protein misfolding or DNA damage. [00:02:16] So think about if somebody has been exposed to radiation for example, where some of these different carcinogens that exist, stuff molecules or chemicals that cause cancer. Why do they cause cancer? Because they're ultimately damaging DNA. So that's an example of some sort of an injurious stimulus. So we could say UV radiation, as an example, or certain chemicals like carcinogens, okay? [00:02:54] So that's what those are going to do, okay? Just as an example, another thing that we can have is we might have a mitochondrial damage. And so what we're going to see here is the mitochondria, as you know the powerhouse of the cell, they're going to be really important. And if for any reason something happens to the mitochondria, if the mitochondria become damaged, that's going to have a whole host of negative effects, and it's going to potentially injure the cell. [00:03:26] So again, mitochondria are responsible for making the ATP inside the cell, and if we have anything that's going to damage the mitochondria, okay, that's going to mean we're not going to be able to make as much ATP. And if we're not making as much ATP, that's what we see here, we see a decrease in ATP. [00:03:45] We don't have the energy to carry out normal cellular functions, and that's what says here by multiple downstream effects. So if we're not able to make as much ATP as we normally would be able to, then other things in the cell aren't going to work. Maybe we're not able to make proteins as well, okay, maybe we can't repair our DNA damage that we have. [00:04:06] Again, there's always going to be some level of DNA damage that's going to be happening, and there's going to be repair that's going to happen. But if we don't have the sufficient ATP to power that process, then that's not going to work. So again, what I'm saying here, just as an example, mitochondrial damage can decrease our ATP levels, and that can lead to other effects, like protein problems and maybe our cell membrane won't be able to be maintained. [00:04:30] Okay, that's what I said before. When these things don't happen in isolation, they can have multiple different effects, that's what I mean by this. So if we damage our mitochondria, can't make ATP, some of these other things might also happen, okay? Okay, the other thing that can happen with mitochondrial damage is this, this increase in ROS. [00:04:49] And so that's going to be a concept we're going to talk about separately in a little bit. And ROS = reactive. Oxygen species that's what ROS means here and that is a fancy term for oxygen-free radicals. And we're going to talk about what that means separately. The point will be this though, that any time that we have mitochondrial damage, it might increase these reactive oxygen species or these oxygen free radicals. [00:05:33] And that will have lots of different effects that will damage our different lipids. Those lipids make our cell membrane, it'll damage our proteins, or damage our DNA. So you can see how this mitochondrial damage can also cause cell membrane damage. It could also cause these things, again, these things can happen by themselves. [00:05:52] The membrane damage, the DNA folding damage, those can happen by themselves. But if we have mitochondrial damage, it can also cause these other things to also happen, okay? One other cellular injury mechanism, that we have, I won't talk about too much here, is this entry of calcium into the cell, okay? [00:06:11] If we get too much calcium into the cell for any reason, that could be because the cell membrane isn't working properly. Or there's some kind of change in the ion channels, or there's just a different diffusion gradient, basically that's going to be another injurious mechanism. You can see it's going to impact mitochondrial permeability, but it's going to also activate multiple different enzymes inside the cell. [00:06:34] A lot of different enzymes are dependent on Cclcium levels, and so it's going to have some downstream effects. But just to go full circle, back in that very first slide, we talked about cell injury and injurious mechanisms. What we're doing here is we're expanding and saying, what are some of those different cell injury mechanisms? [00:06:55] What are those different injurious stimuli and these are some of those examples. So one common clinical cause of cell injury, cell death, potentially organ death potentially whole body death is ischemia. So ischemia whenever we see that term, ischemia this is going to mean insufficient Oxygen delivery, I'm going to write O2 for oxygen, To a tissue. [00:07:36] So ischemia is insufficient oxygen delivery to a tissue. And so you can think about if somebody has a heart attack, there's a big blockage in one of their arteries. And so their cardiac muscle is not getting enough oxygen, so their heart is undergoing ischemia. If somebody has a stroke, there's a clot in a blood vessel in the brain somewhere. [00:07:57] That tissue in the brain that's not getting blood going to it is experiencing ischemia. So those are just some examples of ischemia. So with ischemia what we see here, here is a clot that is stuck in a blood vessel, okay? So that means that the mitochondria isn't getting oxygen to it, so we're not getting enough blood, we're not getting enough oxygen, so the mitochondria can't do its job. [00:08:23] This means it's got less oxidative phosphorylation or energy production, aerobically, so we're going to have less ATP. And ATP is essential to so many different functions in the cell. So now that sodium, potassium pump can't work, and so we have all these other effects. We won't worry about the specifics of what they are, but we will end up with different imbalances in different ions in the cell. [00:08:47] We're going to have more ATP is going to be made anaerobically by glycolysis. So this is going to use up glycogen, it's going to change our pH balance in the cell. A change in pH balance is going to cause further damage in the cell, okay? There's going to be some other issues with ribosomes, and eventually we're going to have less protein synthesis. [00:09:06] So you can see this downstream effect, because we have this one clot here, and now we're not getting oxygen to the mitochondria. We have all these other downstream effects, and that's what this second diagram is showing here. We start off with low oxygen levels and now because we have less ATP coming in, all these different things happen. [00:09:25] We have phospholipids are being lost, lipids are being broken down. Some of the cytoskeleton that's damaged and before you know it, the whole membrane is damaged. And so again, this is just one example of an injurious stimuli all resulting from lack of oxygen going to the tissue. Now we have membrane damage, and as we saw previously, membrane damage is its own form of injury. [00:09:48] So it started off with insufficient oxygen and we'll say, the mitochondria is not doing what it needs to do, so this can't happen. And now we have a second type of cellular injurious stimulus, we've got membrane damage. So all these things compound upon each other. Ultimate way that cells respond to stress can vary, okay? [00:10:14] And so we're going to start by looking at this, this is our normal cells. Here`s four normal, happy, healthy cells. It doesn't matter what kind of cells they are, all in homeostasis. And so the one example that we already talked about is one response to cellular stress is hypertrophy. [00:10:31] So we talked about that with weight training hypertrophy. So anytime you see hyper, that means something is getting bigger or an increase. And anytime you see the word trophy that has something to do with size, so hypertrophy means an increase in cell size. So we start off with four cells, we still have four cells. [00:10:57] But they're all bigger and great example of this is weight training, weight training gives us bigger muscles. We put stress on the cells and now we get bigger muscles as a result of it. The cells themselves are getting bigger, Wwe don't have more of those cells. They're just getting bigger, same thing can happen with obesity. [00:11:17] We, Basically start putting more lipids into the cells, into our adipose cells, and they get bigger. And there's lots of different types of pathological processes which can cause hypertrophy. The opposite of hypertrophy is atrophy, okay? So it's a different type of cell stress and atrophy. Again, we've got that trophy that has something to do with size, a means, usually anytime we see a means without, okay? [00:11:49] So we hear something like acellular that means without cells. Or we hear of an asexual organism or something that produces asexually, it means without sexual reproduction. Anything we see a means without, atrophy, maybe the a doesn't make a whole lot of sense there. It's not like without cells, but it's a shrinking of cells, okay? [00:12:08] So this is the opposite of hypertrophy, the cells shrink. So again, if you have a lot of sedentary behavior, if you're not contracting your muscles, okay? Such as maybe if somebody is in a coma, or somebody has their arm in a cast, or whatever, they're not contracting their muscles. [00:12:25] Or maybe they've got a neurologic disease where they can't contract their muscles, the cells, instead of getting bigger, they're going to get smaller. So that's atrophy but again, you can see it's still the same number of cells. There's still all four, they're just smaller, okay? Another type of response is hyperplasia, anytime you see plasia, that means number of cells. [00:12:53] So hyper, we already said, means increase, and plasia is number of cells. So hyperplasia is an increase in the number of cells. So that could be one response to cellular stress is we might have an increase in the number of cells, or we might even have a combination of both. [00:13:14] We might have hypertrophy and hyperplasia, both the number of cells increase and how big they are, that changes, okay? So that could be another adaptation that happens to stress and then we could also have something called metaplasia. Metaplasia is a different stress response where you can see both we have a change in the number of cells, so there's some hyperplasia involved in this. [00:13:44] So I'll just draw a little line here but the cells also, they don't quite look the same. You can see original cells here were kind of mostly square, but these are starting to be a slightly different change in shape. There's some kind of structural change to the cells, okay? [00:14:01] And that's what metaplasia is. It's like just this in, there's a change in the size, but there's also some a little bit subtle changes in the shape of the cells. And eventually with prolonged cell stress, these can become dysplasia. Where now these cells don't look anything like the original, there's some that might have hypertrophied a little bit. [00:14:21] There's some that have atrophied in size, the cell shapes looks different. And so this is dysplasia here. And so dysplasia is something that you'll hear in terms of like with cancer, you'll hear about dysplastic cells, cancer, there's all these abnormal changes to the tissue and a tumor might be big because there's lots of cells. [00:14:43] So there's that hyperplasia component, but they could also have this dysplasia component too, where the cells don't look anything like the original cells. So that's what we talk about when we talk about dysplasia. This slide is a nice little summary slide that brings a lot of these concepts together it's very similar to that first slide that we had. [00:15:03] We're just weaving in a few extra things here. So anytime we've got stress to the cells of the body, we've got our stress, there's going to be some sort of altered functional demand, okay, in the case of weight training we're putting more stresses upon the muscles. We're requiring greater mechanical stimuli, and maybe we'll be able to adapt and maintain that level of stress. [00:15:27] So maybe this is some sort of adaptation, okay? Or we might have some sort of reversible cell injury, and regardless if it's reversible, we get back to normal so our stress is maintained. And we could have all these possible adaptations to do this change in stress. We might have atrophy, or we might have any of these other things we talked about on the previous slide, hypertrophy, hyperplasia. [00:15:57] Metaplasia or display or dysplasia, but if we remove the stressor, so if we remove whatever was causing the stress, if we get rid of that stimulus, we're probably going to return back to normal. Okay, so again, think about it. If somebody has done a lot of weight training and has had a lot of muscle hypertrophy. [00:16:17] And then they stop training, what's going to happen to the muscles? The muscles are going to get smaller, they're going to go back to normal. If somebody's been doing the opposite, if they've been doing a bunch of sedentary behavior and they've had a lot of atrophy, but now they start getting back to a normal level. [00:16:31] So you had somebody that was in a cast and now you take the cast off and they start moving around again. The cells are going to get back to normal. If there's some sort of other injurious response, some sort of chemical stimulus or ultraviolet radiation or something like that that was causing maybe some metaplasia or dysplasia. [00:16:49] And we take away that stimulus, that stress was removed, we're going to return back to normal function. So again, just a nice little, we talk about some of these different adaptive responses, and we talk about what happens if we are under stress. And then if we move them, a lot of those adaptive responses go away. [00:00:01] >> To understand health and disease, we need to have a strong understanding of, cellular stress, cellular injury, and cellular death, and how all of these relate to one another. Is the general paradigm that will describe how cells respond to stressors placed upon them. So we're going to start off with our normal cell, our normal healthy cell, that is in a state of homeostasis or equilibrium, everything is functioning as normal. [00:00:37] And what could happen is if we can place some sort of stressor upon it, and there's lots of different types of stressors. This could be something like exercise, so if we are lifting weights and contracting our muscles and applying this force onto our muscles, that self is stressful. [00:01:00] And as anybody that's ever lifted weights knows, that stress that we put upon the cell will maybe result in some changes to the cell. In the short term, we might get a little bit sore, we'll talk about that in detail another point, but eventually it's going to lead to adaptation, adaptation is a good thing, okay? [00:01:19] If we've put a lot of stress upon a cell, it's going to to adapt to it, in the case of strength training, we put physical forces upon the cell and eventually we adapt. How do we adapt? By getting bigger muscles, we develop more contractile proteins, so that's one possible thing that we could do. [00:01:38] Stress a cell, and it adapts, and that's good, okay? However, if we place too many stressors upon a cell, before they have a time sufficient, time to adapt, or the cells don't have the resources that they need to fully repair either the cells. Or the extracellular matrix that they surround, if we can't adapt for some reason, then we're going to have an injury, okay? [00:02:09] And an injury is obviously something that there's something bad that has happened, we're either impairing the structure of the cell, or function of the cell, okay? That is in injury, now, we talked about if we put stressors upon the cell and we fail to adapt, or if we just have a downright injurious stimulus. [00:02:32] So, it's one thing if I go and do a bunch of weight training and maybe I do too much fit beyond the ability to adapt. It's a very different thing If I just take a muscle and I hit it with a hammer or baseball bat as hard as I can, that's just going to be blatantly injuring the cells, okay? [00:02:49] So some things are going to be stressors, and some things are going to be injurious stimuli. Either way, we're going to result in an injury in this concept of cell injury. Now, two things can happen from here, we can have a reversible injury. And again, that's going to be mild and transient, transient just means temporary. [00:03:11] And so it reverses, and eventually it gets back together, now it goes back to normal homeostasis. Now again, we have to differentiate between Normal homeostasis and adaptation. If I go and I lift weights, and my muscles are going to adapt to that, and now my muscles are stronger than before, that's adaptation. [00:03:33] If I lift weights, and I'm doing way too much, and over-exerting myself, and I'm not giving my muscles a chance to adapt. Maybe I'm actually not going to have much of an adaption, I'm just going to get injury and eventually it's going to be reversible, and I'm going to go back to my normal healthy self, okay? [00:03:51] Same thing with an injurious stimuli, if I take an injurious stimuli like hitting my muscles with a baseball bat, or something like that, that's not a way to train. We're not going to get bigger muscles by just, clubbing ourselves with a baseball bat. It's just going to cause injury, and best case scenario it's this reversible injury and we go back to as good as we were before. [00:04:12] So again that's something that's important to recognize, stressors will cause adaptation. Injuries, if they're reversible, best case scenario, we go back to where we started, okay? So, that's the difference between, stress that leads to adaptation, versus a reversible injury, a reversible injury just gets us back to where we started. [00:04:32] However, that's in the case of mild and temporary injuries, if we have something that's really severe, and really potentially progressive, that can result in an irreversible injury. The cells structure, and or function, is permanently altered, and so it's irreversible. And from there, we could go down two general pathways, we could have something called necrosis. [00:04:59] Which is one type of cell death, or we could have apoptosis, which is a different type of cell death, okay? Necrosis is going to be a little bit more we'll call it messy, there's going to to be cell membranes, kind of exploding and leaking out stuff. And it's a lot of times it might require some kind of clinical intervention to clean it up. [00:05:27] Apoptosis, you might have heard of it as programmed cell death, where there's going to be a series of events where the cell just kind of it implodes, or self destruction. You think of that way, and it's a little bit cleaner of a phenomenon for lack of a better term, don't get too caught up in the difference between necrosis and apoptosis right now. [00:05:47] Just recognize that they are different types of cell death, and they are going to to come after an irreversible injury. One important factor that's going to determine whether an injury is reversible, and leads back to a normal, healthy, functional cell, back in homeostasis or irreversible is the duration of injury. [00:06:12] And so that's what this figure here shows, on the x-axis, we have duration of injury, and this is just as a general model. This is going to to be different for each type a tissue, it's going to be different for different types of injurious stimuli. So we're not saying that this x axis represents seconds or days or weeks or anything. [00:06:29] It just depends, just kind of tryna share the concept here, and on the y axis here, we've got the magnitude of effect, and so, as an example, we'll talk about something like a crush injury. Imagine that you're going rock climbing, and a boulder falls on your leg and starts to crush the muscles in it. [00:06:54] And you could probably imagine, that if we got a bunch of friends with you, and they see this happen. And they see your muscles get crushed by this boulder, which again, is an unfortunate situation, but it does happen. And if your friends all quickly band together and lift that heavy boulder off of your leg, is your muscle going to be lingered? [00:07:16] Yeah, but if that boulder was only crushing those muscles on your leg, for a few seconds, or maybe even a few minutes. You're probably going to to have something that's a little bit more reversible of a cell injury. However, if this boulder is stuck on your leg for three or five days, you could probably imagine that there's going to to be a lot more damage that's going to to continue to happen during that time period. [00:07:42] And it's going to be an irreversible injury, and so that's an example of how the duration of injury is going to affect the ultimate outcome. If you're able to try to reverse your eliminate injurious stimuli quickly, it has more chances of becoming reversible, if not, it's going to be more likely Irreversible. [00:08:03] Same thing if you think about something like a myocardial infarction, or a heart attack. If the cardiac muscle is starved of oxygen for a few seconds, it might get injured, but it can recover. If it's starved of oxygen for an hour, it's going to be a lot less likely to recover, so that's the idea behind that. [00:08:21] That's the first general idea, of, time is going to to determine if an injury is reversible or irreversible. And then just a little bit more on that, is once we cross this line into irreversible injury. So again, it's going to to be dependent on cell function if we're able to intervene pretty quickly. [00:08:41] So if we're able to intervene, very quickly in the cycle a few seconds or maybe, a few minutes depending on the injurious stimulus, okay? Maybe there's only a slight decrease in cell function, but after a certain period of time. We're going to be getting to a point where the cell function is so far down that the cell is not able to maintain its homeostasis, and it's going to start dying. [00:09:02] And so what this has just meant to show here is that at the early stages of, if you've had an injury that has been long enough to be irreversible, but not necessarily ongoing for a really prolonged time. There might be some sort of biochemical alterations that lead to cell death, and you might not even see any immediate signs of cell death. [00:09:34] But eventually, the longer the injury has gone on, over time, we're going to start seeing changes on electron microscope. And eventually, under a light microscope, you'll see cellular changes, and eventually, if something is really severe and really prolonged, you're going to to see gross morphological changes. So something that's visible to naked eye, and so this is more important from a pathology perspective for a pathologist. [00:09:57] This is going to help give a little bit more of an idea about how long an age Injury took to happen, how severe it was. But again that's just the basic concept of, how cell injuries might be reversible or not and how it's related to the timeline of injury. [00:10:20] This is just meant to be a brief overview of necrosis versus apoptosis, again, these are two different pathways of cell death. And again, just a general overview to get an appreciation, we have with necrosis here's our normal cell. And there's some sort of injury that happens to it, and we'll say it's reversible injury well, then it'll recover. [00:10:44] But if this injury is so severe, there's so much disruption that it's going to happen, then we're going to get to this point of a progressive, irreversible injury. And what you can see in this diagram here, is there's inflammatory cells that come in, we'll talk about inflammatory inventory cells separately in the course. [00:11:03] So there's going to be a lot of inflammation that's going to be happening, and then the cells can be breaking down. There's going to be a bunch of stuff leaking out of it, and it's going to look a very certain way under a microscope, and that's going to be our necrosis. And again, anytime we see inflammation, inflammation is going to a lot of times be associated with some sort of clinical manifestation. [00:11:26] You might there might be some pain, there might be a greater risk of infection. So anytime we've got death by necrosis, it's going to be, for lack of a better word, messier. And we might be more likely to need some kind of clinical intervention to clean it up, okay? [00:11:46] So that's just the idea behind that, if somebody has gone hiking in, mountain climbing or something and gets a gang. And they get frostbite and their fingers or their nose become gangrene, gangrene is one four minute necrosis and that's it's going to have to be treated by somebody. Otherwise, there's going to be a risk of infection, there might be some amputations and stuff that happen. [00:12:08] That's necrosis, it's messy, apoptosis is going to happen, we've got this normal cell. There's some sort of injury that happens to it, and what we see here, again, don't get caught up in the details, but it's going to look different, it's going to look different under a microscope than this. And there's going to to be this whole programming inside the cell, that's going to to be this organized breakdown of the cell. [00:12:33] And eventually, it's going to to come in and be eaten by a phagocyte, which is just one type of immune cell we'll talk about. We'll talk about some macrophages and stuff, a little bit later, so it's going to be some sort of immune system cell that comes and eats it up. [00:12:47] But it's going to be a different immune process than necrosis, okay? And so this is just kind of, you've got the cell breaking itself down kind of, just self destructing itself. But it's not going to have as much leaking out and you've got, a different immune response happening to clean up the debris. [00:13:07] And so a lot of times, the immune system is kind of doing the cleaning up, as a general statement, there's no intervention necessary that's to clean up the mess from cell death. Now that might have some sort of clinical consequences that might need to be addressed, but there's not a mess that's an inflammatory mess that's left behind. [00:13:31] Again, just as a broad general statement of, apoptosis versus necrosis.