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Basic Pathology > Inflammation > Flashcards

Inflammation Flashcards

1
Q

Inflammation Process

A
  1. Recognition of injurious agent by sentinel cells (macrophage / dendritic / mast).
  2. Recruitment of leukocytes and plasma proteins.
  3. Removal of injurious agent by phagocytes, vasodilation and increased vascular permeability.
  4. Regulation of response.
  5. Repair (return to normal state or fibrous scar formed).
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2
Q

Acute Inflammation:
Major cell involved in Acute Respiratory Distress Syndrome

A

Neutrophils.

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3
Q

Inflammation (Acute and Chronic):
Major cell / molecule involved in Asthma

A

Eosinophils.
IgE antibodies.

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4
Q

Acute Inflammation:
Major cell / molecule involved in Glomerulonephritis

A

Antibodies.
Complement.
Neutrophils.
Monocytes.

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5
Q

Acute Inflammation:
Major cell / molecule involved in Septic Shock

A

Cytokines.

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6
Q

Chronic Inflammation:
Major cell / molecule involved in Arthritis

A

Lymphocytes.
Macrophages.
?antibodies.

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7
Q

Chronic Inflammation:
Major cell / molecule involved in Atherosclerosis

A

Lymphocytes.
Macrophages.

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8
Q

Chronic Inflammation:
Major cell / molecule involved in Pulmonary fibrosis

A

Macrophages.
Fibroblasts.

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9
Q

Acute Inflammation

A
  • Fast onset (minutes - hours).
  • Main cells involved: neutrophils.
  • Usually mild and self-limiting tissue injury.
  • Prominant local and systemic signs.
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10
Q

Chronic Inflammation

A
  • Slow onset (days).
  • Main cells involved: monocytes / macrophages, lymphocytes.
  • Severe and progressive tissue injury.
  • Few local and systemic signs.
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11
Q

Blood Vessel Changes and Role in Acute Inflammation

A

Changes:
* Changes in vascular flow.
* Increased vascular permeability.

Role:
* Maximise movement of plasma proteins and leukocytes out of circulation to area of injury / infection (Exudation).

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12
Q

Exudate

A
  • Extravascular fluid.
  • High protein concentration.
  • High cellular debris.
  • Indicates increased vascular permeability –> inflammatory process.
  • Cloudy appearance due to WBC
  • Specific gravity > 1.02.
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13
Q

Transudate

A
  • Extracellular fluid.
  • Low protein concentration.
  • Little to no cellular debris.
  • Low specific gravity.
  • Protein = mostly albumin.
  • Indicates osmotic or hydrostatic imbalance WITHOUT increased vascular permeability.^
  • Translucent and straw-coloured appearance. NB. EXCEPTION: peritoneal effusion due to lymphatic blockage (Chylous effusion) which appears milky from presence of lipids.

^NB: Normal hydrostatic pressure = 32mm Hg (arterial capillary end) and 12mm Hg (venous capillary end).
Mean colloid osmotic pressure = 25 mm Hg.

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14
Q

Acute Inflammation:
Blood Vessel Changes:
- What are the changes in vascular flow, what mediates it, and why does it occur

A

Vasodilation.^

  • Main mediator = histamine.
  • Action: Affects arterioles –> new capillary bed formed –> increased blood flow –> heat and erythema –> increased permeability of vessels –> exudation –> slow blood flow in vessels and increased viscosity (stasis) –> accumulation of neutrophils (leukocyte recruitment).

^ Earliest manifestation.

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15
Q

Acute Inflammation:
Blood Vessel Changes:
- Vascular permeability

A

Increased.

2 mechanisms-

Contraction of endothelial cells:

  • Chemically mediated.
  • Mediators: histamine, bradykinin, leukotrienes.
  • Rapid.
  • Short-lived (minutes).

Endothelial damage:

  • Causes: direct damage (e.g. thermal burns), induced by microbial toxins, neutrophil adherance.
  • Rapid.
  • May be long-lived (hours to days).
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16
Q

Acute Inflammation:
Lymphatic System Changes

A
  • Increased lymph flow to assist with drainage of excess fluid, cell debris, leukocytes and microbes.
  • Proliferation of vessels to handle increased load.
  • Secondary inflammation of lymph vessels (lymphangitis^) or lymph nodes (lymphadenitis).

^ Red streaks near skin wound = lymphangitis from bacterial infection.

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17
Q

Leukocyte Recruitment to Acute Inflammation Sites:
-Why, key cells, process

A
  • Role: eliminate offending agent.
  • Key cells: Neutrophils, macrophages.
  • Multiple mediators e.g. adhesion molecules, chemokines.

Process:
1. Margination, rolling and adhesion to endothelium.
2. Migration across endothelium and vessel wall.
3. Migration towards site of injury via chemotactic stimulus.

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18
Q

Acute Inflammation:
Leukocyte Recruitment:
- Margination, rolling and adhesion

A

Margination = leukocyte redistribution to periphery of vessels due to vasodilation and stasis.

Rolling = recognition of and binding to adhesion molecules (selectins) slowing movement of leukocytes.

Adhesion = slowing of movement allows binding to adhesion molecules (integrins) which firmly binds leukocyte to endothelium.

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19
Q

Acute Inflammation:
Leukocyte Recruitment:
-Selectins - activated by, types, bind to

A

Activated by cytokines (e.g.TNF, IL-1, chemokines) from tissue macrophages, mast cells and endothelial cells which have encountered microbes or dead tissues.

3 types:
1. L-selectin (on leukocytes).
2. E-selectin (on endothelium).
3. P-selectin (on platelets and endothelium).

Bind to^:
1. Sialyl-Lewis X and other ligands on endothelium.
2. Sialyl-Lewis X on leukocytes.
3. Sialyl-Lewis X on leukocytes.

^Bind with low affinity and fast “off-rate” –> easily disrupted by blood flow –> “rolling” (bind > detach > bind)

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20
Q

Acute Inflammation:
Leukocyte Recruitment:
- Integrins - where are they found, types, ligands, and mediator’s.

A

Found on leukocytes.
Activated by chemokines produced at injury site.

Types:
1. VLA-4 (beta 1 integrin)
2. LFA-1 (beta 2 integrin).
3. MAC-1 (beta 2 integrin).
4. alpha 4 beta 7.

Ligands^ expressed on endothelium:
1. Vascular cell adhesion molecule-1 (VCAM-1).
2. Intercellular adhesion molecule-1 (ICAM-1), ICAM-2.
3. ICAM-1, ICAM-2.
4. VCAM-1, MAdCAM-1 (gut endothelium).

^Ligands activated by TNF and IL-1.

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21
Q

Acute Inflammation:
Leukocyte Recruitment:
- Migration across endothelium

A

Transmigration process = Diapedesis.

Intercellular junction adhesion molecules^ involved = CD31.

NB. CD31 is AKA PECAM-1 (platelet endothelial cell adhesion molecule).

^NB.: leukocyte adhesion molecules deficiencies –> increased susceptibility to bacterial infections.

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22
Q

Acute Inflammation:
Leukocyte Recruitment:
- Migration to injury site

A

Process = chemotaxis = movement along a chemical gradient.

Chemical gradient produced by endogenous and exogenous chemoattractants.

Endogenous chemoattractants:
* Cytokines (e.g IL-8).
* Complement system (e.g. C3a, C5a).
* Arachidonic acid metabolites (e.g. leukotriene B4 [LTB4]).

Exogenous chemoattractants:
* Bacterial products (e.g. peptides, lipids).

How:
1. Chemoattractants bind leukocytes at transmembrane G protein-coupled receptors.
2. Activation of second messengers within leukocyte.
3. Polymerisation of actin at leading edge and localisation of myosin filaments at the back of cell.
4. Extension of filopodia by actin.
5. Pulling of cell in direction of filopodia.

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23
Q

Acute Inflammation:
Leukocyte recruitment:
Exceptions to normal leukocyte infiltrate

A
  • Pseudomonas infections - neutrophils continuously recruited for days.
  • Viral infections - lymphocytes usually first cell.
  • Hypersensitivity reactions - lymphocytes, macrophages, plasma cells.
  • Helminth infections - eosinophils.
  • Allergic reactions - eosinophils.

Normal infiltrate = neutrophils (6-24 hours) followed by monocytes (24-48 hours).

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24
Q

What is the main receptor neutrophils bind to to activate pathogen destruction?

A

Toll like receptors.

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25
Q

How do neutrophils digest pathogens

A

Through:

  • ROS (Reactive Oxygen Species).
  • Reactive Nitrogen species (derived from nitric oxide)^.
  • Lysosomal enzymes.

^NB. More common in macrophages than neutrophils.

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26
Q

What are the causes of Chronic Inflammation?

A
  • Persistant infection by difficult to eradicate microbes (e.g. TB).
  • Immune-mediated inflammatory disease (e.g. Bronchial asthma, Rheumatoid arthritis, MS, IBD).
  • Prolonged exposure to potentially toxic agents (e.g. silicosis, atherosclerosis).
  • Repetitive acute inflammation or persistent injury (e.g. Chronic cholecystitis, chronic peptic ulcer).
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27
Q

Cells in chronic inflammation

A

Mononuclear cells:

  • Macrophages.
  • Lymphocytes.
  • Plasma cells.

Other:

  • Eosinophils (seen in immune reactions and parasitic infections).
  • Mast cells.
  • Neutrophils (seen in chronic bacterial infections e.g. osteomyelitis)
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28
Q

Which type of inflammation is expected to be observed in a patient with sarcoidosis?

A

Granulomatous inflammation

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29
Q

What is a Granuloma and why does it form?

A

What it is:

  • Central core of caseous necrosis (NB. ONLY seen in granulomas associated with certain infectious organisms e.g. TB and called tubercles).
  • Aggregation of activated macrophages (epithelioid^).
  • Collar of mononuclear leucocytes (plasma cells and lymphocytes).
  • Some macrophages may fuse, forming multinucleate giant cells (Langhans-type giant cells).

Why it forms:

  • Cellular attempt to contain an offending agent that is difficult to eradicate.^^

^Macrophages which develop abundant cytoplasm and resemble epithelial cells.
^^This form of granuloma = immune granuloma.

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30
Q

What is the first stage of wound healing?

A

Haemostasis.

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31
Q

What are the steps of wound healing

A
  1. Haemostasis (< 1 week post injury).
  2. Inflammation (< 1 week post injury).
  3. Proliferation / Re-epithelialisation (1 - 2 weeks post injury).
  4. Remodelling (2 - 3 weeks post injury).
  5. Maturation (months post injury).
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32
Q

Diseases causing transudate

A
  • Congestive heart failure.
  • Nephrotic syndrome.
  • PE.
  • Hypoalbuminaemia.
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33
Q

What are Neutrophil extracellular traps, what do they consist of, what produces them, and what is their function?

A

What it is:
* Extracellular fibrillar networks of neutrophil clear material.
* Viscous net.

Consist of:

  • Nuclear chromatin (including histones and associated DNA).^
  • Granule proteins (antimicrobial peptides and enzymes).

Produced by:

  • Neutrophils in response to infectious pathogens (bacteria, fungi) and inflammatory mediators (chemokines, cytokines, complement, ROS).

Function:

  • Concentrate antimicrobial substances at sites of infection.
  • Trap microbes.
  • Helps to prevent microbe spread.

^Source of nuclear antigens in systemic autoimmune diseases such as Lupus (reaction against self DNA and nucleoproteins).

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34
Q

Which pathway regulates the sprouting and branching of new vessels in inflammation and healing?

A

NOTCH pathway

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35
Q

Which factor triggers the alternate pathway in a patient with GNB pneumonia?

A

Lipopolysaccharide.

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36
Q

Neutrophil inability to phagocytose and kill organisms is due to which problem?

A

Diminished opsonisation.

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37
Q

What does a deficiency of integrins and selectins cause in neutrophils in inflammation?

A

Prevents rolling (selectins) and adhesion (integrins) of neutrophils along, and to, the blood vessel wall.

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38
Q

What does a microtubular protein defect cause in neutrophils in inflammation?

A

Prevents movement of neutrophils through the blood vessel wall.

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39
Q

Which cell causes osteophyte formation in osteoarthritis?

A

Chondrocytes.

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40
Q

What pathological abnormality would be expected in inflammation of serosal surfaces of the heart and detected by the presence of a friction rub?

A

Fibrinous exudate.

Protein-rich exudate with fibrin strands and inflammatory cells.

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41
Q

What causes the tissue destruction that accompanies abscess formation in acute inflammation?

Cerebral abscess appears as an enhancing ring like lesion

A
  • Release of lysosomal enzymes from neutrophils.
  • Aided by release of reactive oxygen species.
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42
Q

What causes vasodilation in inflammation?

A
  • Histamine.
  • Prostaglandins.
  • NO.
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43
Q

What causes vascular permeability in inflammation?

A
  • Histamine.
  • Serotonin.
  • C3a and C5a.
  • Bradykinin.
  • Leukotrienes.
  • PAF.
  • Substance P.
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44
Q

What causes Chemotaxis in inflammation?

A
  • TNF.
  • IL-1.
  • Chemokines.
  • C3a and C5a.
  • Leukotrienes.
  • Bacterial products.
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45
Q

What causes fever in inflammation?

A
  • IL-1.
  • TNF.
  • Prostaglandins.
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46
Q

What causes pain in inflammation?

A
  • Prostaglandins.
  • Bradykinin.
  • Substance P.
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47
Q

What causes tissue damage in inflammation?

A
  • Lysosomal enzymes of leukocytes.
  • ROS.
  • Nitric oxide.
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48
Q

Acute inflammation:
Leukocyte activation:
- What do G-protein coupled receptors on leukocytes recognise?

A
  • Bacterial products.
  • Chemokines.
  • Lipid mediators.
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49
Q

Acute inflammation:
Leukocyte activation:
- What is the cellular response and outcome of binding to G-protein coupled receptors?

A

Cellular response:

  • Cytoskeleton changes.
  • Signal transduction.

Outcome:

  • Increased integrin activity –> adhesion to endothelium.
  • Chemotaxis –> migration into tissue.
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50
Q

Acute inflammation:
Leukocyte activation:
- What does microbe binding to TLR on leukocytes cause?

A
  • Production of mediators (e.g. arachidonic acid metabolites, cytokines) –> amplification of inflammation.
  • Production of ROS and lysosomal enzymes –> killing of microbe.
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51
Q

Chronic Inflammation:
-What are Classically Activated macrophages (M1) and what are they triggered by

A

What they are:

  • Macrophages with microbicidal activity.
  • Causes inflammation.

Triggered by:

  • Microbial products (e.g. Toll like receptor ligands, IFN-gamma).
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52
Q

Chronic inflammation:
- What are Alternatively activated macrophages (M2) and what are they triggered by

A

What they are:

  • Macrophages involved with tissue repair and fibrosis.
  • Cause anti-inflammatory effects.

Triggered by:

  • IL-13.
  • IL-4
53
Q

What is the abnormality in Chediak Higashi syndrome and what is the consequence of this?

A

Abnormality:
Defect in microtubule function –> inability for lysosome to fuse with phagosome –> bacteriacidal defect (i.e. unable to lyse microbes).

Consequence:
Increased susceptibility to STAU infections.

54
Q

What is the manifestation of leukocytes with inherited defects in adhesion?

A

Recurrent bacterial infections.

55
Q

What are the manifestations of leukocytes with inherited defects in phagolysosomes?

A
  • Chediak Higashi Syndrome.
  • Neutropaenia.
  • Defective granulation.
  • Delayed microbial killing.
56
Q

What are the manifestations of leukocytes with inherited defects in microbicidal activity?

i.e. Chronic Granulomatous disease

A

Susceptibility to recurrent bacterial infections.

57
Q

What are the manifestations of leukocytes with acquired deficiencies?

i.e. following Chemotherapy.

A

Bone marrow suppression.

58
Q

What causes release of acute phase proteins in inflammation?

A
  • IL-1.
  • IL-6.
59
Q

What causes leukocyte production in bone marrow in inflammation?

A
  • IL-1.
  • Il-6.
  • TNF.
60
Q

What causes reduced cardiac output in inflammation?

A

TNF

61
Q

What stimulates thrombus formation in inflammation?

A

TNF

62
Q

What causes insulin resistance in skeletal muscle in inflammation?

A

TNF

63
Q

What do NSAIDs inhibit and what is the consequence of this?

A

Inhibit:
Cyclooxygenase (COX-1 and COX-2)

Consequence:

  • Inability to produce prostaglandins –> reduced pain and fever.
  • SE: gastric ulceration.^

^NB. Selective COX-2 inhibitors incrase risk of thrombotic cardiovascular and cerebrovascular events.

64
Q

What can you see in chronic inflammation?

A
  • Mononuclear cells (macrophages, lymphs, plasma cells).
  • Tissue destruction.
  • Attempts at healing
    - Angiogenesis
    - Fibrosis
65
Q

What is serous inflammation and what are some examples?

A

What it is:
* Inflammation marked by Watery, protein-poor, cell poor fluid.
* Derived from serum OR from mesothelial cell secretions.

Examples:

  • Pleural effusion.
  • Skin blister from burn or viral infection
66
Q

What is an effusion?

A

Accumulation of fluid in a serous cavity.

67
Q

Where are mesothelial cells found?

A

Lining cavities:

  • Peritoneal
  • Pleural
  • Pericardial
68
Q

What is Fibrinous inflammation, where does it occur and what are some examples?

A

What it is:

  • Inflammation in more severe injury.
  • Greater vascular permeability–> fibrinous exudate.
  • Large molecules (e.g. fibrinogen –> fibrin strands^) to pass through endothelium.
  • Protein-rich.
  • Inflammatory cells +.

Where it occurs:

  • Serosal surfaces (e.g. pericardium).
  • Mucous membranes.
  • Lungs (Pleura).
  • Meninges.

Examples:

  • Pericarditis.
  • Dysentery.
  • Pneumonia.

^Histology: eosinophilic meshwork of threads OR an amorphous coagulum.

69
Q

What is Suppurative (Purulent) Inflammation, what organisms typically cause purulant inflammation and what are some examples?

A

What it is:

  • Inflammation causing large amounts of purulent exudate (pus).
  • Contains:
    • Neutrophils.
    • Necrotic cells.
    • Oedema fluid.

Organisms:

  • Pyogenic organisms (e.g. Staphylococci).

Example:

  • Abscess.
  • Bacterial meningitis.
  • Acute appendicitis.
70
Q

What is Granulomatous inflammation and what are the causes?

A

What it is:
Form of chronic inflammation.
Chrctrsd by:
* Collections of activated macrophages.
* +/- T lymphocytes.
* +/- necrosis.

Causes:

  1. Microorganisms.
  2. Foreign body precipitants.
  3. Ideopathic / immunological.
71
Q

Granulomatous inflammation causes:
Microorganisms:
-Examples

A
  • TB (caseating granuloma [tubercle].
  • Leprosy.
  • Syphillis.
  • Cat-scratch disease (rounded or stellate granuloma).
  • Parasites (e.g. schistosomiasis)
72
Q

Granulomatous inflammation Causes:
Foreign body precipitants:
-Examples

A
  • Silicon or beryllium in lungs.
  • Urate crystals (gout).
  • Suture material.

Granulomas are known as Foreign body granulomas

73
Q

Granulomatous inflammation Causes:
Ideopathic / immunologic:
-Examples

A
  • Crohn’s.
  • Sarcoidosis.
74
Q

Describe Langhans Giant Cells and what disease are they commonly associated with?

A

Description:
* Large cell.
* Horseshoe shaped nuclei.
* Nuclei found in periphery.

Disease:
TB

75
Q

Describe Foreign-body giant cells.

A
  • Large cell.
  • Multiple nuclei.
  • Nuclei scattered throughout cell (can be central).
76
Q

Steps of wound healing:
Haemostasis:
-What is involved and what are the key cells

A

What is involved:

  • Vascular constriction.
  • Platelet aggregation.
  • Fibrin plug formation.
  • Release of growth factors and cytokines.
  • Hypoxia.

Key cells:

  • Platelets.
77
Q

Steps of wound healing:
Inflammation:
-What is involved and what are the key cells

A

What is involved:

  • Neutrophil infiltration.
  • Monocytes differentiate to macrophages.
  • Lymphocyte infiltrate.
  • Fibroblasts and endothelial cells activated for granulation tissue (wound debridement).

Key cells:

  • Neutrophils.
  • Monocytes.
  • Macrophages.
78
Q

Steps of wound healing:
Proliferation / Re-epithelialisation:
-What is involved and what are the key cells

A

What is involved:

  • Granulation tissue established.
  • Keratinocyte migration to the wound and proliferation of keratinocytes (Re-epithelialisation / epidermal resurfacing.
  • Angiogenesis.
  • Collagen synthesis (provides tensile strength^).
  • ECM formation.
  • Fibroplasia.

Key cells:

  • Keratinocytes.
  • Fibroblasts.
  • Endothelial cells.

^Clinical relevance = collagen formation required before sutures can be removed, therefore, suture removal commonly done in 1-2 weeks (are exceptions for rapid healing areas, children and immunosuppressed / diabetics)

79
Q

Steps of wound healing:
Remodelling:
-What is involved and what are the key cells

A

What is involved:

  • Less inflammatory cells, more tissue.
  • Re-epithelialisation completed.
  • Mature granulation tissue (scar formation).
  • Collagen remodelling.
  • Vascular maturation and regression.
  • Wound may contract.
  • ECM degradation.

Key cells:

  • Myofibroblasts.
80
Q

Steps of wound healing:
Maturation:
-What is involved

A
  • Mature fibrous scar under thinned epidermis.
  • Flattened rete ridges of epidermis.
  • No dermal papillae.
  • No regeneration of appendigeal structures.

i.e. Hypertrophic scarring with thickened collagenous bundles.

81
Q

Diseases causing exudate

A
  • Pneumonia.
  • Cancer.
  • TB.
  • Viral infection.
  • Autoimmune.
82
Q

What are the two mechanisms for angiogenesis?

A
  1. Existing vessels.
  2. Endothelial precursors cells (ECPs).
83
Q

Mechanisms of angiogenesis:
Existing vessels:
-How

A
  • Vasodilation and increased permeability of existing vessels.
  • Degradation of ECM.
  • Migration of endothelial cells.
  • New vessel formation.
84
Q

Mechanisms of angiogenesis:
Endothelial precursor cells (ECPs):
-How

A
  • ECPs recruited from bone marrow to tissue.
  • New vessels formed.

NB. ECPs increased in ischaemic patients.

85
Q

Angiogenesis growth factors and receptors

A
  • VEGF:
    • secreted by mesenchymal and stromal cells.
    • Function: endothelial cell migration and proliferation.
  • NOTCH:
    • Modulates vasculogenesis.
  • Pericytes / smooth muscle cells:
    • Stabilises newly formed vessels.
  • Angiopoietin 1:
    • Matures new blood vessel.
  • Angiopoietin 2:
    • Stimulates angiogenesis via VEGF.
86
Q

Angiogenesis regulators

A

Proteins from ECM:

  • Integrins - Direct endothelial cell migration.
  • Proteinases - remodel tissue.
87
Q

Acute inflammation:
Leukocyte activation:
- What is the cellular response and outcome of microbe binding to leukocyte phagocytic receptor?

A

Cellular response:

  • Phagocytosis of microbe into phagosome.
  • Production of ROS.
  • Production of lysosomal enzymes.

Outcome:

  • Microbicidal activity of leukocytes.
  • Killing of microbes.
88
Q

Acute inflammation:
Leukocyte activation:
- What is the cellular response and outcome of cytokine binding to leukocyte cytokine receptor?

A

Cellular response:

  • Production of ROS.
  • Production of lysosomal enzymes.
  • Production of mediators (e.g. arachidonic acid metabolites, cytokines).

Outcome:

  • Microbicidal activity of leukocytes.
  • Killing of microbes.
  • Amplification of inflammatory reaction.
89
Q

Acute inflammation:
What are the steps in phagocytosis

A
  1. Recognition and attachment of pathogen / particle to be ingested.
  2. Engulfment with subsequent phagocytic vacuole formation (phagosome).
  3. Killing of the microbe and degradation of the ingested material.
    • Requires fusion of phagosome with lysosome (phagolysosome).
90
Q

Acute inflammation:
What increases the efficiency of phagocytosis and what are the most common examples.

A

Opsonins.

Examples:

  • IgG antibodies.
  • C3b.
  • Mannose-binding lectin.
  • Collectins.
91
Q

What is the Respiratory burst?

A

The oxidative reaction in neutrophils which produce ROS.

Molecules required:
* Nicotinamide-adenine dinucleotide phosphate (NADPH).
* Oxygen.
* NADPH oxidase (oxidises NADPH –> NADP in the presence of oxygen to also form superoxide anion, a ROS).

92
Q

What is ‘Frustrated phagocytosis’, when does it occur, and what does it cause?

A

What is it:

  • Leukocyte response.
  • Activation and release of lysosomal enzymes into extracellular environment.

When does it occur:

  • When leukocytes are unable to surround and ingest pathogens / foreign material easily (e.g. imune complexes deposited on glomerular basement membrane).

Causes:

  • Damage to normal host tissue.

When the leukocyte gets “frustrated”, it becomes super destructive and destroys everything including host tissue.

93
Q

Which T lymphocyte and associated cytokine is important in acute inflammation, what is it’s function in acute inflammation, and what issue does it cause if an individual is deficient in this?

A

Th17 cells –> cytokine IL-17.

Role in acute inflammation:

  • Induces secretion of chemokines –> recruitment of other leukocytes.

Deficiency of Th17 / IL-17:

  • Increased susceptibility to fungal and bacterial infections.
  • Develop “cold abscesses” (particularly in skin).
94
Q

What are common stop signals for termination of acute inflammatory response?

A
  • Lipoxins (arachidonic acid metabolite).
  • Transforming Growth Factor-beta (TGF-beta).
  • IL-10.
  • Neuronal impulses (cholinergic).
95
Q

Mediators of inflammation:
What are the vasoactive amines?

A
  • Histamine.^
  • Sertonin.

^Main vasoactive amine.

96
Q

Mediators of inflammation:
Vasoactive amines:
-Histamine role and histmine triggers

A

Role:
* Arteriole dilation.
* Increased vascular permeability.
* Endothelial activation.

Triggers:
* Physical injury.
* Antien binding to IgE abs on Mast cells.
* C3a and C5a.
* Neuropeptides (Substance P).
* Cytokines (IL-1 and IL-8).

97
Q

Mediators of inflammation:
What are the Arachidonic acid metabolites?

A
  • Prostaglandins.
  • Leukotrines.
98
Q

Mediators of inflammation:
How are arachidonic acid metabolites formed

A
  1. Cell membrane phospholipids release arachidonic acid through phospholipases (mainly Phospholipase A2).
  2. Synthesis of arachidonic acid by cyclooxygenase OR 5-lipoxygenase.

Cyclooxygenase pathway (COX-1 and COX-2) produces:

  • Prostacyclin (PGI2).
  • Thromboxane A2 (TXA2).
  • Prostaglandin (PG) G2, H2, D2, E2.

5-lipoxygenase pathway produces:

  • Leukotrienes.
  • Lipoxin.
99
Q

Mediators of inflammation:
Arachidonic Acid Metabolites:
-Prostacyclin (PGI2) role

A
  • Vasodilation.
  • Inhibits platelet aggregation.
  • Enhances other mediators involved with increasing vascular permeability and chemotaxis.
100
Q

Mediators of inflammation:
Arachidonic Acid Metabolites:
-Thromboxane A2 (TXA2) role

A
  • Vasoconstriction.
  • Promotes platelet aggregation.
101
Q

Mediators of inflammation:
Arachidonic Acid Metabolites:
-PGD2 and PGE2 roles

A
  • Vasodilation.
  • Increased vascular permeability.
  • Leukocyte chemoattractant (PGD2).
  • Pain (PGE2).
  • Fever (PGE2).
102
Q

Mediators of inflammation:
Arachidonic Acid Metabolites:
-Leukotrienes (LT) role

A
  • Increased vascular permeability (LT C4, D4, and E4).^
  • Chemotaxis (LT B4).
  • Leukocyte adhesion (LT B4).
  • Leukocyte activation (LT B4).
  • Bronchospasm (LT C4, D4, and E4).^^

^More potent than histamine.
^^Basis for leukotriene receptor antagonists in asthma.

103
Q

Mediators of inflammation:
Arachidonic Acid Metabolites:
-Lipoxin (LX) role

A

Anti-inflammatory:
* Inhibit neutrophil adhesion.
* Inhibit neutrophil chemotaxis.

104
Q

What do steroids inhibit?

A

Transcription of genes encoding many inflammatory proteins.

E.g.

  • Phospholipase A2.
  • COX-2.
  • IL-1.
  • TNF.
  • Inducible nitric oxide synthase (iNOS).

  • Broad spectrum antiinflammatory agents.
105
Q

Mediators of inflammation:
What are cytokines and what are common examples of these?

A

What they are:

  • Proteins that mediate and regulate immune and inflammatory reactions.

Examples (Acute inflammation):

  • TNF.
  • IL-1.
  • IL-6.
  • Chemokines.
  • IL-17.

Examples (Chronic inflammation):

  • IL-12.
  • IFN-gamma.
  • IL-17.
106
Q

Mediators of inflammation:
Cytokines:
-TNF, IL-1 roles

A
  • Endothelial activation.
  • Activation of leukocytes and other cells.
  • Systemic acute phase response^ - fever (IL-1 > TNF), metabolite abnormalities, hypotension (TNF), promotion of lipid and protein metabolism and suppression of appetite –> cachexia (TNF).

^IL-6 also implicated here.

107
Q

Mediators of inflammation:
-What are chemokine and what are their roles in acute inflammation and in the mainenance of tissue architecture

A

What are they:

  • Family of small proteins.

Roles (Acute inflammation):

  • Stimulate leukocyte attachment to endothelium.
  • Chemoattractants for leukocytes.

Roles (Maintenance of tissue architecture):

  • Organise cell types in different anatomic regions of tissue (e.g. T and B lymphocytes in discrete areas of spleen and LNs).
108
Q

Mediators of inflammation:
Complement:
-Roles

A
  • Leukocyte chemotaxis (C5a)
  • Leukocyte activation.
  • Direct target killing (MAC - C6-C9).
  • Vasodilation through stimulation of histamine (C3a, C5a, C4a).
  • Activates lipoxygenase pathway (C5a).
  • Act as opsonins (C3b)
109
Q

Mediators of inflammation:
Complement:
-What are the three pathways and what do they all lead to?

A

Pathways:

  • Classical.
  • Alternative.
  • Lectin.

Lead to:

  • Formation of C3 convertase enzyme –> cleaves C3 into C3a and C3b.
110
Q

Mediators of inflammation:
Complement:
-Classical pathway initiators

A
  • Antibody (IgG or IgM) - antigen complexes.
  • Complex binds to C1 –> C1 activation.
111
Q

Mediators of inflammation:
Complement:
-Alternative pathway initiators

A

Microbial surface molecules e.g.:

  • Endotoxin.
  • LPS.
  • Complex polysaccharides.
  • Cobra venom.
112
Q

Mediators of inflammation:
Complement:
-Lectin pathway initiators

A
  • Mannose-binding lectin - microbe CHO binding.
  • Directly activates C1.
113
Q

What is the significance of the inability to form a Membrane Attack Complex (MAC)?

A

Predisposes to Neisseria infections

114
Q

What disease is caused by deficiency of C1 inhibitor?

A

Hereditary angioedema.

115
Q

What disease is caused by an acquired deficiency of glycophosphatidylinositol (GPI) anchors and why?

A

Paroxysmal Nocturnal haemoglobinuria.

Why:

  • GPI anchors regulate complement activation.
  • No GPI anchors = no regulation –> excess complement activation –> RBC lysis (sensitive to complement mediated lysis).
116
Q

What disease is caused by an inherited defect of complement factor H and why?

A

Haemolytic uraemic syndrome.

Why:

  • Factor H role = inhibit alternative pathway.
  • Defective Factor H = unregulated alternative pathway –> coplement deposits in glomerular vessels –> endotherlial damage and platelet rich thrombi.
117
Q

What disease is linked to polymorphisms in complement Factor H gene?

A

Age-related macular degeneration.

118
Q

What is an ulcer?

A

Local defect, or excavation, of the surface of an organ or tissue that is produced by the shedding of inflamed necrotic tissue.

Only occurs when tissue necrosis and inflammation exist on or near a surface.

119
Q

What are macrophages in the liver called?

A

Kupffer cells.

120
Q

What are macrophages in the spleen and lymph nodes called?

A

Sinus histiocytes.

121
Q

What are macrophages in the CNS called?

A

Microglial cells.

122
Q

What are macrophages in the lung called?

A

Alveolar macrophages.

123
Q

What is the role of T and B lymphocytes in chronic inflammation?

A

Amplify and propogate chronic inflammation through a cycle of cellular reactions, involving macrophages and cytokines, which when prolonged result in granuloma formation.

124
Q

What are common acute phase proteins?

A
  • CRP.
  • Fibrinogen.
  • Serum amyloid A.
  • Hepcidin.
  • Thrombopoietin.
125
Q

What are the systemic effects of inflammation (AKA acute-phase response).

A
  • Fever.
  • Increased acute-phase proteins.
  • Leucocytosis.^
  • Other: (Tachycardia, rigors / chills, anorexia, somnolence, malaise)
  • Severe: Septic shock (DIC, hypotension, metabolic disturbance [e.g. insulin resistance and hyperglycaemia]).

^Exceptions: Typhoid, rickettsiae, some protozoa (cause leucopaenia).

126
Q

How does liver regeneration work?

A

2 methods:

  1. From existing hepatocyte cells.
  2. From progenitor stem cells (located in liver).
127
Q

Liver regeneration from existing hepatocytes

A
  1. Macrophages (Kupffer cells) release IL-6.
  2. Stimulate hepatocytes (which are in phase G0) to express growth factor receptors.
  3. EGF and HGF bind to receptors.
  4. Hepatocytes enter G1.
  5. Growth of hepatocytes.
  6. TGF-beta stimulates termination of proliferation when liver regenerated.
128
Q

Which mediator contributes to giant cell formation in granulomatous inflammation and which cells secrete this molecule?

A

Mediator = Interferon-gamma.
Secreted by = activated T cells.

129
Q

Giant cells on histology indicate what type of inflammation and the formation of what?

A
  • Granulomatous inflammation.
  • Granloma formation.

Basic Pathology (14 decks)

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