Outcomes of Injury and Chronic Inflammation

by Richard Mitchell, MD, PhD

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    00:01 So, Broad strokes.

    00:03 Injury, not otherwise specified, could be infection, could be trauma, could be just sterile necrosis.

    00:10 It typically elicits in a very stereotypical way, vascular responses and cellular responses, that's acute inflammation.

    00:18 We get the edema, increased vascular permeability, we get the increased blood flow, and we get the recruitment of neutrophils, acute inflammation.

    00:27 And then in a stereotypical way, acute inflammation, as we've talked about, gets converted to chronic inflammation involving the macrophage population.

    00:36 So that's the usual sequence of events.

    00:39 However, there are always exceptions in medicine, and biology.

    00:43 And there are a few exceptions to this paradigm.

    00:46 So some forms of injury, don't go through the acute inflammatory to chronic inflammation process.

    00:55 So, Persistent injury.

    00:56 If I continue to injure a tissue over and over and over again, without giving any time for kind of recovery, the vasculature continues to only recruit chronic inflammatory cells.

    01:09 It will not go back through the process of doing acute inflammatory cell recruitment.

    01:15 Viral infections.

    01:17 Turns out, neutrophils are worthless against viruses.

    01:21 Viruses, or intracellular pathogens.

    01:24 Neutrophils only really work on things that they can see and eat, and they cannot see a virus when it's inside a cell.

    01:30 So if we have a viral infection, in the vast majority of cases, we will not recruit neutrophils.

    01:36 We will only recruit chronic inflammatory cells.

    01:39 Lymphocytes, and macrophages.

    01:42 And then autoimmune disease.

    01:44 So when the body recognizes self inappropriately, So this is all sort of colitis. This is rheumatoid arthritis.

    01:52 This is lupus.

    01:53 This is a variety of the autoimmune diseases that we'll cover in a subsequent topic.

    01:59 Autoimmune disease also tends to elicit primarily a chronic inflammatory response.

    02:03 There are some exceptions.

    02:05 But in general, persistent injury, viral infections, and autoimmune disease, all go directly into chronic inflammatory infiltrates, with all the attendant mediators that come with that chronic inflammation.

    02:20 So to give you, I've been using the term chronic inflammation.

    02:24 And haven't really explained myself.

    02:26 So let's talk a little bit more about this.

    02:28 Chronic inflammation is mononuclear cell inflammation.

    02:31 As opposed to polymorphonuclear leukocyte inflammation, which is going to be neutrophils, or acute inflammation.

    02:37 So the mononuclear cells that are part of chronic inflammation, lymphocytes and macrophages.

    02:42 And they both will contribute, as we'll see, in a subsequent talk, they actually communicate with each other, they actually stimulate each other.

    02:50 So they are important.

    02:52 The major feature and I'm going to emphasize this many times is the macrophage.

    02:57 It's going to be the most important mononuclear cell that's involved in chronic inflammation.

    03:03 Chronic inflammation, just like the name implies, can be prolonged.

    03:07 So it not only does it come on second after acute inflammation, but it can also persist for weeks, or a year.

    03:14 We show a whole calendar here, or many years or for a lifetime.

    03:18 So for example, rheumatoid arthritis can have a persistent injury to joint for a person's lifetime.

    03:26 So it's a very prolonged process.

    03:29 An important concept about chronic inflammation is that it is responding to a particular tissue injury, whatever is driving that initial tissue injury may persist.

    03:39 So there will be some damage that's from that.

    03:42 But there will also be damage, potentially, from the response.

    03:47 Macrophages are not totally benign creatures.

    03:50 They elaborate a lot of mediators, and can cause substantial tissue injuries.

    03:55 So it's not just the original tissue injury, but it's the chronic inflammatory response that also drives that.

    04:02 What's shown here in the diagram is a normal colon, kind of histologic section.

    04:07 And there is very few inflammatory cells and the little glands nice and round, they are very happy.

    04:15 In the bottom one is ulcerative colitis an autoimmune disease associated with chronic inflammatory cells that are basically attacking the epithelium.

    04:23 There's lots more inflamed inflammation that's in between the glands and the glands now become quite irregular.

    04:30 In fact, the damage to these glands can be so much that over a period of time, we increase the risk for acquiring new mutations and turning this into cancer.

    04:41 So it's not just the original insult.

    04:43 In this case, autoimmune disease, but it's the response and how it drives subsequent events? In chronic inflammation, we are hopefully, in fact, the goal is to go to regenerate the tissue to make it whole again.

    05:00 To restore completely normal function.

    05:02 But in the event that we can't, we're going to make a scar.

    05:07 And repair, in most cases, healing in most cases, as we'll talk about in a subsequent talk is all about somewhere on that spectrum between perfect regeneration and complete scar.

    05:19 In an almost no cases that one or the other, it's often some combination.

    05:25 In the event that we're going to have a scar, we need to have new blood vessels.

    05:29 We've destroyed blood vessels as part of the injury.

    05:31 We need to now make new ones that's angiogenesis.

    05:34 and we'll talk more about that.

    05:37 And then once we have angiogenesis, we will have matrix deposition, and that will form fibrosis.

    05:44 And I'll use interchangeably fibrosis with scar, that's laying down new extracellular matrix.

    05:51 The picture there is a very hypertrophic, angry looking scar.

    05:55 We'll talk about that at the very end of this series, because it's one of the complications of wound healing.

    About the Lecture

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

    Included Quiz Questions

    1. Autoimmune diseases
    2. Helminth infections
    3. Thermal injury
    4. Ischemia
    5. Ultraviolet light exposure
    1. It can be involved in the pathogenesis of cancer.
    2. Polymorphonuclear leukocytes are the predominant cells.
    3. It is characterized by vascular and cellular phases.
    4. It can lead to the formation of an abscess.
    5. The peak of the chronic inflammatory response is reached within 5 days after the injury.
    1. Angiogenesis
    2. Recruitment of macrophages
    3. Recruitment of neutrophils
    4. Formation of granuloma
    5. The proliferation of epithelial cells

    Author of lecture Outcomes of Injury and Chronic Inflammation

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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