Chapter 3: Inflammation and Repair

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1

What is inflammation?

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A response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents.

2

What are the two types of inflammation?

  1. acute
  2. chronic
3

Which type of inflammation involves the initial, rapid response to infections and tissue damage?

acute

4

What type of cells are associated with acute inflammation?

neutrophils

5

Which type of inflammation occurs if the initial response fails to clear the stimulus?

chronic

6

What type of cells are associated with acute inflammation?

macrophages, lymphocytes

7

What are the cardinal signs of inflammation? (5)

  1. heat (calor)
  2. redness (rubor)
  3. swelling (tumor)
  4. pain (dolor)
  5. loss of function (functio laesa)
8

When is inflammation terminated?

When the offending agent is eliminated.

9

What four types of stimuli trigger inflammatory reactions?

  1. infections (bacterial, viral, fungal, parasitic)
  2. tissue necrosis (regardless of the cause)
  3. foreign bodies (splinters, dirt, sutures)
  4. immune reactions (also called hypersensitivity)
10

What is the first step in inflammatory responses?

The recognition of microbes and necrotic cells by cellular receptors and circulating proteins.

11

What are the steps of the inflammatory response? (5)

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  1. recognition of the injurious agent
  2. recruitment of leukocytes
  3. removal of the agent
  4. regulation (control) of the response
  5. resolution (repair)
12

What are the three major components of acute inflammation?

  1. dilation of small vessels
  2. increased vascular permeability
  3. emigration of the leukocytes
13

What is the term for an extravascular fluid that is high in protein and contains cells?

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exudate

14

What does the presence of an exudate indicate?

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inflammation

15

What is the term for an extravascular fluid that is low in protein and contains little to no cells?

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transudate

16

What does the presence of an exudate indicate?

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osmotic imbalance

17

What is the term for an excess of fluid in the interstitial tissue or serous cavities?

edema

18

What is the term for an inflammatory exudate rich in leukocytes and microbes?

pus

19

What mechanisms are responsible for increased vascular permeability in acute inflammation? (3)

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  1. retraction of endothelial cells, resulting in opening of interendothelial spaces
  2. endothelial injury, resulting in endothelial cell necrosis and detachment
  3. transcytosis, or the movmenet of fluids and proteins through the endothelial cell
20

How is edema due to the increased vascular permeability of inflammation drained?

lymphatics

21

What is the term for inflammation of lymphatics or lymph nodes due to inflammatory reactions?

lymphadenitis

22

What type of blood cells are recruited to sites of inflammation to eliminate the offending agents?

leukocytes

23

Which are the most important leukocytes in typical inflammatory reactions? (2)

  1. neutrophils
  2. macrophages

(the ones capable of phagocytosis)

24

As the blood flow slows early in inflammation, more white cells assume a peripheral position along the endothelial surface. What is this called?

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margination

25

What are the two major families of molecules involved in leukocyte adhesion and migration?

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  1. selectins
  2. integrins
26

Which molecules mediate the initial weak interactions between leukocytes and endothelium?

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selectins

27

Which molecules mediate the firm interactions between leukocytes and endothelium?

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integrins

28

Which cytokines activate integrins on leukocyte plasma membranes to allow for adhesion?

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chemokines

29

Which cytokines increase expression of ligands for integrins on endothelial cells to allow for adhesion?

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TNF and IL-1

30

After adhesion on the endothelial surface, leukocytes migrate through the vessel wall by squeezing between cells at intercellular junctions. What is this called?

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transmigration

31

After exiting the circulation, leukocytes move in the tissues toward the site of injury along a chemical gradient of chemoattractants. What is this called?

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chemotaxis

32

What cells predominate in the inflammatory infiltrate during the first 6 to 24 hours of acute inflammation?

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neutrophils

33

What cells predominate in the inflammatory infiltrate after 24 to 48 hours of acute inflammation?

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macrophages

34

What are the most successful therapeutics ever developed for chronic inflammatory diseases?

Agents that block TNF,

35

What is the collective term for the leukocytic responses to microbes or dead cells?

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leukocyte activation

36

What are the functional responses that are most important for destruction of microbes and other offenders? (2)

  1. phagocytosis
  2. intracellular killing
37

What are the three steps of phagocytosis?

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  1. recognition and attachment of the particle
  2. engulfment, with vacuole formation
  3. killing or degradation of the material
38

The efficiency of phagocytosis can be enhanced if microbes are coated by proteins that have a high affinity for phagocyte receptors. What is this called?

opsonization

39

What agents are involved in the elimination of phagocytized microbes and materials? (3)

  1. reactive oxygen species (ROS)
  2. reactive nitrogen species
  3. lysosomal enzymes
40

In neutrophils, rapid generation of ROS is tightly linked to phagocytosis. What is this called?

respiratory burst

41

What three anti-oxidant enzymes protect host cells from the harmful ROS generated to eliminate phagocytized microbes and materials?

  1. superoxide dismutase
  2. catalase
  3. glutathione peroxidase
42

What are the three types of nitric oxide synthase (NOS)?

  1. endothelial (eNOS)
  2. neuronal (nNOS)
  3. inducible (iNOS)
43

Which type of NOS is expressed when macrophages are activated by cytokines or microbial products?

inducible nitric oxide synthase (iNOS)

44

Neutrophils and monocytes contain granules packed with enzymes and anti-microbial proteins. What is the term for exocytosis of these granules?

degranulation

45

What are neutrophil extracellular traps (NETs)?

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Extracellular networks of neutrophil chromatin that bind to anti-microbial substances engulf microbes.

46

What are mediators of inflammation?

The substances that initiate and regulate inflammatory reactions.

47

What are the two broad classes of mediators of inflammation?

  1. cell-derived, produced locally by cells
  2. plasma-derived, from circulating precursors
48

What are the three major cell types that produce mediators of acute inflammation?

  1. tissue macrophages
  2. dendritic cells
  3. mast cells
49

What are the two major vasoactive amines?

  1. histamine
  2. serotonin
50

What are the vasoactive effects of histamine?

It dilation of arterioles and increases the permeability of venules.

51

Which type of histamine receptors mediate its vasoactive effects?

H1 receptors (H2 receptors are found in gastric parietal cells)

52

What fatty acid found in membrane phospholipids is the precursor to lipid mediators of inflammation?

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arachidonic acid

53

What two lipid mediators are produced from the arachidonic acid in membrane phospholipids?

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  1. prostaglandins
  2. leukotrienes
54

What is another term for prostaglandins and leukotrienes?

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eicosanoids

55

What two major classes of enzymes synthesize eicosanoids from arachidonic acid?

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  1. cyclooxygenases
  2. lipoxygenases
56

Which class of enzymes synthesize prostaglandins from arachidonic acid?

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cyclooxygenases

57

Which class of enzymes synthesize leukotrienes and lipoxins from arachidonic acid?

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lipoxygenases

58

Which cyclooxygenase is produced in response to inflammatory stimuli and also constitutively expressed?

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cyclooxygenase-1 (COX-1)

59

Which cyclooxygenase is induced by inflammatory stimuli, but is low or absent in most normal tissues?

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cyclooxygenase-2 (COX-2)

60

What are the most important prostaglandins in inflammation? (5)

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  1. PGE2
  2. PGD2
  3. PGF2a
  4. PGI2 (prostacyclin)
  5. TXA2 (thromboxane A2)
61

What are the effects of PGD2 and PGE2?

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They cause vasodilation and increase permeability of postcapillary venules.

62

What are the effects of TXA2 (thromboxane A2)?

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It is a vasoconstrictor and potent platelet-aggregating agent, and thus promotes thrombosis.

63

What are the effects of PGI2 (prostacyclin)?

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It is vasodilator and potent antiplatelet agent, and thus prevents thrombosis.

64

What are the effects of LTC4 and its metabolites, LTD4 and LTE4?

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They cause intense vasoconstriction, bronchospasm, and increased permeability of venules.

65

What four types of anti-inflammatory drugs act on the pathway of eicosanoid synthesis from arachidonic acid?

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  1. cyclooxygenase inhibitors (e.g. ibuprofen)
  2. lipoxygenase inhibitors (e.g. zileuton)
  3. corticosteroids (e.g. prednisone)
  4. leukotriene receptor antagonists (e.g. Montelukast)
66

What is the advantage of an anti-inflammatory drug causing selective inhibition of COX-2?

COX-1 generates PGs in involved in inflammation as well as PGs that have physiologic functions, such as protecting gastric epithelial cells; COX-2 only generates PGs involved only in inflammation; thus selective COX-2 inhibition could be anti-inflammatory with fewer adverse effects, such as gastric ulceration.

67

What is the disadvantage of an anti-inflammatory drug causing selective inhibition of COX-2?

Selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of antithrombotic PGI2, while leaving intact the COX-1-mediated production of prothrombotic TXA2.

68

What are cytokines?

Proteins secreted by many cell types that mediate and regulate immune and inflammatory reactions.

69

Which cytokines promote adhesion of leukocytes to endothelium and their migration through vessels?

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TNF and IL-1

70

What are the most important roles of TNF and IL-1 in inflammation?

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  1. endothelial activation
  2. activation of leukocytes and other cells
  3. systemic acute-phase response
71

What explains the cachexia that accompanies some chronic infections and cancers?

These conditions result in sustained production of TNF, which regulates energy balance by promoting lipid and protein catabolism and by suppressing appetite.

72

What type drug is highly effective in the treatment of chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, or IBD?

TNF antagonists

73

What are chemokines?

A family of small proteins that act primarily as chemoattractants for specific types of leukocytes.

74

What are the four major groups of chemokines?

  1. C-X-C (attract neutrophils)
  2. C-C (attract monocytes, eosinophils, basophils, and lymphocytes)
  3. C (attract lymphocytes)
  4. CX3C (attract monocytes and T cells)
75

What are the two main functional classes of chemokines?

  1. inflammatory chemokines stimulate leukocyte attachment to endothelium
  2. homeostatic chemokines organize cells in different regions of the tissues
76

What is the complement system?

A collection of over 20 soluble proteins and their receptors that function in host defense against microbes and pathologic inflammatory reactions.

77

What is the critical step in complement activation?

The proteolysis of the third (and most abundant) component, C3.

78

The critical step in complement activation is the proteolysis of C3. What are the three pathways by which this can occur?

  1. classical pathway (antibodies)
  2. alternative pathway (endotoxins)
  3. lectin pathway (mannose-binding)
79

All three pathways of complement activation lead to the formation of an enzyme. What enzyme is this?

C3 convertase

80

All three pathways of complement activation lead to the formation of C3 convertase. What is the function of C3 convertase?

It splits C3 into two functionally distinct fragments, C3a and C3b.

81

C3 convertase splits C3 into two functionally distinct fragments, C3a and C3b. What is the function of C3a?

It acts as a chemotactic agent for neutrophils, monocytes, eosinophils, and basophils

82

C3 convertase splits C3 into two functionally distinct fragments, C3a and C3b. What is the function of C3b?

It is converted into C5b, which binds to C6–C9 to form the membrane attack complex (MAC).