Overview of Chronic Inflammation and Repair

by Richard Mitchell, MD, PhD

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    00:01 Alright, welcome.

    00:03 What we're going to cover right now is a overview of inflammation.

    00:09 We've already talked about cell injury and cell death.

    00:12 We've talked about the acute inflammatory response, the response that comes first after injury.

    00:20 And now we're going to get into the world of chronic inflammation and wound healing.

    00:26 So that's where we are in the sequence.

    00:29 And we're going to start with this.

    00:31 So this is kind of where we left off with the acute inflammation.

    00:36 This is sterile necrosis.

    00:38 This represents a myocardial infarct, and all of those big pink areas are coagulation necrosis, and those are myocytes that have died as part of a heart attack, a myocardial infarct.

    00:49 And we have now and about 24 to 48 hours, after that acute infarct, we've recruited in all these neutrophils.

    00:57 So there is a huge inrush of neutrophils who are going to start the degradation process.

    01:03 And make sure that that is sterilized.

    01:06 So no bacteria can set up shop in this necrotic debris.

    01:10 So that's just the beginning of the process.

    01:13 Likewise, let's look at this. This is kidney.

    01:15 You can see the glomeruli, you can see renal tubules, you can see vascular congestion.

    01:20 In the middle of that there's no architecture, that's an abscess.

    01:25 So in this setting, we have had an accumulation of bacteria and neutrophils that are basically duking it out with one another.

    01:34 And as a consequence, we have vast dead zone in the middle, just necrotic debris, and bacteria, and neutrophils.

    01:43 That's an abscess.

    01:44 And again, that's just the beginning.

    01:46 We can't leave that there. We need to somehow clean this up.

    01:50 Similarly, you can have inflammatory states where we've had markedly increased vascular permeability.

    01:55 We've had exudates, where we have protein and red cells, and occasionally other white cells that get out into that.

    02:04 And that's what we're looking at here.

    02:06 All that pink stuff is because of a significant exudation of protein.

    02:13 But we can't leave that line around either.

    02:14 That's a really good tissue medium for culturing bacteria and that would be a terrible thing.

    02:20 So we need to get rid of that.

    02:22 So coagulation necrosis with acute inflammation, abscess formation, exudates.

    02:29 We need to get rid of those.

    02:31 So this is just the beginning.

    02:33 This is at the end of the acute inflammation, and now into the chronic inflammation repair.

    02:38 So that's kind of setting the stage.

    02:42 Outcomes of acute inflammation.

    02:45 So once we have acute inflammatory cells, and all of their mediators brought in there are couple different pathways for outcomes.

    02:54 One, is that we progress in a very stereotyped way to chronic inflammation.

    02:59 And if we have minimal tissue injury, and the tissues can regenerate, the chronic inflammatory result will be resolution.

    03:08 We'll get things pretty much back to normal.

    03:10 We will neutralize the mediators that got made during the acute inflammatory process.

    03:15 The vessels will go back to being normal, they won't be leaking anymore, and they won't be dilated.

    03:20 Will drain away through the lymphatics, all the necrotic debris, and all the extra cells that came in, and the macrophages will clean up and drive the regeneration process.

    03:31 That's beautiful.

    03:32 That's what we want to have happen every time we have acute inflammation.

    03:37 Goes through the chronic inflammatory pathway, and then resolve.

    03:41 But sometimes we have pyogenic organisms.

    03:44 Pyogenic just means pus forming, and we'll get a huge abscess.

    03:49 Once that happens, we are going to have to go through chronic inflammation to resolve this.

    03:54 But there's been as we already saw with that first example, there's going to be so much tissue injury and that abscess, We can't regenerate it. It's gone, it's absolutely gone.

    04:04 So there's substantial tissue destruction.

    04:06 The tissues may not be able to regenerate.

    04:09 And in the setting of abscess, or just increased vascular permeability, we get those exudates, we have to organize those through chronic inflammation.

    04:21 But in that setting, we have maximal substantial tissue destruction and tissues cannot regenerate.

    04:28 So the result is going to be scar.

    04:31 And in reality, in almost every situation after acute inflammation, the tissues are somewhere on the spectrum between complete resolution, and complete scar.

    04:42 And it's never usually perfectly one or the other.

    04:47 So the outcomes of injury and inflammation.

    04:50 It's a spectrum from regeneration to scar.

    04:51 And it's dependent on the type of the injury, the nature of the injury.

    04:55 How intense the injury was? How much tissue has been damaged? How much host response there was? So if we have a huge inflammatory response, and all those mediators get released, and all the proteases get released, we're gonna have big time tissue destruction.

    05:10 On the other hand, if we don't have much host response and the bacteria run amok, we're gonna have a lot more damage.

    05:17 So it's, there's a lot of variables in there.

    05:21 The cell and tissue type.

    05:22 So some tissues will regenerate beautifully.

    05:25 Skin does a pretty good job.

    05:27 Heart doesn't do a very good job at all.

    05:30 And that's because of the regenerative capacity of the cells, and each cells in the skin can regenerate cells in the heart, cannot.

    05:40 What happens on the spectrum from regeneration to scar also depends on how well we maintain the matrix integrity.

    05:46 So if we completely destroy it, seen an abscess, that's going to end up being mostly a scar.

    05:53 And then the ability of stem cells to regenerate the tissues and how capable the tissues are of kind getting back to normalcy.

    06:05 So it all depends on a number of variables, as indicated on this slide.

    06:11 I'm going to give you a particular kind of schematic roadmap that's going to be seen, over, and over, and over again, as we talk about the stages after acute inflammation.

    06:22 So we have some activity on the y-axis and time on the x-axis.

    06:27 And we'll put in some hours and some days on the x-axis.

    06:30 But the activity on the y-axis is going to be quite variable.

    06:35 When we have our initial insult at time zero, we have that vascular response. We've talked about that.

    06:41 That's the edema, the tumor, the increased vascular permeability, that is the initial vascular response of injury. Okay.

    06:51 Shortly thereafter, we have the peak of the neutrophil infiltrate.

    06:56 that's the acute inflammatory response.

    06:58 So edema, the vascular response is first, neutrophils second.

    07:02 Even as the neutrophils are beginning to go away, we are now recruiting in the chronic inflammatory phase.

    07:08 the macrophages, okay. And they will come in as a wave.

    07:14 And then all goes according to plan, we get regeneration.

    07:18 That's the ideal.

    07:20 So <inaudible> inflammation, leading to acute and chronic inflammation, and then to regeneration.

    07:26 But what happens if the tissue can't regenerate? Or we have too much damage? Well, there are a couple more steps then, okay.

    07:32 So we will still have the edema, the acute inflammation and chronic inflammation.

    07:37 But now in tissues that will lead to scarring or damage that will lead to scarring, we will have a stage where we will have new growth of blood vessels.

    07:46 This is called granulation tissue.

    07:48 It's a neovascularization process.

    07:50 and we will spend a little bit of time talking about how that happens.

    07:54 And then on top of that granulation tissue is a provisional matrix.

    07:58 You can kind of think of it as railroad tracks.

    08:00 We will bring in fibroblasts that will synthesize matrix and will get scar.

    08:06 So, as I said before, the process of resolving injury is somewhere on the spectrum between complete regeneration and complete scar.

    08:15 And most things in most tissues is somewhere between those two.

    08:21 So just kind of keep this series of peaks in mind and then we will fill in some of the details but this is the big picture.

    08:30 So welcome to the world now of chronic inflammation and healing.

    08:35 And you're going to love talking about this.

    About the Lecture

    The lecture Overview of Chronic Inflammation and Repair by Richard Mitchell, MD, PhD is from the course Acute and Chronic Inflammation.

    Included Quiz Questions

    1. Increased lymphatic drainage
    2. Increased neutrophil recruitment
    3. Decreased release of anti-inflammatory cytokines
    4. Vasodilation
    5. Increased endothelial permeability
    1. Replacement by scar tissue
    2. Complete resolution
    3. Replacement by a granuloma
    4. Metastasis to other sites
    5. Replacement by gangrenous tissue
    1. Increased vascular permeability
    2. Recruitment of neutrophils
    3. Recruitment of macrophages
    4. Formation of granulation tissue
    5. Formation of scar tissue
    1. ...the amount of exudate released.
    2. ...the nature of the injury.
    3. ...the regenerative capacity of the cells.
    4. ...the intensity of host responses.
    5. ...the integrity of the extracellular matrix.

    Author of lecture Overview of Chronic Inflammation and Repair

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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