Transcription
Now, we have reached one of the most fundamental processes in pathology: inflammation.
Inflammation is a protective response of the body. Its purpose is not to damage the body, but to eliminate the cause of injury, remove damaged cells, and initiate tissue repair. It is a vital mechanism because without inflammation, we would not be able to heal wounds, fight infections, or restore damaged tissues.
However, it is important to understand that the same processes that protect us can also become harmful. For example, we will later discuss autoimmune diseases and conditions such as asthma where inflammation becomes excessive or uncontrolled.
Today, we will look at two main types of inflammation, acute and chronic, and the mechanisms behind them.
Inflammation usually begins in response to a stimulus such as a pathogen. However, it is not always caused by infection. It can also be triggered by factors such as toxins or physical injury. For instance, after intense exercise, muscle soreness is partly due to inflammation, which helps repair overloaded muscle fibers. In this case, no infectious agent is involved.
Ultimately, the goal of inflammation is to respond to a stimulus and restore homeostasis in the body. This process often includes eliminating the cause of damage, removing necrotic or dead cells, and initiating tissue repair.
So, what exactly is inflammation? The concept of inflammation was already described by ancient Roman physicians who identified the classic signs of inflammation, many of which are still relevant today. They described five key features, and those five key features are as follows.
The first is calor or heat, which we can describe nowadays as increased body temperature. The second is dolor, meaning pain. So, inflammation brings also pain. The third is rubor or redness, which we also often see in an inflamed spot or place. The fourth is tumor, which refers to swelling, not exactly a tumor, so it's swelling of the inflamed place. And the fifth sign is often considered a result of the previous four and is called functio laesa, meaning loss or impairment of function. As you can see, these classical signs are still used today to recognize inflammation.
And as mentioned before, inflammation can generally be divided into two main types, acute and chronic. And we'll start with acute inflammation. This is a rapid and short-term response to tissue damage, and its main goal is to quickly deliver immune cells to the site of injury, along with fluids, proteins, and inflammatory mediators. Together, these components help to limit and eliminate the cause of damage, if possible, of course. However, if the cause cannot be removed, acute inflammation may progress into chronic inflammation.
During acute inflammation, several important processes take place, which we will now look at in more detail.
First, the blood vessels react. One of the key changes is vasodilation, meaning widening of blood vessels, as you know. This process is mainly caused by histamine, although other inflammatory mediators are also involved. But this one, histamine, will be probably the most important one. As a result of local vasodilation, more blood flows to the affected area, which leads then to the typical signs of redness and warmth or heat.
Along with vasodilation, there is also an increase in vascular permeability, mainly in the capillaries. The endothelial cells, as you see here, begin to separate slightly from one another, creating small gaps between them. Through these gaps, plasma leaks out of the bloodstream, of course, into the surrounding tissues. While earlier the redness was caused by increased blood flow, this fluid leakage leads to another key sign of inflammation, swelling or edema.
As plasma leaves the capillaries, the blood that remains becomes more concentrated, which increases its viscosity. At the same time, the endothelium starts expressing adhesion molecules, which you see here as little hooks, and these allow immune cells to attach to the vessel wall. Among these cells, neutrophils are especially important. They are attracted not only by the signals from the body, but also by substances released from microbes, if there are some microbes that caused the inflammation. And this is why neutrophils are usually the first leukocytes to arrive at the site of inflammation.
First, they attach to the endothelium because of these adhesion molecules, and then, thanks to these gaps that we have between epithelial cells, they move out of blood vessels into the surrounding tissue. This next step is the migration of neutrophils to the site of inflammation. The presence of neutrophils is actually one of the key features that characterizes acute inflammation.
Once neutrophils arrive, they act very quickly, almost like vacuum cleaners engulfing pathogens and other unwanted debris. So, this process is, of course, called phagocytosis, and it is one of their main functions, so main functions of neutrophils. Their movement toward the site of inflammation is guided by inflammatory mediators following what is known as a chemical gradient.
After carrying out phagocytosis, neutrophils eventually reach their capacity, they become filled with cellular debris and microorganisms, and at that point, they undergo apoptosis or programmed cell death in which the cell breaks down and is removed. So, what you see here is this fragmentation we talked about already in the previous section.
Now, speaking about inflammatory mediators involved in this process, let's name some of the most important ones. As I already mentioned, histamine is one of the key mediators here. In general, inflammation is regulated by a whole range of mediators. These are chemical signals that act like a coordinated system, almost like an organized army, activating processes, attracting cells, and causing changes in the body.
First of all, histamine is mainly released from mast cells, but also from basophils and platelets. Now, a brief clarification: what are mast cells? Mast cells, you see here in this picture, these are tissue-resident leukocytes. Unlike basophils, they are not found in the bloodstream, but are located directly in tissues, for example, in the skin, mucous membranes, and around small blood vessels. Their cytoplasm contains basophilic granules, which makes them somewhat similar, actually, in structure to basophils. It is believed that mast cells and basophils originate from a common precursor, although the exact differentiation pathway is still not entirely clear, and that's why mast cells were not discussed in hematopoiesis. In any case, mast cells are structurally similar to basophils, although their nucleus, as you see, is typically more rounded. What is important is that mast cells are always located in tissues and not circulating in the blood. These cells are capable of releasing a wide variety of substances involved in inflammation, which is why they are most often discussed in the context of inflammatory processes. Histamine, as I mentioned earlier, causes vasodilation and increases vascular permeability, making it one of the most important inflammatory mediators.
Next, we have prostaglandins. These are also produced by mast cells, but in reality, many different types of cells can produce them. Prostaglandins are responsible for pain and fever, and they are also targets of nonsteroidal anti-inflammatory drugs, such as ibuprofen, aspirin, and diclofenac, which reduce these symptoms.
Next, we have leukotrienes, which are also mainly released from mast cells again, although other leukocytes can produce them in smaller amounts. Thus, you have the name leukotrienes. Leukotrienes are particularly important in asthma, because they can cause bronchospasm and also increase vascular permeability.
Next, we have cytokines, especially tumor necrosis factor alpha and interleukins. These are mainly produced by macrophages, as you already know, but also by other cells, such as T lymphocytes, say, mast cells, endothelial cells, and fibroblasts. Fibroblasts are the main cells of connective tissue and responsible for producing its components, including collagen. But, as you can see here, they also can produce cytokines. Cytokines play a key role in activating the endothelium, attracting additional immune cells, and also inducing fever.
And finally, there's the complement system, which is already present in the blood. When activated, most often through the classical pathway in response to antigens, it helps to destroy bacterial membranes, effectively lysing the bacteria. It also enhances phagocytosis of other cells, making it easier for leukocytes to eliminate pathogens.
As mentioned, some of these mediators also contribute to the development of fever. And how does this work? Well, in this case, the thermoregulatory center is directly affected. First of all, fever is a systemic manifestation of inflammation. This means that the inflammatory process is no longer limited to a small local area, but has spread more widely throughout the body. The main mediators responsible for fever are interleukin 6, also interleukin 1, as stated here, and tumor necrosis factor alpha. These cytokines act on the hypothalamus directly, where the body's thermoregulation center is located. Under normal conditions, this center maintains a stable internal temperature, what we call a set point. However, these cytokines raise the set point, and as a result, the body starts producing more heat, leading to an increase in body temperature.
But, what's the purpose of this? So, fever actually has a protective role. It slows down the growth of pathogens. And for some microorganisms, high temperatures can even be lethal. Historically, before antibiotics were available, this effect was even used therapeutically. For example, in the treatment of syphilis, patients were sometimes deliberately infected with milder forms of malaria because malaria causes very high fevers up to 40 to 41° C. At such high temperatures, the syphilis bacteria could be destroyed. Although this method could be effective, it also is very risky, of course, since the patient could die from malaria itself. However, at that time, severe complications of untreated syphilis, such as brain damage and organ failure, were also life-threatening. So, this approach was sometimes used.
Overall, fever can be seen as a protective mechanism that helps the body fight infections. In addition, higher body temperature activates the immune system, so further supporting the body's defensive response. So, overall, a fever can be considered a good thing, of course, still up to a certain point.
However, if the inflammatory response is prolonged, if acute inflammation fails to eliminate the cause of damage, it progresses into chronic inflammation. Chronic inflammation is characterized by a different set of immune cells. So, while acute inflammation is dominated by neutrophils, chronic inflammation is mainly associated with lymphocytes and macrophages. This is because neutrophils have a relatively short lifespan. They perform phagocytosis and quickly undergo cell death. In contrast, monocytes or macrophages are more durable and can survive longer in tissues. And lymphocytes, on the other hand, respond more slowly than neutrophils and are recruited to the site of inflammation later, acting as more specialized cells. For example, they are responsible for tasks such as antibody production. In this sense, lymphocytes and macrophages can be seen as the main regulators or directors, if you want to say so, of chronic inflammation.
Macrophages continue to perform phagocytosis, including the removal of necrotic tissue, which is often present in chronic inflammation, and they also continue to release cytokines and activate lymphocytes. Regarding lymphocytes, there are two main types, as you know, T cells and B cells. T cells help regulate the immune response and release additional cytokines, while B cells differentiate into plasma cells and produce antibodies.
In addition to tissue destruction, chronic inflammation may also lead to fibrosis. This means the damaged areas are replaced by connective tissue, which helps close and stabilize the injury. However, although this is an effective repair mechanism, it is functionally disadvantageous, because the replaced area can no longer perform its original function. Once fibrosis develops, normal tissue usually does not regenerate in that specific area. And finally, chronic inflammation can also lead to the formation of granulomas, although not in all cases. Overall, chronic inflammation reflects a situation where the immune system is overloaded or unable to resolve the underlying problem.
Now, and although you won't become pathologists, it is still useful to briefly look at what chronic inflammation looks like in tissues. In the first image here, I have highlighted monocytes in yellow. As you can see, these are relatively large cells that clearly stand out from the surrounding cells. Their presence is a strong indicator that inflammation has progressed to the chronic stage. In green, I have marked also a group of neutrophils. It is important to understand that neutrophils do not completely disappear in chronic inflammation. They are still present. However, their role becomes less dominant and their functions are largely taken over by macrophages. By this stage, many neutrophils have already performed their function and reached the end of their lifespan.
In the second image, we can again see macrophages, and this image of a macrophage is particularly interesting because it shows a macrophage that has phagocytosed two neutrophils. Normally, neutrophils undergo apoptosis, as I said, and are later broken down, but sometimes macrophages engulf them even before that process is fully completed. Additionally, in such histological samples, you may also see reddish or brownish macrophages, and this indicates that the macrophage has phagocytosed erythrocytes, and the color comes from hemoglobin. So, that's why they are reddish or brownish. And by the way, all these pinkish structures here in these pictures, the large pink structures you see here are blood vessels.
So, in addition to macrophages, another key cell type present here is lymphocytes. So, we see them here and here and here. And basically, overall, these can be recognized as smaller, darker cells. They appear dark because they have a large nucleus that takes up most of the cell, leaving very little cytoplasm. In fact, most of the small dark structures you see in both images are lymphocytes. So, this gives you a general overview of how chronic inflammation appears at the tissue level.
So, this was just a brief overview. Earlier, I mentioned granulomas, and let's now look at what a granuloma is. So, it is a special form of chronic inflammation, and it represents the body's attempt to isolate something it cannot eliminate. The main coordinating cells here are still macrophages and lymphocytes. Imagine that there's a cluster of bacteria or some other persistent foreign material. The body responds by forming a kind of wall around it made up of macrophages and other immune cells. This structure surrounds the pathogen or foreign body that cannot be easily destroyed or digested. A classic example is tuberculosis, where granulomas form in the lungs around clusters of bacteria. Granulomas can also develop in diseases like my, before-mentioned syphilis in the later stages and in certain autoimmune conditions. In this way, the pathogen is prevented from spreading further. However, at the same time, a localized accumulation of immune cells forms. So, essentially, a compact mass composed mainly of macrophages and lymphocytes.
So, inflammation is a precisely regulated protective response that operates in two main modes, acute and chronic. Acute inflammation is fast and effective. It acts quickly to eliminate the cause of damage, and it is essential for survival. When this response is successful, the tissue can recover. On the other hand, if the cause of injury cannot be resolved, the process shifts to chronic inflammation. And chronic inflammation is long-lasting and persistent. And although [clears throat] it is still a defensive mechanism, sadly, it can eventually become destructive to the organism itself.