Transcription
Fundamentals of Pathology, Chapter 2
This chapter deals with inflammation, inflammatory disorders, and wound healing.
Uh, as a brief introduction, before we even begin the discussion, um, we should remind ourselves, uh, what infl—what inflammation actually is. And, um, maybe the easiest way to do this would be to, uh, to make a simple diagram. So I'm going to create a little space here for that. Um, imagine that this is a blood vessel, and we're well aware of the fact that within blood vessels, um, is flowing inflammatory cells—for example, neutrophils. Also present within blood vessels are lymphocytes, and within blood vessels is fluid and other important proteins. Now, essentially, the goal of inflammation is to take what is in the blood vessel and to put it out here into the tissue space, usually in response to an infection. If the neutrophils are the primary cells that come out of the blood vessel and into the tissue space, we call that acute inflammation; and if the lymphocytes are the primary cells that come out into the tissue space, then we call that chronic inflammation. And that's a very, very simplistic way of looking at inflammation, but I do think that that's the way—that's sort of the global picture that we have to have in mind before we move forward. So let's go back and and and review what's in your text. So we said that inflammation allows inflammatory cells, plasma proteins, and fluid to exit the blood vessel and enter the interstitial space. And and remember that the interstitial space is basically the the tissue space outside of the blood vessel; it's where where the um inflammation is actually occurring. And this can be divided into acute inflammation and chronic inflammation. And again, acute inflammation will be hallmarked by neutrophils, and chronic inflammation by lymphocytes.
So your book—your text then, um, goes into acute inflammation, and that's going to be the next major subtopic. Acute inflammation is characterized by two things: number one, edema; and number two, neutrophils. Now, edema—what we're referring to is fluid that comes from the blood vessels and begins to accumulate within the tissue space, uh, and that's what causes—that's what causes the swelling that we normally see when there is inflammation. And then neutrophils refers to the key inflammatory cell that comes out of the connective tissue—sorry, out of the blood vessel into the connective tissue space—that then defines acute inflammation. Here's a picture of acute inflammation, and it highlights a little bit of what we've uh discussed. First of all, notice that um we are—we are outside of the blood vessel. Here's a blood vessel, and here's a blood vessel, and and the vast majority of what you see on your screen here is actually the uh tissue space. And so we notice that within the tissue space are these multilobated cells, which actually are neutrophils—all of these cells that I'm circling here. And each of these cells—um, the fact that there are neutrophils present indicates that this—that we're dealing with acute inflammation. Now, at the same time, notice that there is this separation—by this sort of white—by this—by this uh white fluid—of the tissue space, and all this separation represents edema, or the fluid that's actually uh building up within the tissue space. And so again, the hallmarks of acute inflammation are um neutrophils along with edema.
So the next important point to be aware of is that acute inflammation arises in response to two important stimuli—again, two important stimuli. The first is infection, and I think we're all well aware of the fact that when there's infection, particularly bacterial infection, one of the key responses is going to be the—is going to be the neutrophilic response, which will then come in and create—which will then come in and destroy the organisms. So I don't think that is so uh important at this particular junction because we were familiar with it. But what perhaps is a little more important is the fact that tissue necrosis is something that leads to acute inflammation, and this is um the second major stimulus of acute inflammation. Now, go back and remind ourselves, uh, from Chapter 1 that there are two types of cell death: the first is necrosis, and the second is apoptosis. And one of the key distinguishing features between necrosis and apoptosis is that necrosis is followed by acute inflammation. This is a very important sort of high-yield point—so that whenever there is tissue necrosis, one of the responses of the body to that necrosis will be to send neutrophils in to destroy the tissue. And once the tissue is destroyed, it will then um kick off the healing and repair uh phases of of um of of sort of wound healing. And and so basically, um, this is important because it's a tissue necrosis is as another mediator of acute inflammation.
Now, uh, some classic examples that we're going to touch on later that you should be familiar with: one of the things that we're going to discuss when we talk about myocardial infarction is a response to the body—what happens 12 hours after an infarction, what happens pathologically 24 hours after an infarction, and um and at that point we're going to learn that 24 hours after an infarction, one of the key hallmarks on a slide is going to be the presence of acute inflammation and neutrophils. Um, another important point clinically here would be that let's say a patient has a myocardial infarction; one of the things that's going to occur with that myocardial infarction will be an increase in the patient's white count, and what the white count will predominantly contain are neutrophils, because neutrophils are being generated and they are being pushed—will then be subsequently pushed off into the um the dead—the dead tissue. So very important to know that tissue necrosis is also a cause of acute inflammation.
What's the goal in each of these um in each of these um circumstances? Well, the goal in the case of infection would be to eliminate the pathogen. So the neutrophils come in; they consume—that's the way by which neutrophils kill—they eat, and they—they eat and then they destroy that which they eat. So they consume and then destroy the pathogen. And in the case of um tissue necrosis, the goal would be to clear the necrotic debris. That's the purpose of the acute inflammation: the neutrophils come in, and then they consume the dead or dying tissue, and then they destroy that tissue so that it can be subsequently cleared so that healing can actually begin.
One of the other important features of acute inflammation is the fact that it is an immediate response—the—it is—is a very quick response of the body—happens basically—the the acute inflammation, once it's kicked off, very quickly fluid begins to build up within the tissue, and within 24 hours the neutrophils have pretty much arrived and and are and are sort of at the peak of their function. And so it's a very, very quick response; it's an immediate response. However, um, at the expense of that quickness is specificity—so that it has a limited specificity. Now—now what I mean by limited specificity is that it's not like the chronic um inflammatory response where you have an—where you have an antibody or a T-cell receptor against a very specific antigen. In this particular case, it's sort of a general—generalized response against the the stimulus; you don't have a very specific attack of a particular antigen. And um it is an example—or basically it is one component of innate immunity. So this requires us to take a step back to understand innate immunity. What is innate immunity? The innate immunity basically includes the the following: it includes the epithelium that covers body surfaces; um, the epithelium protects against infection; it includes the mucus that's secreted by cells, because the mucus layer that's produced by those cells protects against infection; it includes the complement system—the complement system is a series of proteins that are present in an inactive state within the serum but can be activated to generate an inflammatory response; um, and it includes some cells—for example, mast cells, which are widely distributed throughout tissue and can help to activate the immune response; macrophages, which have the ability to consume—consume pathogens and then present them to further the immune response; neutrophils, as we're going to discuss in significant detail what the neutrophils do, but they're part of innate immunity; eosinophils, basophils, etc. So the innate immune system is a—is a broad system that's non-specific that defends the host against um against microbes. And um another way to understand the innate immunity would be to contrast it against adaptive immunity. What is adaptive immunity? It is a specific response, but it takes longer to generate—so it's not as quick—um, and it includes things like—in particular the lymphocytes, which um are—which produce antibodies and have T-cell receptors that are very—that are against a very specific target. So that's innate immunity—the immune system. In particular here, acute inflammation is mediated by several factors, and examiners like to ask questions about these factors, and these factors sort of produce a symphony called acute inflammation. And so it is important to be aware of the individual factors, and we're going to take a little bit of time to go through each of these.
So the first are Toll-like receptors, also called TLRs. And Toll-like—Toll-like receptors are actually present on cells of the innate immune system—for example, macrophages and dendritic cells. And um the Toll receptors, they have the ability to recognize something called PAMPs—PAMPs—pathogen-associated molecular patterns. These are uh patterns of molecules that are present on pathogens, and um they're commonly present on pathogens. And the Toll-like receptors, they recognize these general patterns, and when they see this pattern, they rec—that then lets the body know that there is an invader present within the body, and that turns on the the acute inflammatory response. In this particular case, the classic example—or one of the—one of the very high-yield examples, I should say—is something called CD14. CD14 is a Toll-like receptor, and it is present on the surface of macrophages, and it has the ability to recognize lipopolysaccharide, or LPS. Now, recall—and which is actually important—high-yield—that LPS is on the outer membrane of gram-negative bacteria. So all gram-negative bacteria have LPS on their outer membrane. So LPS is sort of like a PAMP; it's a pathogen-associated molecular pattern, and it is recognized by CD14. When CD14 sees that PAMP, it then activates the immune system, and this again is very high-yield. You do have to know that CD14 is present on macrophages and that it recognizes this PAMP, which is lipopolysaccharide. Once the Toll receptors bind its PAMP, that results in activation, and a signal is sent to the nucleus. And one of the key um proteins—it's a transcription factor that's upregulated—is called NF-κB. Very high-yield. NF-κB is—we can say sort of the molecular switch; it's the on switch. So the Toll-like receptor gets activated, which then results in upregulation of NF-κB, and NF-κB is a molecular switch which turns on the acute inflammatory response. Once NF-κB is generated, that activates multiple immune response genes, which then leads to—to the production of multiple immune mediators. So this becomes very high-yield. Toll-like receptors are also present on cells of adaptive immunity, meaning they're also present on the lymphocytes, and therefore they play an important role in mediating chronic inflammation.
The next of the mediators is arachidonic acid. Arachidonic acid is actually released from the phospholipid cell membrane by phospholipase A2. And once arachidonic acid—it is released, it can be acted on by one of two pathways: there is a cyclooxygenase pathway, and there is a 5-lipoxygenase pathway. Each of these are distinct pathways, and they produce distinct—they generate distinct products. So the cyclooxygenase pathway produces prostaglandin—PG—prostaglandin—that's the key uh derivative of this pathway. And the prostaglandin—the three key prostaglandins are prostaglandin I2, D2, and then prostaglandin E2. And together these three—prostaglandin I2, D2, and E2—they mediate vasodilation, and they mediate increased vascular permeability. Now, vasodilation—it's important to know that the vasodilation occurs at the level of the arteriole, generally speaking. Wherever you're going to hear me talk about vasodilation in this particular discussion, it occurs at the level of the arteriole. And the increased vascular permeability—and the increased vascular permeability—generally speaking, will occur at the postcapillary venule. It's important to know both of these—i.e., that vasodilation occurs at the arteriole and that um increased vascular permeability occurs at the postcapillary venule. In addition, prostaglandin E2 also mediates fever and pain. And the way I remember that is sort of fever is—is—is mediated by E2—so prostaglandin E2 mediates fever—fever. So anyway, whatever helps you to remember it, but you do need to know that prostaglandin E2 mediates fever and it also mediates pain.
Lipoxygenase—the lipoxygenase pathway produces leukotriene, and um leukotriene—it produces—in particular—leukotriene B4, and then C4, D4, and E4. So leukotriene B4—the key feature of that is that it attracts and activates neutrophils—very important. Leukotriene B4 attracts and activates neutrophils. Okay, I'm going to take a step back here and now remind you that there are three key mediators—some people might say four—so let's say four key mediators that actually attract and activate neutrophils. Uh, the first is leukotriene B4; the second is C5a; the third is IL-8; and the fourth are bacterial products. So these four mediators—is some—these are the four that you need to um sort of store away in the back of—of your mind. Another group of leukotrienes that are important are leukotrienes C4, D4, and E4. Now, leukotrienes C4, D4, and E4—what they do is they mediate vasoconstriction; they cause bronchospasm; and they increase vascular permeability—so three actions: vasoconstriction, bronchospasm, and increased vascular permeability. Leukotriene C4, leukotriene D4, and leukotriene E4—basically what they do is they contract smooth muscle; they cause smooth muscle to contract. So the arteriole is lined by smooth muscle, and when that um arteriole contracts—you get—smooth muscle contracts—we get vasoconstriction. The bronchus is lined by smooth muscle—or contains smooth muscle in its wall—and so when that smooth muscle contracts, we're going to get bronchospasm. And increased vascular permeability occurs when the pericytes—which are—which contain smooth muscle contractile function—um, when the pericytes contract, it will separate or pull apart the endothelial cells. Um, so that might require a little bit of an explanation. So let me—let me go back and remind you of a little bit of normal histology. Let's come here, and this is basically—I'm going to draw you a blood vessel. Let's pretend that we're in the postcapillary venule—or in a—in a—in the capillary bed. And so this is a blood vessel, and you recall from your histology that the blood—blood vessel is lined by endothelial cells, and the endothelial cells look like that, um, and that underneath the endothelial cells, on occasion, is a second cell which sits like this—sort of above the basement membrane—which is called a pericyte. Now, the pericyte um contains contractile function, and when this pericyte contracts, it will separate or pull apart the endothelial cells—um, so that—let's pretend that these are two endothelial cells—so that when this contracts, it will open up the space between these two endothelial cells, and that sort of then opening of the space allows for fluid to leak from the postcapillary venule out into the tissue space. Uh, and so again, when we think about—as I've said—when we think about these prostaglandins—or sorry—these um leukotrienes—leukotriene C4, D4—uh, let's erase that—leukotriene C4, D4, and E4—they're going to mediate vasoconstriction by—by causing constriction of the arteriole—the—the smooth muscle of the arteriole; um, they're going to mediate bronchospasm by causing constriction of the smooth muscle wall of the bronchus; and then increased vascular permeability by causing smooth muscle contraction—or of the pericytes—which again contain contractile function. So that's the way I remember leukotrienes.
The next of the um mediators of acute inflammation are mast cells. And mast cells are widely distributed throughout the connective tissue of the body. There are three things—or three mechanisms—by which mast cells can be activated. Number one: tissue trauma. The first way by which mast cells are activated is tissue trauma. Whenever tissue trauma occurs, the mast cells get activated, and they will then help to mediate the acute inflammatory response. The second way by which mast cells can be activated are by the complement proteins C3a and C5a. C3a and C5a are byproducts of the activation of the complement system. We'll talk about them in more detail in a few minutes; however, it's important to bear in mind here that these two proteins—C3a and C5a—they activate mast cells. And the third way by which mast cells can be activated—and perhaps the one that we're most familiar with—is crosslinking of surface Ig by antigen. So the idea here is that you've got a mast cell, and we know that the mast cells express Ig on their surface. And so here's one Ig—one Ig molecule—and here's another Ig molecule. And if an antigen comes by and crosslinks these two Ig molecules, that then activates the mast cell. So important to remember that there are three ways by which the mast cell is activated: number one, tissue trauma; number two, complement proteins C3a and C5a; and number three, crosslinking of cell surface Ig by antigen. Now, once the mast cell gets activated, it undergoes an immediate response, and the immediate response is—is—is the—it results in the dumping of histamine granules. The immediate response results in the dumping of preformed histamine granules. These histamine granules—they mediate two things: number one, the histamine granules cause vasodilation. How will vasodilation occur? You've already understood this: it will occur by dilating the smooth muscle of the arterioles. So the smooth muscle of the arteriole will dilate, which will then result in vasodilation. At the same time, the histamines also have the ability to increase vascular permeability. Where will increased vascular permeability occur? The postcapillary venule. So histamine has two primary functions: vasodilation at the level of the arteriole and increased vascular permeability at the level of the postcapillary venule. That's the immediate response that sort of occurs right when the—when the—when the histamine gets activated—that's—sorry—right when the mast cell gets activated. The mast cell, once it dumps its preformed histamine granules, will also have a delayed or a late response in which it produces arachidonic acid metabolites, particularly leukotrienes, and these leukotrienes allow for maintenance of the acute inflammatory response. Very important, because it's a common uh question that can show up on examinations. Uh, I could ask you, for example, um, you know, that a patient has uh mast cells which activate the acute inflammatory response, and several hours later the acute—the acute inflammatory response continues. Uh, what is the major mechanism by which mast cells will allow for the progression of the acute inflammatory response? And the answer would be the production of arachidonic acids, particularly leukotrienes—high-yield. Leukotrienes are sort of the second phase of the mast cell response.
The next um group of uh of proteins that are important in acute inflammation is complement. Um, this is a group of pro-inflammatory serum proteins that complement inflammation; they assist inflammation; they help inflammation. Um, we're all familiar with the fact that complement circulates as inactive precursors, and these precursors must be activated for the complement system to then uh cause its—to produce its effect. The activation of the complement system occurs in three—by three particular pathways. Uh, the first is the classical pathway. The class—in the classical pathway, C1—which is an early complement protein—binds to IgG or IgM, which is bound to an antigen. So if IgG or IgM gets bound to an antigen, C1 can bind to that bound antibody and then activate the complement cascade. Now, that's called the classical pathway. And there's a famous pneumonic concerning this pathway: that "GM makes classic cars." So the company GM uh makes classic cars. And so IgG or IgM results in activation of the classical pathway. The second pathway uh that's important for act—that—that by which complement can be activated is the alternative pathway. The alternative pathway result—results in activation of complement by microbial products. So the microbial products—they actually um directly result in the activation of complement, uh, and so this is the alternative pathway—that's pretty straightforward to understand. The third pathway is the mannose-binding lectin pathway, also known as the MBL pathway. Now, the mannose-binding lectin pathway gets activated when MBL binds mannose on microorganisms. And the—once the mannose is bound by MBL, that then—that then allows for the activation of complement. And so this is the third way by which complement can be activated. The result of activation of complement is a little bit complicated but can be summarized in uh in just a very few simple principles. All pathways sort of lead to the same um sort of same result, which is that eventually C3 convertase gets generated. When C3 convertase gets generated, C3 convertase converts C3 to C3a and C3b. And then C3b joins in to help to produce C5 convertase, and C5 convertase converts C5 to C5a and C5b. And then C5b actually complexes with C6 through C9 to produce something called the membrane attack complex. And the membrane attack complex produces a hole within the membrane that allows for lysis of the microorganism. So these are really the three key results: C3 convertase generating C3a and C3b; C5 convertase generating C5a and C5b; and then C5b joining with C6 through C9 to form the membrane attack complex. So the key products that are generated by the complement system include C3a and C5a, and we know what they do: they trigger mast cell degranulation. Um, can you remember just sort of a couple from a couple slides back—what are the key activators of mast cells? Number one: tissue trauma; number two: C3a and C5a; and number three: crosslinking by—crosslinking of anti—crosslinking of surface Ig by antigen. Excellent. So again, we want to burn these three—three—three key things in the back of our mind—these are the three ways by which mast cells get activated. The immediate response of the mast cell would be dumping of preformed histamine granules; the histamines mediate vasodilation and increased vascular permeability; and do you remember what the delayed response would be—or the late response? Excellent—production of arachidonic acid metabolites, in particular leukotrienes. And again, all that sort of the high-yield summary concerning mast cells. Um, the next uh key—one of the other key products of uh of the complement system is C5a. C5a is important because it is a chemoattractant for neutrophils; um, it's sort of one of the things that helps to activate and bring in the neutrophils. So I can stop here and say: do you remember the four key products that result in the activation and bringing in of neutrophils? Leukotriene B4, C5a, IL-8, and bacterial products. Excellent. So those are the four key things that bring in the neutrophils. Now, another product is C3b, which is an opsonin for phagocytosis. What's an opsonin? Basically, remember that when the neutrophils get into tissue, the way by which they destroy things is going to be phagocytosis: they go in there, they consume things, and then they bring—they—they destroy that which they consume. So that's called phagocytosis—to eat things from the outside world. Now, phagocytosis is usually blind—i.e., the neutrophil just sort of goes in and grabs things randomly and begins to consume it once it's activated. However, one of the ways by which that phagocytosis can be assisted is by opsonins, and opsonins are proteins that um the neutrophil can recognize, which then tell it to consume that which is attached to that protein. And so one important opsonin is C3b. And we—we'll talk a little more—a little bit more about opsonins a little later in our discussion. And the final key product of the complement is—system is the membrane attack complex. Basically, if you have a microbe and complement gets activated on the microbe, a membrane attack complex is produced, and that creates a hole in the cell membrane, which then disregulates the relationship of that cell to the outside world and then results in death of that cell. So the membrane attack complex—again—is formed by the C—um C5b, which then goes off—and allows to join—joins with C6 to C9 to then produce the membrane attack complex. So these are some of the key products, and again, relatively high-yield for examinations.
The next um of the acute inflammatory mediators is uh Hageman factor. Hageman factor is an inactive pro-inflammatory protein that's produced in the liver, and and it gets activated on exposure—upon exposure—to subendothelial or tissue collagen. So this is um this is one of the important factors that helps to activate acute inflammation. And I would say, if one important thing for examinations that you want to remember—remember about Hageman factor—I would say that Hageman factor plays an important role in DIC, especially in…
Severe gram-negative sepsis. So, when there's severe gram-negative sepsis, the gram-negative organisms also have the ability to activate Hageman factor. And that activation of Hageman factor plays an important role in DIC. Um, and the reason it plays an important role in DIC is because Hageman factor, in turn, it activates the following systems: it activates coagulation and the fibrinolytic system, allowing for the development of DIC. It also activates complement and the kinin system. But this activation of the coagulation and fibrinolytic systems is relatively high-yield. Again, you want to tie that into sort of one mechanism by which DIC can occur. Um, and again, the other things that Hageman factor does: it activates complement, which helps to mediate acute inflammation, and then activates something called the kinin system.
So what is the kinin system? The kinin system cleaves high-molecular-weight kininogen to bradykinin. And bradykinin mediates vasodilation, increased vascular permeability, and pain. Uh, the way I remember bradykinin is that it sort of does the same thing as histamine, i.e., vasodilation and increased vascular permeability, but in addition, it mediates pain. And we could stop here and remind ourselves that what are the two things that mediate pain? Prostaglandin E2. Remember prostaglandin E2 mediates fever and pain. And the second of them is bradykinin. So pain, which is normally experienced with an acute inflammatory response, is actually mediated by two things: bradykinin and prostaglandin E2. I'm just trying to sort of hammer home some of the high-yields so that you take them away from this lecture.
Once acute inflammation um is activated, all of these mediators are are sort of played together as a symphony, and that symphony is going to result in the cardinal signs of inflammation. So now we're sort of putting together all the mediators and saying, so what is the overall result? And the overall result is the are the cardinal signs of acute inflammation. So what are these signs? Well, I'm these were very familiar with: rubor, or redness and warmth; uh, that's called calor. This is the first of the two key cardinal signs. Uh, it's not it's not sufficient for examination purposes to just know the cardinal signs, but instead you have to know what mediates them and why they occur.
So let's just think for a second: if we're going to get redness in a tissue, the way by which we're going to get redness is by increasing the amount of blood, because that's what's going to give the red color to the tissue. And so redness actually occurs due to vasodilation, and vasodilation will be mediated at the level of the arterioles. Once vasodilation occurs, increased blood will go into the tissue, and when there's increased blood within the tissue, that will provide the redness that we see in acute inflammation. So it's mediated by vasodilation; it occurs at the arteriolar smooth muscle; and the key mediators are histamine—remember that histamine mediates vasodilation—prostaglandins, in particular prostaglandin I2, D2, and E2, and bradykinin. These are all key mediators of vasodilation. Um, and the most important of these is actually histamine. Histamine is the the primary molecule that mediates this this response. So that's the way by which we get redness.
Now, in the same way we get warmth, it's the exact same mechanism, because what is warmth? Warmth is basically an increased amount of warm blood within um that particular area of tissue; that's what makes it warm. It's there's an increased amount of blood, and the blood is actually warm. So why would we get increased why would we get the warmth? How would that occur? That would occur by vasodilation at the level of the arteriolar smooth muscle, and the key mediators are again going to be histamine, which is number one, and then prostaglandins, in particular prostaglandin I2, D2, and E2, um, and bradykinin. So again, not hard, but important to understand the the basis of what we're going to see clinically.
The next of the key features that we see in acute inflammation clinically is swelling, also called tumor. Um, and swelling—how is that going to occur? It occurs by leakage of fluid from the postcapillary venules into the interstitial space. Um, again, I've already kind of explained this, but it's important to know that that leakage occurs at the postcapillary venules, and the key mediators are going to be histamine. Histamine is is sort of the number one mediator, and another important mediator is going to be tissue damage. And the idea here is that if you've got a blood vessel, right, and it's lined by endothelial cells, normally fluid cannot get out from normally fluid cannot leave the blood vessel space. However, if you damage the endothelium so that there is uh, you know, disruption of the wall of the blood vessel due to tissue damage, fluid can easily leak out. So um, that's what's going to result in the swelling. Number one: histamine, um, which which actually helps to separate the endothelial cells, and tissue damage, which actually disrupts the endothelial cells. So that's going to result in swelling.
Pain is another cardinal sign of inflammation. When a patient has acute inflammation, it's often the reason is often painful, and there's two things that mediate pain, and I've already covered them: bradykinin, which um which was generated by um from high-molecular-weight kininogen, and then number two: prostaglandin E2, which remember prostaglandin E2 mediates what? Fever and pain. Very good. So um, prostaglandin E2 and bradykinin, they the mechanism by which they allow for the formation of pain or the feeling of pain is that they sensitize the sensory nerve endings. They sensitize the sensory nerve endings, and the um the next sign of uh, or I would say the final sign of acute inflammation, at least the final cardinal sign of acute inflammation, is fever. And fever—the mechanism is very important to know; examiners love to go after this. So the way by which fever occurs is that the macrophages—and that's important—the macrophages release IL-1 and TNF. Um, and IL-1 and TNF basically get into the bloodstream; they go through the blood; they then um hit the perivascular cells of the hypothalamus, so that the temperature regulation of the body is mediated in the hypothalamus. Um, and in those cells, that increase COX activity—the COX or cyclooxygenase activity increases—prostaglandin E2, which then, remember, leads to fever. As I've said many times before, prostaglandin E2 raises the temperature set point in the hypothalamus.
So let's let's review that one more time because it's super high-yield. Macrophages produce IL-1 and TNF. The IL-1 and TNF gets into the perivascular cells of the hypothalamus; it increases COX activity; and the increased COX activity is going to result in the production of prostaglandin E2. Prostaglandin E2 will then raise the temperature set set point, creating fever. And so these are um these are sort of the key mediators of acute inflammation that we need to be familiar with, and at the same time, we need to understand that these key mediators are going to are actually going to create a symphony of acute inflammation that's going to result in the classic or cardinal findings of acute inflammation, and that really uh closes off this particular section.