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ACEM Primary Written > Fundamentals: Pathology - Acute and chronic inflammation > Flashcards

Fundamentals: Pathology - Acute and chronic inflammation Flashcards

1
Q

Describe the sequence of events in acute inflammation

A
  1. Vascular changes:
    - Mediators including histamine and NO induce vasodilation (sometimes follows transient vasoconstriction), resulting in increased blood flow and erythema
    - Increased vascular permeability occurs via a variety of mechanisms, leading to oedema
    - Stasis of blood flow causes vascular congestion and activation by a variety of mediators causes endothelial cells to increase expression of adhesion molecules
  2. Lymphatic changes:
    - Lymph flow is increased
    - Hyperplasia of lymphoid follicles occurs in lymph tissue, with increased numbers of lymphocytes and macrophages
  3. Leukocyte changes:
    - Leukocytes extravasate into the interstitial space via margination, rolling, and adhesion to endothelium followed by migration across the vessel wall and towards the chemotactic stimulus
    - Leukocytes recognise offending agents via receptors, triggering their removal via phagocytosis and intracellular killing
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2
Q

Describe the mechanisms of increased vascular permeability in inflammation, where each occurs, their respective triggers, and their duration

A
  1. Retraction of endothelial cells (occurs in venules, triggered by mediators including histamine and NO, rapid and short-lived i.e. minutes)
  2. Endothelial injury (occurs in arterioles, capillaries and venules; caused by burns and some microbial toxins; rapid and may be long-lived i.e. hours to days)
  3. Leukocyte-mediated vascular injury (occurs in venules and pulmonary capillaries, associated with late stages of inflammation, long-lived i.e. hours)
  4. Transcytosis (occurs in venules, induced by VEGF)
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2
Q

Describe the steps involved in leukocyte recruitment and activation

A
  1. Margination: stasis pushes leukocytes to the periphery, they align along the endothelial surface
  2. Rolling: leukocytes transiently bind to endothelial adhesion molecules via receptors called selectins, detach and bind again thereby slowing down
  3. Adhesion: leukocytes bind more firmly to receptors called integrins
  4. Migration/diapedesis: leukocytes migrate through interendothelial spaces via binding to adhesion molecules including PECAM-1 (aka CD-31)
  5. Chemotaxis: locomotion of leukocytes through tissues to the site of inflammation, in the direction of the gradient of various chemoattractants
  6. Recognition of microbes and dead tissue: leukocytes are activated when they bind microbial products (via TLRs or via GPCRs recognising N-formylmethylpeptides), opsonins (e.g. Ab, complement proteins, lectins) or cytokes (e.g. IFN-y)
  7. Leukocyte activation: signaling pathways are triggered by receptor binding resulting in phagocytosis and intracellular killing of the offending agent
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2
Q

Give some examples of exogenous and endogenous chemoattractants

A

Exogenous: microbial products
Endogenous: cytokines (e.g. IL-8), complement system components (e.g. C5a), arachidonic acid metabolites (e.g. leukotriene B4)

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3
Q

Describe the process of phagocytosis

A
  1. Leukocytes bind offending agent (directly or via opsonins or cytokines)
  2. Leukocytes engulf offending agent in phagosome
  3. Phagosome fuses with lysosome to form phagolysosome
  4. Offending agent is degraded via lysosomal enzyme activity and directly via ROS/NO
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4
Q

Identify 7 cell-derived chemical mediators of inflammation

A
  1. Vasoactive amines: histamine, serotonin
  2. Arachidonic acid metabolites: leukotrienes, prostaglandins, lipoxins (which unlike other two inhibit inflammation)
  3. Platelet-activating factor
  4. ROS
  5. NO
  6. Cytokines
  7. Chemokines
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5
Q

What cells release histamine?

A

Mast cells
Basophils
Platelets

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6
Q

What cells release serotonin as part of the inflammatory response?

A

Platelets

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7
Q

What cells release prostaglandins and leukotrienes?

A

Mast cells
Leukocytes

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8
Q

What cells release platelet-activating factor?

A

Mast cells
Leukocytes

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9
Q

What cells release ROS?

A

Leukocytes

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10
Q

What cells release NO?

A

Endothelium
Macrophages

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11
Q

What cells release cytokines?

A

Mast cells
Endothelium
Macrophages

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12
Q

What cells release chemokines?

A

Leukocytes
Activated macrophages

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13
Q

Identify 3 plasma protein-derived chemical mediators of inflammation

A
  1. Complement products (C5a, C3a, C4a)
  2. Kinins
  3. Proteases activated during coagulation (e.g. thrombin)
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14
Q

Where are the plasma protein-derived chemical mediators of inflammation produced?

A

In the liver

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15
Q

Which chemical mediators of inflammation induce vasodilation?

A

Histamine
Prostaglandins
NO

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16
Q

Which chemical mediators of inflammation increase vascular permeability?

A

Histamine and serotonin
C3a and C5a (indirectly via inducing release of vasoactive amines from mast and other cells)
Bradykinin
Leukotrienes (C4, D4, E4)
PAF
Substance P

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17
Q

Which chemical mediators of inflammation induce chemotaxis and leukocyte recruitment and activation?

A

TNF and IL-1
Chemokines
C3a and C5a
Leukotriene B4
Bacterial products (e.g. N-formylmethylpeptides)

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18
Q

Which chemical mediators of inflammation produce fever?

A

TNF and IL-1
Prostaglandins

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19
Q

Which chemical mediators of inflammation induce pain?

A

Prostaglandins
Bradykinin

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20
Q

Which chemical mediators of inflammation are responsible for tissue damage?

A

Lysosomal enzymes of leukocytes
ROS
NO

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21
Q

What role does histamine play in the inflammatory response?

A

Vasodilation
Increased vascular permeability
Endothelial activation

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22
Q

What role does seratonin play in the inflammatory response?

A

Vasodilation
Increased vascular permeability

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23
Q

What role do prostaglandins play in the inflammatory response?

A

Vasodilation
Pain
Fever

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24
Q

What role do leukotrienes play in the inflammatory response?

A

Increased vascular permeability
Chemotaxis
Leukocyte adhesion and activation

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25
Q

What role does platelet-activating factor play in the inflammatory response?

A

Vasodilation
Increased vascular permeability
Chemotaxis
Leukocyte adhesion
Degranulation
Oxidative burst

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26
Q

What role does ROS play in the inflammatory response?

A

Killing of microbes
Tissue damage

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27
Q

What role does NO play in the inflammatory response?

A

Vascular smooth muscle relaxation
Killing of microbes

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28
Q

What role do cytokines play in the inflammatory response?

A

Local endothelial activation (increased adhesion molecules)
Fever
Pain
Anorexia
Hypotension
Decreased vascular resistance leading to shock

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29
Q

What role do chemokines play in the inflammatory response?

A

Chemotaxis
Leukocyte activation

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30
Q

What role do complement proteins play in the inflammatory response?

A

Vasodilation via mast cell stimulation
Chemotaxis
Leukocyte activation

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31
Q

What role do kinins play in the inflammatory response?

A

Vasodilation
Increased vascular permeability
Pain
Smooth muscle contraction

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32
Q

What role do coagulation cascade proteases (e.g. thrombin) play in the inflammatory response?

A

Endothelial activation
Leukocyte recruitment

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33
Q

List 4 important cytokines involved in acute inflammation

A

TNF
IL-1
IL-6
Chemokines

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34
Q

List 3 important cytokines involved in chronic inflammation

A

IL-12
IFN-y
IL-17

35
Q

What cells produce TNF?

A

Macrophages
Mast cells
T lymphocytes

36
Q

What cells produce IL-1?

A

Macrophages
Endothelial cells
Some epithelial cells

37
Q

What cells produce IL-6?

A

Macrophages
Other cells

38
Q

What cells produce chemokines?

A

Macrophages
Mast cells
T lymphocytes
Endothelial cells
Other cells

39
Q

What cells produce IL-12?

A

Macrophages
Dendritic cells

40
Q

What cells produce IFN-y?

A

T lymphocytes
NK cells

41
Q

What cells produce IL-17?

A

T lymphocytes

42
Q

What role does TNF play in inflammation?

A

Stimulates expression of endothelial activation molecules and secretion of other cytokines
Systemic effects

43
Q

What role does IL-1 play in inflammation?

A

Similar to TNF
Greater role in fever

44
Q

What role does IL-6 play in inflammation?

A

Systemic effects (acute phase response)

45
Q

What role do chemokines play in inflammation?

A

Recruitment of leukocytes to site of inflammation
Migration of cells to normal tissue

46
Q

What role does IL-12 play in inflammation?

A

Increases production of IFN-y

47
Q

What role does IFN-y play in inflammation?

A

Macrophage activation (and therefore increased ability to kill microbes and tumour cells)

48
Q

What role does IL-17 play in inflammation?

A

Recruitment of neutrophils and monocytes

49
Q

Outline three sites of local action of TNF and IL-1, and their respective effects

A
  1. Vascular endothelium: increased adhesion molecule expression, increased production of IL-1 and chemokines, increased procoagulant and decreased anticoagulant activity
  2. Leukocytes: activation, cytokine production
  3. Fibroblasts: proliferation, increased collagen synthesis
50
Q

What are the systemic effects of TNF and IL-1?

A

Fever
Leukocytosis
Increased acute phase proteins
Decreased appetite
Increased sleep/somnolence

51
Q

What are the three possible outcomes of acute inflammation and under what conditions does each occur?

A
  1. Complete resolution: usually when insult is limited or short-lived with little tissue damage
  2. Fibrosis: occurs after substantial tissue destruction, in tissues incapable of regeneration, or when there is abundant fibrin exudation in tissue or serous cavities that cannot be adequately cleared
  3. Chronic inflammation: acute to chronic transition occurs when acute inflammatory response cannot be resolved, either due to persistence of injurious agent or interference with normal process of healing
52
Q

What are the four morphologic patterns of acute inflammation?

A
  1. Serous
  2. Fibrinous
  3. Suppurative/purulent
  4. Ulcers
53
Q

Describe pattern of serous inflammation and give examples (see picture after answer)

A

Outpouring of thin fluid derived from plasma or from mesothelial cell secretions; collects in cavities as an effusion (e.g. pleural, pericardial, peritoneal) or under epidermis as a blister

54
Q

Describe pattern of fibrinous inflammation and give examples (see picture after answer)

A

Large vascular leaks +/- local procoagulant stimulus results in production of fibrinous exudate
Characteristic of inflammation in lining of body cavities (e.g. meningitis, pericarditis)
If not removed via fibrinolysis and macrophage activity, may stimulate fibroblast and blood vessel growth to cause scarring, in a process called organisation

55
Q

Describe pattern of suppurative inflammation and give examples (see picture after answer)

A

Production of purulent exudate consisting of neutrophils, liquefactive necrosis and oedema fluid
Certain bacteria (e.g. Staph) are pyogenic

56
Q

What is an abscess?

A

Localised collection of purulent inflammatory tissue

57
Q

Describe pattern of ulceration and give examples (see picture after answer)

A

Local defect or excavation of the surface of an organ or tissue, produced by sloughing of inflamed necrotic (e.g. in GI or GU tract, or in skin and subcutaneous tissue due to ischaemic necrosis in elderly with vascular conditions)

58
Q

Are peptic ulcers an example of acute or chronic inflammation?

A

Have features of both

59
Q

What are the three main functions of the complement system?

A
  1. Inflammation
  2. Phagocytosis
  3. Cell lysis
60
Q

What is the complement system?

A

Plasma protein system involved in both innate and adaptive immunity
>20 proteins involved, some numbered C1-9

61
Q

How does the complement system contribute to inflammation?

A

C3a, C5a and C4a induce histamine release from leukocytes, causing vasodilation and increased vascular permeability
C5a induces chemotaxis
C5a activates the lipooxygenase pathway of AA metabolism, increasing production of prostaglandins and leukotrienes

62
Q

How does the complement system aid phagocytosis?

A

C3b and iC3b act as opsonins

63
Q

How does the complement system cause cell lysis?

A

MAC (composed of multiple C9 molecules) deposits on cells and increases their permeability to water and ions, causing lysis

64
Q

Describe the three pathways of complement system activation

A
  1. Classical: C1 binds Ag-bound Ab (IgG or IgM)
  2. Alternative: triggered by microbial surface molecules (e.g. endotoxins, LPS), complex polysaccharides, cobra venom and other substances
  3. Lectin: plasma mannose-binding lectins bind to carbohydrates on microbes and directly activates C1
65
Q

Describe the complement cascade

A

C1 is activated by the classical, alternative or lectin pathway
C3 convertase is formed and cleaves C3 into C3a and C3b
C3a recruits and activates leukocytes
C3b acts as opsonin for phagocyte
C3b also binds other C3b molecules to form C5 convertase
C5 convertase cleaves C5 into C5a and C5b
C5b acts on C6-9 to form MAC

66
Q

How does fever occur as part of the inflammatory response?

A

Pyrogens stimulate prostaglandin synthesis in the hypothalamus (PGE2 especially important)
Temperature is raised by 1-4 degrees

67
Q

How do NSAIDs reduce fever?

A

Inhibit COX preventing prostaglandin synthesis

68
Q

Compare and contrast the activity of exogenous and endogenous pyrogens

A

Exogenous pyrogens (e.g. LPS) cause direct leukocyte activation and release of TNF and IL-1 (endogenous pyrogens), which increase COX activity thereby increasing AA metabolism resulting in increased prostaglandin production

69
Q

Give 4 examples of acute phase proteins

A

CRP
Fibrinogen
Serum amyloid A
Hepcidin

70
Q

What cytokine stimulates CRP and fibrinogen production?

A

IL-6

71
Q

What cytokine stimulates SAA production?

A

IL-1

72
Q

How does leukocytosis occur as a result of inflammation?

A

Cytokines cause accelerated release of cells from bone marrow
Prolonged infection also increases production of precursor cells via colony-stimulating factors

73
Q

Give three examples of infections which can cause leukopenia

A

Typhoid
Rickettsiae
Protozoal

74
Q

How do rigors, chills, anorexia, somnolence and malaise occur as part of the inflammatory response?

A

Most likely due to the action of cytokines directly on brain cells

75
Q

How does septic shock occur?

A

High microbial burden causes production of enormous quantities of cytokines, which then cause DIC, CV failure (NO), hypoglycaemia (hepatic dysfunction) and other metabolic disturbances

76
Q

Define chronic inflammation

A

Inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist in varying combinations

77
Q

List three causes of chronic inflammation and give an example of each

A
  1. Persistent infection (e.g. mycobacteria, syphilis)
  2. Immune-mediated inflammatory diseases (due to AI disease e.g. RA, allergy e.g. bronchial asthma, or unregulated immune response to microbes e.g. IBD)
  3. Prolonged toxic exposures (exogenous e.g. silicosis or endogenous e.g. toxic plasma lipid components in atherosclerosis)
78
Q

Identify the three morphologic features of chronic inflammation

A
  1. Infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells)
  2. Tissue destruction
  3. Attempts at healing by connective tissue replacement of damaged tissue
79
Q

Compare the contrast the three main morphologic features of acute and chronic inflammation

A

Acute: vascular changes, oedema, predominant neutrophil infiltration
Chronic: tissue destruction, fibrosis and angiogenesis, predominant mononuclear infiltrate

80
Q

Outline the two main roles of macrophages in chronic inflammation and how these are achieved

A

Inflammation and tissue injury: via reactive oxygen and nitrogen species, proteases, cytokines including chemokines, coagulation factors, AA metabolites
Repair: via growth factors (e.g. PDGF, FGF, TGF-B), fibrogenic cytokines, angiogenic factors (FGF), “remodelling” collagenesis

81
Q

What is a tertiary lymphoid organ?

A

Collection of plasma cells, lymphocytes and antigen-presenting cells which resembles lymphoid tissue, occurring in some strong inflammatory reactions (e.g. in RA)

82
Q

Define granuloma

A

Focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells, surrounded by a collar of mononuclear leukocytes, primarily lymphocytes and occasionally plasma cells

83
Q

Give examples of diseases which cause granulomatous inflammation

A

TB
Sarcoidosis
Cat-scratch disease
Leprosy
Syphilis
Brucellosis
Berryliosis
Reactions of irritant lipids
Some AI diseases (e.g. Crohn’s)

84
Q

What features are characteristic of a tubercle?

A

Tubercle: granuloma produced in TB
Central caseous necrosis with acid-fast bacilli

85
Q

What are giant cells? What two types of giant cell are there?

A

Fused epithelioid cells (therefore multinuclear)
Langhans’ type: peripherally arranged nuclei
Foreign body-type: haphazardly arranged nuclei

86
Q

What are the two types of granulomas?

A
  1. Immune
  2. Foreign body
87
Q

Compare and contrast the appearance of a foreign body and an immune granuloma

A

Foreign body: from inert material too large to be phagocytosed, epithelioid cells and foreign body-type giant cells are apposed to the surface of the foreign body
Immune: when injurious agent is poorly degradable or particulate; macrophages engulf, process and present foreign peptide to antigen-specific T lymphocytes which are then activated and release cytokines, with subsequent activation of more T cells and macrophages (which then transform into epithelioid cells and multinucleate giant cells)

ACEM Primary Written (150 decks)

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