Transcription
At the beginning of the lecture, we talked about disease as a process, its ethology and its pathogenesis. But now, let's go one step deeper right to where disease actually begins. And that is the cellular level.
No matter what the ethological factor is, whether it's an infection, a toxin, hypoxia, trauma, or an autoimmune reaction, the first thing that detects and has to respond to it is the cell. When something happens, a cell essentially has two main possible directions. The first one is adaption. The cell tries to adjust to the new conditions and survive and sometimes it succeeds. The second possibility is injury. If the stress is too great, the cell begins to suffer and this can ultimately lead to cell death. To a large extent, the entire course of pathophysiology is built around these two fundamental mechanisms.
Now let's go through these adaption mechanisms step by step. So when a cell is exposed to increased stress or a hostile environment, it doesn't immediately die. The first response is adaption. The cell tries to change in a way that allows it to continue functioning under these new conditions. It's important to remember that adaption is reversible and in some cases it's even physiologically normal. So not everything we are discussing here is necessarily pathological. Now let's take a closer look at the different types of adaption one by one.
So first hypertrophy. Not everything we're talking about is pathological. By definition, hyper means increased, enlarged. You know that already. Hypertrophy refers to an increase in cell size. As a result, the tissue and often the whole organ also increases in size. This increase is usually a response to an increased functional demand or workload rather than simply an excess of nutrients. Although the word trophy is here so trophic means connected with feeding or feeding demands. So the cell adapts by producing more structural and functional components allowing it to handle the stress.
Stress can occur as part of physiological processes. As I told you, not always everything is pathological, but of course it can also be pathological. In either case, some form of stress acts on the cell and the cell response by enlarging. A classic example of physiological hypertrophy is skeletal muscle growth during regular physical exercise. When muscles are subjected to greater workload than they are accustomed to, muscle cells begin producing more contractile proteins mainly actin and meosin. As a result, the muscle increases in size and becomes better in performing the required function.
On the other hand, in pathological hypertrophy, classical example is left ventricular hypertrophy. In case of hypertension, when blood pressure is elevated, the heart has to pump against higher resistance. To compensate, cardiammyioytes increase in size, allowing them to generate more force. One important point to add, hypertrophy can occur on its own, but sometimes it appears together with hyperplasia, which we'll discuss next. However, pure hypertrophy typically occurs in tissues where cells cannot divide. So, this is important to write it down. For example, in the heart, cardiammyioytes have a very limited capacity to proliferate. And in skeletal muscle where the muscle fibers also do not significantly replicate mainly only hyperplasia happens. So in these tissues adaption mainly happens by increasing cell size rather than the next increasing cell number and increasing cell number is hyperplasia.
So hyper again means excessive or too much and plasia refers to formation of growth. So hyperplasia literally means increased growth or more precisely an increase in the number of cells. So this is important. An increase in cell number can only occur in tissues where cells are actually capable of dividing. So cells that cannot divide because they no longer have a functional stem cell pool. These cells are not able to undergo hyperplasia. And here I have some examples. These include the cardiomyioytes as I told you earlier fully differentiated skeletal muscle fibers and also neurons.
Just like hypertrophy, hyperplasia can either be physiological or pathological. For physiological examples, think of the enlargement of the female breast during pregnancy where glandular tissue increases in response to hormonal stimulation. Another good example is the liver which has a remarkable ability to regenerate after partial resection. So after part of it has been surgically removed.
On the other hand, pathological hyperlasia can be seen for example in benign prostatic hyperplasia in men. In this case, the prostate gland increases in size and as it enlarges, it can compress the urethra and interfere with urine flow. And as I mentioned a bit earlier, in tissues where cells are capable of dividing, that is where there's a functional stem cell population. Hypertrophy and hyperplasia can often occur together as a response to stress. Some examples include the uterus, bone tissue, the liver, and the skin. And here by this picture, I mean the skin as an organ, and not just the hand here that's drawn. A very typical example where both hypertrophy and hyperplasia occur simultaneously as part of physiological response to stress is pregnancy. During pregnancy, the uterus enlarges significantly. And this happens through a combination of both hypertrophy, meaning an increase in cell size, and hyperplasia, meaning an increase in cell number.
All right, let's move on. Atrophy. I think the term itself is fairly self-explanatory. At the cellular level, atrophy refers to a decrease in cell size, a decrease in function or both decrease in cell size and function. And naturally, if the individual cells shrink or lose function, the organ they make up will also decrease in size and functional capacity.
A very classic example is skeletal muscle atrophy, muscle fiber shrink after prolonged disuse. I've included an example of astronauts, but in real clinical practice, you're much more likely to see patients who aren't astronauts, of course, but rather individuals who have been bedridden for a long time or required to stay immobile. In any case, after immobilization, muscles lose protein content, decrease in size, and their functionality declines. The good news is however is that in such cases the process is often reversible. With rehabilitation and physical exercise muscle mass and function can largely be restored.
There are also other types of atrophy of course for example the nervation atrophy when the nerve supply to a muscle is lost. In this case, the process is much less reversible because the muscle no longer receives the signals it needs to function. Atrophy can also occur due to aging as well as due to decreased hormone levels. For instance, in older age, we can observe brain atrophy, not always of course, but sometimes where the thickness of the cerebral cortex decreases.
And finally, there are also physiological examples. One classic case is the involution of the thymus. As a person grows, the thymus gradually shrinks. And in this context, its earlier role, particularly its involvement in development processes of the immune system is no longer as critical in the same way. So the gland decreases in size, its cells undergo atrophy and its function diminishes significantly.
And finally, metiplasia which I already mentioned in the introduction. Metiplasia is the replacement of one differentiated cell type with another. Let me give you a classic example. The respiratory epithelium in smokers. So normally the respiratory tract is lined with pseudoratified siliated columner epithelium. But under the influence of smoking, this epithelium is gradually replaced by stratified squamus epithelium. On one hand, this change provides some protection. The new epithelium is more resistant to the harmful substances inhaled with cigarette smoke. However, it comes at a cost. It reduces mucus clearance, disrupts the siliary function and if the irritation continues, it also increases the risk of cancer. So metablasia is an adaptive response. But in the long term, it can become a risk factor for more serious pathology. Importantly, like most adaptive processes, metablasia is usually reversible if the harmful stimulus is removed.
And with that we covered the main types of cellular adaption. Now let's move on to the mechanisms of cell injury. There are several but we'll focus on three major ones that typically lead to unplanned cell injury. That is injury caused by stress rather than programmed processes. As we said before, when adaption is no longer possible, the cell begins to suffer and this is where injury starts. Cell injury can be reversible or irreversible. Irreversible injury of course ultimately leads to cell death. So let's go through the three main mechanisms here.
ATP depletion. The cell is completely dependent on ATP. Any condition that reduces ATP production such as hypoxia, eskemia or mitochondrial damage will cause ATP levels to drop. And ATP is essentially the cell's energy supply. When it becomes insufficient, several clinical processes fail. For example, the sodium potassium pump, one of the key active transport mechanisms in the cell membrane. This pump stops working and as a result, the cell begins to swell due to water influx. Protein synthesis decreases and cell membranes and organels start to break down. This is often one of the earliest signs that the cell can no longer maintain its internal balance, its homeostasis.
The second mechanism is the disruption of calcium balance across the cell membrane. Normally, calcium concentration is much higher outside the cell than inside. Within the cell, calcium is tightly regulated and stored mainly in the endopplasmic reticulum and mitochondria. However, if the cell membrane or these organels mentioned are damaged, calcium floods into the cytoplasm. Now, calcium is essential for many normal processes, muscle contraction, nerve signal transmission and so on. But in excessive amounts, it becomes highly destructive. Elevated intercellular calcium activates enzymes such as proteases which damage the cytokeleton, phospholipases which destroy cell membranes, endoucleases which damage DNA. So simply an overload of calcium ions can trigger widespread and irreversible cellular damage.
And lastly, the third key mechanism is damage to cell membranes, including both the plasma membrane and the membranes of organels like mitochondria. And this collides a little bit with the previous topic of calcium, of course, because both here are very connected. So when membrane damage becomes severe, the cell is essentially no longer viable. If the damage is too extensive to repair, if the membrane can no longer seal itself, so to speak, the cell will inevitably die. As we already mentioned, membrane damage also worsens calcium influx, creating a kind of vicious cycle where these mechanisms reinforce each other.
So, these processes rarely occur in isolation. They usually happen together and amplify one another especially under severe stress conditions. So the key idea is this. The cell is the central unit where every disease process begins. If the stress is moderate, the cell can adapt. It can hypertrophy, undergo hyperplasia, change its type or reduce its activity. But if the stress is too great, injury occurs. And if the injury is severe enough, the cell dies. In this course, we'll mostly be focusing on nonprogrammed cell death, that is pathological cell injury. But next, we'll go into more detail about the different types of cell injury and death. And ultimately understanding these detailed mechanisms is what allows us to make sense of everything else in pathology from atherosclerosis and inflammation to tumors and organ failure.
So we already talked quite a bit about cell adaptation mechanisms. So cell life. But now let's move on and talk about cell death. We should start by saying that all cells can undergo death. Here for example we see a dying luccoside. Cell death can be broadly divided into two major types. Necrosis and apoptosis.
Necrosis is unplanned. In this case, cells die as a result of injury. You could compare it at the level of a whole organism to a person dying in an accident or due to trauma. It's sudden, uncontrolled, and definitely not planned. Apoptosis, on the other hand, is the natural programmed form of cell death. It's encoded in the cell's DNA. Essentially, the cell already contains the instructions for when and how it should die when the appropriate signal is triggered. You could say the cell initiates its own death. Almost like it's a controlled self-destruction. But unlike necrosis, this is a highly regulated and orderly process. So the key difference here is necrosis is accidental and uncontrolled while apoptosis is intentional and precisely regulated.
Necrosis occurs for example in the case of mechanical injury but also with physical damage such as burns from high temperatures, ultraviolet radiation from the sun or ionizing radiation. It can also result from chemical injuries as well as from lack of nutrients or oxygen. So this is not something the cell plans in any case it's the result of harmful external or internal conditions and I didn't mention also pathogens here viruses bacteria fungi protozoa and so on that can damage and kill human cells.
So what actually happens during necrosis? One of the key events is the disruption of the cell plasma membrane. Once that membrane integrity is lost, calcium ions flood into the cell. So as mentioned before, normally calcium levels inside the cell are kept very low while outside the cell they are very much higher. And this gradient is tightly controlled by active transport mechanisms. Calcium does enter the cell when needed. For example, in muscle cells during contraction, but that's under normal conditions. During necrosis, however, this control is lost. The uncontrolled influx of calcium significantly accelerates cell damage and ultimately contributes to the cell's death. And it is also important to understand that necrosis doesn't occur with just any minor damage. It typically requires significant injury. If the damage at the cellular level is small, let's say there's a tiny disruption in the plasma membrane, this happens on such a microscopic scale that we wouldn't even be able to detect it directly. In these cases, the cell can actually repair itself. Stress signals are activated almost immediately and components of the Golgi apparatus can move toward the site of injury. The GGI complex consists of membrane structures as you see here in the picture and these membranes can be used to patch or receal small defects in the plasma membrane. So if the damage is minor the cell can compensate and recover and necrosis of course does not occur.
But what actually happens during necrosis if it does occur? Let's walk through it. We'll start with normal healthy cell. Then some kind of injury happens. For example, the skin is exposed to hot water or another damaging factor. The first thing that you'll see here is the swelling of the cell. The cell increases in size and the mitochondria also swell significantly. So through the damaged areas of the membrane, calcium enters the cell of course as mentioned before and it activates a range of intracellular enzymes. These enzymes begin to break down key cellular components like they degrade the cell membrane more. They break down proteins, they damage the nuclear membrane and eventually they destroy the DNA and RNA inside the nucleus. So little by little everything inside the cell is being degraded. So the plasma membrane itself becomes increasingly damaged. Small ruptures and holes start to form and eventually there are big ruptures and holes and finally the membrane can no longer hold its structure and it ruptures completely. All the cellular contents at this point including nonfunctional organels are then released into the surrounding tissue and at this point the cell is of course dead.
Now the second type is programmed cell death known as apoptosis. This is when at a certain point the DNA within the cell's nucleus essentially signals that it's time for the cell to undergo what we might call cell suicide. This is a fully programmed process. In contrast to necrosis, the cell does not rupture. Instead, during apoptosis, the cell breaks apart into smaller fragments. Each of these fragments is enclosed within its own piece of plasma membrane. These fragments, often called apoptoic bodies, can then be taken up by other cells in the body. Neighboring healthy cells, can engulf them through endoccytosis. What this means is that cellular components, organels, enzymes, proteins can actually be recycled. Nothing is really wasted. It's a clean, efficient process.
We can even observe apoptosis in normal biological development. For example, during the transformation of a tadpole into a frog. The tail is gradually broken down and its components are reused throughout the organism. In humans, apoptosis is especially important during embryionic development. Early on, the developing hand doesn't have separated fingers. As you see, they're connected by tissue. Apoptosis occurs between the fingers, removing those cells and forming five distinct digits. So, apoptosis is not only normal, it's essential. In fact, it's a beneficial process. If apoptosis is reduced or impaired, it can lead to serious problems. For example, insufficient apoptosis allows damaged or abnormal cells to survive, which then can contribute to tumor development.
And here you can see a schematic representation of apoptosis. What is important is that the structure of the organels is preserved. The mitochondria, for example, do not swell or become dysfunctional. they remain intact and functional. The entire cell simply breaks apart including the nucleus. This process is often referred to as fragmentation. The cell divides into smaller membrane bound pieces or fragments. And that's the key point here. All these fragments are still enclosed by membranes. So everything remains contained. Each fragment is essentially wrapped. Because of that, these fragments then can be taken up and reused by neighboring cells for their own needs.
Another very important difference, apoptosis does not trigger inflammation. In contrast, necrosis definitely leads to an inflammatory response and wherever there is inflammation, you will always find lucasytes involved. But in apoptosis that doesn't happen. Since it's a normal programmed process, everything proceeds quietly. Cells fragment and the fragments are gradually taken up by other cells without causing damage to the surrounding tissue.
And here you can see the comparison. Once again, apoptosis usually occurs as a normal programmed process, most often physiological, although it can also be triggered in pathological situations. For example, the cell may simply age or it may be programmed to die earlier if it has been slightly damaged, for instance, by microorganisms. Necrosis, on the other hand, is always the result of pathological processes. Another key difference, apoptosis typically affects an individual cell. It happens in isolation. neighboring cells are not affected and the organism as a whole usually doesn't even well let's say notice it. In contrast, necrosis affects groups of cells. Multiple cells are damaged at once and this leads to visible or clinically noticeable injury and consequences.
There are also differences in energy use. Apoptosis requires energy. The cell actively uses ATP to carefully dismantle itself into small membranebound fragments so that its components can be reused. Necrosis does not require energy. It's a passive destructive process and the cellular components are not preserved for reuse. Morphologically the processes are very different. As you remember in apoptosis the cell shrinks or rather undergoes this fragmentation into smaller pieces. In necrosis the cell swells and eventually ruptures. In apoptosis the plasma membrane remains intact. In necrosis the membrane's integrity is completely lost. In apoptosis all organals including lizosomes remain intact. In necrosis, lizooal membranes break down and that means these organels are releasing enzymes that digest the cell from within. And as you know, apoptosis is tightly regulated with its mechanisms encoded in the cell's DNA. But necrosis is an unregulated process and occurs as a direct consequence of damage.
And finally, what happens afterward? In apoptosis, the cell fragments are taken up by neighboring cells and reused, making the process so efficient and clean as we discussed. But in necrosis, the released cellular contents cannot be reused. Instead, they trigger inflammation and luccoytes come to clear the debris and destroy what remains. And here we'll be talking about neutrfils and afterwards also macrofasages. So to summarize in one line, apoptosis is controlled, clean and beneficial. Necrosis is uncontrolled, destructive and inflammatory. And lastly, here you can see an illustration of this as well. For example, here we have living cells. In this case, we see programmed cell death, apoptosis, especially here, we see the cell neatly breaking down into smaller fragments. And uh lastly here in contrast we see necrosis a cell undergoing unplanned death. It doesn't divide into smaller pieces. Instead it simply breaks down in a disorganized uncontrolled way.