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Pathology 1st LE > Inflammation and Repair (trans 3) > Flashcards

Inflammation and Repair (trans 3) Flashcards

1
Q

Remember
Inflammation is a response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed to eliminate the offending agents.

A
  • *clinical correlation**
  • Brain edema
  • Deformities in rheumatoid arthritis, atherosclerosis, lung fibrosis, hypersensitivity reactions
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2
Q

Acute Inflammation - the initial rapid response to infections and tissue damage (edema and emigration of leukocytes especially neutrophils)

A

Chronic Inflammation - the protracted phase when an initial response fails to clear the stimulus (lymphocytes and macrophages)

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3
Q

VASCULAR EVENTS (Reactions of blood vessels in acute inflammation):
1. Changes in vascular flow and caliber
brief vasoconstriction – the natural response of the body to an injurious stimulus or agent
vasodilation of arterioles leading to the opening of new capillary beds – one of the earliest manifestations of acute inflammation
increase in hydrostatic pressure. Thus, there is transudate formation. In contrast, exudate formation is due to an increase in vascular permeability
**Remember: At this point there is still no increase in capillary permeability, and therefore, a transudate is produced.

A
  1. Increased vascular permeability (Vascular Leakage) – hallmark of acute inflammation
    Endothelial cell contraction: Also known as the immediate transient response, which occurs rapidly in short durations (15-30 minutes)
    Direct endothelial injury: Also known as the Immediate sustained response or delayed prolonged response (ex. Sunburn and type IV hypersensitivity reaction)
    Leukocyte-mediated endothelial injury
    Increased transcytosis
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4
Q

Due to increased load, lymphatic vessels proliferate during inflammation reactions

A
  • *clinical correlation**
    1. Lymphangitis – secondarily inflamed lymphatics
    2. Lymphadenitis – inflamed lymph nodes due to hyperplasia of lymphoid follicles
    3. Red streaks near a skin wound = telltale sign of an infection in the wound. The streaking follows the course of the lymphatic channels
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5
Q

Endothelial-Leukocyte Adhesion Molecules
P-selectin
Leukocyte molecule:
Major role:

A

Endothelial-Leukocyte Adhesion Molecules
P-selectin
Leukocyte molecule: Sialyl-Lewis X-modified proteins
Major role: Rolling (neutrophils, monocytes, T lymphocytes)

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6
Q

Endothelial-Leukocyte Adhesion Molecules
E-selectin
Leukocyte molecule:
Major role:

A

Endothelial-Leukocyte Adhesion Molecules
E-selectin
Leukocyte molecule: Sialyl-Lewis X-modified proteins
Major role: Rolling and adhesion (neutrophils, monocytes, T lymphocytes)

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7
Q

Endothelial-Leukocyte Adhesion Molecules
GlyCam-1, CD34
Leukocyte molecule:
Major role:

A

Endothelial-Leukocyte Adhesion Molecules
GlyCam-1, CD34
Leukocyte molecule: L-selectin
Major role: Rolling (neutrophils, monocytes)

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8
Q

Endothelial-Leukocyte Adhesion Molecules
ICAM-1 (immunoglobulin family)
Leukocyte molecule:
Major role:

A

Endothelial-Leukocyte Adhesion Molecules
ICAM-1 (immunoglobulin family)
Leukocyte molecule: CD11/CD18 (β2) integrins (LFA-1, Mac-1)
Major role: Adhesion, arrest, transmigration (neutrophils, monocytes, lymphocytes)

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9
Q

Endothelial-Leukocyte Adhesion Molecules
VCAM-1 (immunoglobulin family)
Leukocyte molecule:
Major role:

A

Endothelial-Leukocyte Adhesion Molecules
VCAM-1 (immunoglobulin family)
Leukocyte molecule: VLA-4 (β1) integrin
Major role: Adhesion (eosinophils, monocytes, lymphocytes)

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10
Q

CELLULAR EVENTS (Leukocyte Recruitment to Sites of Inflammation)

  1. Extravasation
  2. Phagocytosis
A

Extravasation
- journey of leukocytes from the vessel’s lumen to the interstitial tissue
- A multistep process that is mediated by adhesion molecules and cytokines called chemokines
Phagocytosis
- ingestion of particulate material (e.g. tissue debris, living or dead bacteria, other foreign cells) by phagocytic cells.
- Most important phagocytic cells are the macrophages.
- Leukocyte receptors: recognize offending agents and deliver them and amplify inflammatory process.

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11
Q

Steps during extravasation

  1. Margination
    - More leukocytes assume a peripheral position along endothelial surface.
  2. Rolling over
    - Leukocytes adhere transiently to endothelium, detach and bind again. This process is mediated by selectins
  3. Adhesion
    - The connective tissue matrix contains proteoglycans that contain INTEGRINS found on the surface of neutrophils. The integrins will be activated and will cause firm adhesion of the neutrophils to the endothelium.
A
  1. Diapidesis
    - Occurs in post-capillary venules; chemokines act on adherent leukocytes to migrate toward chemical concentration gradient; mediated by PECAM-1 or CD31, a member of the immunoglobulin superfamily that serves as adhesion molecules between endothelial cells involved in the migration of leukocytes.
  2. Chemotaxis
    - The unilateral movement of leukocytes toward the site of injury across a gradient
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12
Q

3 Major opsonins:

  1. Fc fragments of IgG antibodies
  2. from complement activation via immune or non-immune mechanisms
  3. Plasma lectins – MBL (Mannose-binding lectin)
A

Phagocytic receptors

  • receptors for microbial products (toll-like)
  • G-protein coupled receptors
  • opsonin receptors
  • cytokine receptors
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13
Q

Steps in phagocytosis

  1. Recognition and attachment
    * *Opsonization – process of coating a particle by opsonins to target it for ingestion/phagocytosis
  2. Engulfment – with subsequent formation of a phagocytic vacuole
    * *Extension of the cytoplasm (pseudopods) flow around the offending particle and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle.
    * *The phagosome fuses with a lysosomal granule resulting to phagolysosome. Degranulation occurs next wherein the granules from lysosome are discharged into the phagolysosome
  3. intracellular destruction of microbes and debris
A

Types of intracellular destruction of microbes and debris

  1. Oxygen-dependent microbial killing: most effective
    * * H2O2-MPO and halide system
  2. Oxygen-independent microbial killing: less effective. Mediated by:
    - BPI (bactericidal permeability increasing protein) - binds bacterial endotoxin
    - Lysozyme
    - Lactoferrin
    - MBP (major basic protein)
    - defensins
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14
Q

REMEMBER

Cells of the adaptive immunity, also contribute to acute inflammation.

A
  • TH17 cells are the most important of these cells.

- Produces cytokine IL-17, which induces secretion of chemokines that recruit other leukocytes.

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15
Q

Leukocyte-Induced Injury (ACUTE)
Acute Respiratory Distressed Syndrome
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Acute Respiratory Distressed Syndrome
Cells and Molecules Involved in Injury: Neutrophils

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16
Q

Leukocyte-Induced Injury (ACUTE)
Acute Transplant Rejection
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Acute Transplant Rejection
Cells and Molecules Involved in Injury: Lymphocytes; antibodies and complement

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17
Q

Leukocyte-Induced Injury (ACUTE)
Asthma
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Asthma
Cells and Molecules Involved in Injury: eosinophils

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18
Q

Leukocyte-Induced Injury (ACUTE)
Glomerulonephritis
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Glomerulonephritis
Cells and Molecules Involved in Injury: Neutrophils, monocytes; antibodies and complement

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19
Q

Leukocyte-Induced Injury (ACUTE)
Septic Shock
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Septic Shock
Cells and Molecules Involved in Injury: Cytokines

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20
Q

Leukocyte-Induced Injury (ACUTE)
Lung Abscess
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (ACUTE)
Lung Abscess
Cells and Molecules Involved in Injury: Neutrophils (and bacteria)

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21
Q

Leukocyte-Induced Injury (chronic)
Arthritis
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (chronic)
Arthritis
Cells and Molecules Involved in Injury: Lymphocytes, macrophages

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22
Q

Leukocyte-Induced Injury (chronic)
Asthma
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (chronic)
Asthma
Cells and Molecules Involved in Injury: Eosinophils; IgE antibodies

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23
Q

Leukocyte-Induced Injury (chronic)
Atherosclerosis
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (chronic)
Atherosclerosis
Cells and Molecules Involved in Injury: Macrophages; lymphocytes

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24
Q

Leukocyte-Induced Injury (chronic)
Chronic transplant rejection
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (chronic)
Chronic transplant rejection
Cells and Molecules Involved in Injury: Lymphocytes, cytokines

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25
Q

Leukocyte-Induced Injury (chronic)
Pulmonary fibrosis
Cells and Molecules Involved in Injury:

A

Leukocyte-Induced Injury (chronic)
Pulmonary fibrosis
Cells and Molecules Involved in Injury: Macrophages; fibroblasts

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26
Q

Defects in Leukocyte Functions
(genetic diseases)
Leukocyte adhesion deficiency 1 (LAD 1)

A

Defective leukocyte adhesion because of mutations in beta chain of CD11/CD18 integrins

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27
Q

Leukocyte Functions
(genetic diseases)
Leukocyte adhesion deficiency 2 (LAD 2)

A

Defective leukocyte adhesion because of mutations in fucosyl transferases required for synthesis of sialylated oligosaccharides (ligands for selectins)

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28
Q

Leukocyte Functions
(genetic diseases)
Chronic Granulomatous Disease (x-linked)

A

Decreased oxidative burst; defect in phagocyte oxidase (membrane components, gp91phox)

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29
Q

Leukocyte Functions
(genetic diseases)
Chronic Granulomatous Disease (autosomal recessive)

A

Decreased oxidative burst; defect in phagocyte oxidase (cytoplasmic component p47phox, p67phox)

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30
Q

Leukocyte Functions
(genetic diseases)
MPO deficiency

A

Decreased microbial killing because of defective MPO-H2O2 system

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31
Q

Leukocyte Functions
(genetic diseases)
Chediak-higashi syndrome

A

Decreased leukocyte functions because of mutations affecting protein involved lysosomal membrane traffic, defective fusion of phagosomes and lysosomes

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32
Q

Leukocyte Functions
(inherited)
Bone marrow suppression: tumors, radiation, and chemotherapy

A

Production of leukocytes

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33
Q

Leukocyte Functions
(inherited)
Diabetes, malignancy, sepsis, chronic dialysis

A

Adhesion and chemotaxis

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34
Q

Leukocyte Functions
(inherited)
Leukemia, anemia, sepsis, malnutrition, diabetes

A

Phagocytosis and microbicidal activity

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35
Q

lysosomal granule contents

Primary Granules

A 
 Myeloperoxidase
 Lysozyme
 Defensins
 Bactericida / permeability increasing protein
 Elastase
 Cathepsins Protease 3
 Glucuronidase
 Mannosidase
 Phospholipase A2
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36
Q

lysosomal granule contents

Secondary Granules

A 
 Lysozyme
 Lactoferrin
 Collagenase
 Complement activator
 Phospholipase A2
 CD11b/CD18
 CD11c/CD18
 Laminin
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37
Q

lysosomal granule contents

Tertiary Granules

A 
 Gelatinase
 Plasminogen Activator
 Cathepsins
 Glucuronidase
 Mannosidase
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38
Q

Neutrophils

  • common inflammatory cells found in acute inflammatory response
  • Manifests in the first 6 to 24 hours after injury
A

Exceptions

  • Pseudomonal infections – neutrophils for 2-4 days
  • Viral infections: lymphocytes
  • Hypersensitivity reactions: eosinophils
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39
Q

Characteristics and Functions of Monocytes/Macrophages

A

a. Regulates inflammatory response
b. Regulates coagulation/fibrinolytic pathway
c. Regulates immune response

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40
Q

Specialized cells with cytoplasmic granules (histamine) which are released in response to type I hypersensitivity reactions

A

Mast cells

**Participates in both acute and chronic inflammatory reactions

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41
Q

Endothelial Cells
Characteristics and Functions:
o Maintains vascular integrity
o Regulates platelet aggregation
o Regulates vascular contraction and relaxation
o Mediates leukocyte recruitment in inflammation

A 
Primary Inflammatory Mediators
o Von Willebrand Factor
o Nitric Oxide
o Endothelins
o Prostanoids
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42
Q

Major cell types that produce mediators of acute inflammation are:

A

platelets, neutrophils, monocytes/macrophages, and mast cells

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43
Q

Actions of Principal Inflammation (cell-derived)
Histamine
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Histamine
Principal sources: Mast cells, basophils, platelets
Actions: Vasodilation, increased vascular permeability, endothelial activation

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44
Q

Actions of Principal Inflammation (cell-derived)
Serotonin
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Serotonin
Principal sources: Platelets
Actions: Vasodilation, increased vascular permeability

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45
Q

Actions of Principal Inflammation (cell-derived)
Prostaglandins
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Prostaglandins
Principal sources: Mast cells, leukocytes
Actions: Vasodilation, pain, fever

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46
Q

Actions of Principal Inflammation (cell-derived)
Leukotrienes
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Leukotrienes
Principal sources: Mast cells, leukocytes
Actions: Increased vascular permeability, chemotaxis, leukocyte adhesion and activation

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47
Q

Actions of Principal Inflammation (cell-derived)
Platelet-activating factor
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Platelet-activating factor
Principal sources: Leukocytes, mast cells
Actions: Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst

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48
Q

Actions of Principal Inflammation (cell-derived)
Reactive oxygen species
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Reactive oxygen species
Principal sources: Leukocytes
Actions: Killing of microbes, tissue damage

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49
Q

Actions of Principal Inflammation (cell-derived)
Nitric oxide
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Nitric oxide
Principal sources: Endothelium, macrophages
Actions: Vascular smooth muscle relaxation, killing of microbes

50
Q

Actions of Principal Inflammation (cell-derived)
Cytokines (TNF, IL-1)
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Cytokines (TNF, IL-1)
Principal sources: Macrophages, endothelial cells, mast cells
Actions: Local endothelial activation (expression of adhesion molecules), fever/pain/anorexia/hypotension, decreased vascular resistance (shock)

51
Q

Actions of Principal Inflammation (cell-derived)
Chemokines
Principal sources:
Actions:

A

Actions of Principal Inflammation (cell-derived)
Chemokines
Principal sources: Leukocytes, activated macrophages
Actions: Chemotaxis, leukocyte activation

52
Q

Actions of Principal Inflammation (plasma protein-derived)
Complement products (C5a, C3a, C4a)
Principal sources:
Actions:

A

Actions of Principal Inflammation (plasma protein-derived)
Complement products (C5a, C3a, C4a)
Principal sources: plasma (produced in the liver)
Actions: Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation)

53
Q

Actions of Principal Inflammation (plasma protein-derived)
Kinins
Principal sources:
Actions:

A

Actions of Principal Inflammation (plasma protein-derived)
Kinins
Principal sources: plasma (produced in the liver)
Actions: Increased vascular permeability, smooth muscle contraction, vasodilation, pain

54
Q

Actions of Principal Inflammation (plasma protein-derived)
Proteases activated during coagulation
Principal sources:
Actions:

A

Inflammation (plasma protein-derived)
Proteases activated during coagulation
Principal sources: liver
Actions: Endothelial activation, leukocyte recruitment

55
Q

REMEMBER
Prostaglandins
- Produced by COX-1 amd COX-2
- Involved in the pathogenesis of pain and fever in inflammation

A
  1. PGD2 – chemoattractant for neutrophils; major prostaglandin made by mast cells
  2. PGE2 – hyperalgesic; makes skin hypersensitive to painful stimuli
  3. PGE2 and PGD2 – causes vasodilatation and increases the permeability of post-capillary venules => edema formation
  4. PGF2α – stimulates contraction of uterine and bronchial smooth muscle and small arterioles
56
Q

Lymphocytes

  • Predominate in viral infections
  • Characterized as basophilic nucleus
  • Together with monocytes-macrophages and plasma cells, lymphocytes are associated with chronic inflammation
  • Mobilized in antibody and cell-mediated immunologic and non-immunologic reactions
A

Types of lymphocytes:

  1. B lymphocytes
    - Gives rise to plasma cell
    - Plasma cell is responsible for antibody production and delayed hypersensitivity
  2. T Lymphocytes
  3. NK cells
  4. Null cells
    * *Activated T-lymphocytes produce cytokines, which also recruit IFN-ϒ-a powerful activator of macrophages. This could make inflammatory reaction chronic or severe.
57
Q

Eosinophils

  • Characterized as bi-lobed nucleus
  • Occur in:
    1. Allergic reactions (IgE-mediated)
    2. Parasitic infestations
  • Granules contain Major Basic Protein (MBP) toxic to parasites and cause lysis of epithelial cells which will cause tissue damage in hypersensitivity reactions
  • Modulates mast cell-mediated reactions
A 
Primary Inflammatory Mediators
o Reactive oxygen metabolites
o Lysosomal granule enzymes (primary crystalloid granules; major basic protein, eosinophil cationic protein. Eosinophil peroxidase, acid phosphatase, Beta-glucuronidase. Arylsulfatase B, Histaminase)
o Phospholipase D
o Prostaglandins of E series
o Cytokines
58
Q 
Platelets
Characteristics and Functions:
o Thrombosis; promotes clot formation
o Regulates permeability
o Regulates proliferative response of mesenchymal cells
A 
Primary Inflammatory Mediators
o Dense granules (serotonin, Ca+2, ADP)
o Alpha-Granules (Cationic proteins, fibrinogen and coagulation proteins, platelet-derived growth factor)
o Lysosomes (acid hydrolases)
o Thromboxane A2
59
Q

Fibroblast
Characteristics and Functions:
o Produce extracellular matrix and proteins
o Mediate chronic inflammation and wound healing

A 
Primary Inflammatory Mediators
o IL-6
o IL-8
o Cyclooxygenase-2
o Hyaluronan
o PGE2
o CD40 expression
o Matricellular proteins
o Extracellular proteins
60
Q

REMEMBER

  • Mediators are generated either from cells or from plasma proteins
  • Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis or are synthesized de novo in response to a stimulus.
  • Major cell types that produce mediators of acute inflammation are platelets, neutrophils, monocytes/macrophages, and mast cells
  • Plasma-derived mediators are produced mainly in liver and present in circulation as inactive precursors that must be activated
A 
CELL-DERIVED MEDIATORS
1. Vasoactive Amines: Histamine and Serotonin
2. Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins
3. Platelet-Activating Factor (PAF)
4. ROS
5. NO
6. Cytokines and Chemokines
7. Lysosomal Constituents of Leukocytes
8. Neuropeptides
PLASMA PROTEIN-DERIVED MEDIATORS
1. Complement System
2. Coagulation and Kinin systems
61
Q

Cell-derived mediators

Preformed in secretory granules: Histamine, serotonin and lysosomal enzymes

A

Newly synthesized: Prostaglandins, Leukotrienes, Platelet-Activating Factor, ROS, NO and cytokines

62
Q 
Plasma protein-derived mediators
Factor XII (hageman factor) activation: kinin system  (bradykinin), coagulation/fibrinolysis
A

Complement activation: C3A C5A, C3B C5b-9

63
Q

CELL-DERIVED MEDIATORS

Vasoactive Amines: Histamine

A

O Comes mainly from mast cells
O Released by mast cell degranulation in response to variety of stimuli
O Causes dilation of arterioles and increases venule permeability
O Considered to be the principal mediator of the immediate transient phase of increased vascular permeability
O Vasoactive effects mediated mainly by binding to H1 receptors on microvascular endothelial cells

64
Q

CELL-DERIVED MEDIATORS

Vasoactive Amines: Serotonin

A

o Similar to histamine
o Present in platelets and certain neuroendocrine cells, e.g. in the GIT
o Stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate, and antigen-antibody complexes
o Platelet release reaction, key component of coagulation, also increases vascular permeability

65
Q 
CELL-DERIVED MEDIATORS
Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins
A
  • Biologically active lipid mediators
  • Serve as intracellular or extracellular signals to affect a variety of biologic processes, including inflammation and hemostasis
  • Release of AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A2
  • Synthesized by two major classes of enzymes: Cyclooxygenases (prostaglandins) and Lipoxygenases (leukotrines and lipoxins)
66
Q 
CELL-DERIVED MEDIATORS
Arachidonic Acid (AA) Metabolites: Prostaglandins
A
  • Produced by COX-1 amd COX-2
  • Most important ones in inflammation are PGE2, PGD2, PGF2α, PGI2, amd TxA2
  • Involved in the pathogenesis of pain and fever in inflammation
    1. PGD2 – chemoattractant for neutrophils; major prostaglandin made by mast cells
    2. PGE2 – hyperalgesic; makes skin hypersensitive to painful stimuli
    3. PGE2 and PGD2 – causes vasodilatation and increases the permeability of post-capillary venules => edema formation
    4. PGF2α – stimulates contraction of uterine and bronchial smooth muscle and small arterioles
67
Q 
CELL-DERIVED MEDIATORS
Arachidonic Acid (AA) Metabolites: Leukotrienes
A
  • Produced by lipoxygenase enzymes, 5-lipoxygenase, predominant in neutrophils and is more potent than histamine in increasing vascular permeability
  • Leukotriene B4 (LTB4) – potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes
  • LTC4, LTD4, and LTE4 – causes intense vasoconstriction, bronchospasm, and increase vascular permeability
68
Q 
CELL-DERIVED MEDIATORS
Arachidonic Acid (AA) Metabolites: lipoxins
A
  • Inhibitors of inflammation
  • Inhibit leukocyte recruitment and cellular components of inflammation
  • Inverse relationship between production of lipoxins and leukotrienes
69
Q

CELL-DERIVED MEDIATORS

Platelet-Activating Factor (PAF)

A

 Factor that causes platelet aggregation
 Causes vasoconstrictioin and bronchoconstriction
 At extremely low concentrations, induces vasodilation and increases venular permeability with a potency 100-10000 times greater than that of histamine
 Increase leukocyte adhesion to endothelium, chemotaxis, degranulation, and the oxidative burst

70
Q

CELL-DERIVED MEDIATORS

Reactive Oxygen Species

A
  • Causes endothelial cell damage, injury to other cell types and inactivation of antiproteases
  • Implicated in the following responses of inflammation
    o Endothelial cell damage
    o Injury to other cell types
    o Inactivation of antiproteases
71
Q 
CELL-DERIVED MEDIATORS
Nitric Oxide (NO)
A
  • Dual actions in inflammation:
    1. Contributes to vascular reaction (promotion of vasodilation)
    2. Inhibits cellular component of inflammatory responses
  • NO and its derivatives are microbicidal; mediator of host defense against infection
72
Q

CELL-DERIVED MEDIATORS

Cytokines and Chemokines

A
  • Produced principally by activated lymphocytes and macrophages; also by endothelial, epithelial, and connective tissue cells
  • Major cytokines, IL-1 and TNF, induce systemic acute-phase responses associated with infection or injury:
    1. Induce endothelial activation (expression of adhesion molecules)
    2. Synthesis of chemical mediators, cytokines, chemokines, growth factors, eicosanoids , and NO
    3. Production of enzymes associated with matrix remodeling
    4. Increases thrombogenicity of endothelium
    5. (TNF) augment response of neutrophils to bacterial endotoxin
73
Q

2 functions of chemokines

A
  1. Stimulate leukocyte recruitment inflammation

2. Control normal migration of cells

74
Q

4 major groups of chemokines

A

C-X-C, C-C, C and CX3C

75
Q

Chemokine

C-X-C (also called α-chemokines)

A

act on neutrophils; secreted by macrophages, endothelial cells; causes activation and chemotaxis of neutrophils; inducers are microbial products, IL-1 and TNF; eg. IL-8

76
Q

Chemokine

C-C (or β chemokines)

A

include monocyte chemoattractant protein, eotaxin, macrophage inflammatory protein 1-α; attract monocytes, eosinophils, basophils, lymphocytes but not neutrophils

77
Q

Chemokine

C (or γ-chemokines)

A

specific for lymphocytes

78
Q

Chemokine

CX3C: fractalkine

A

2 forms:
 Cell surface-bound protein is induced on endothelial cells by inflammatory cytokines and promotes strong adhesion of monocytes and T cells
 Membrane-bound protein: soluble form and has potent chemoattractant activity for the same cells

79
Q

CELL-DERIVED MEDIATORS

Lysosomal Constituents of Leukocytes

A

 Acidic proteases – degrade bacteria within phagolysosomes
 Neutral proteases – degrade extracellular components
 If unchecked, the destructive effect of lysosomal constituents can potentiate further inflammation and tissue damage – checked by system of antiproteases in the serum or tissue fluids
α1- antitrypsin – major inhibitor of neutrophil elatase

80
Q

CELL-DERIVED MEDIATORS

Neuropeptides

A

 Neurokinin A and Substance P
 Play a role in initiation and propagation of an inflammatory response
 Functions: transmission of pain signals, regulation of BP and increasing vascular permeability

81
Q 
ANTI-INFLAMMATORY DRUGS
Cyclooxygenase inhibitors (aspirin, NSAIDs)
A

o Inbibits both COX-1 and COX-2  inhibiting prostaglandin synthesis
o Aspirin: irreversibly acetylating and inactivating cyclooxygenases

82
Q

ANTI-INFLAMMATORY DRUGS

Selective COX-2 inhibitors

A

o Anti-inflammatory without the toxicities of nonselective inhibitors such as gastric ulceration
o Impairs endothelial production of prostacyclin (vasodilator and inhibitor of platelet aggregation)
o However, tilts balance towards thromboxane formation that promotes vascular thrombosis

83
Q

ANTI-INFLAMMATORY DRUGS

Lipoxygenase inhibitors

A

o Agents that inhibit leukotriene production or block its receptors are useful in the treatment of asthma (eg. Montelukast)

84
Q

ANTI-INFLAMMATORY DRUGS

Broad-spectrum inhibitors and corticosteroids

A

o Reduces transcription of genes encoding COX-2, PLA2, pro-inflammatory cytokines (IL-1 and TNF) and iNOS

85
Q

Vasodilation

Mediators:

A

Prostaglandins
Nitric oxide
Histamine

86
Q

Increased vascular permeability

Mediators:

A 
Histamine & serotonin C3a & C5a (by liberating vasoactive amines)
Bradykinin
Leukotrienes C4, D4, E4 
PAF
Substance P
87
Q

Chemotaxis, leukocyte recruitment and activation

Mediators:

A

TNF, IL-1
Chemokines
C3a, C5a
Leukotriene B4 (Bacterial products, e.g., N-formyl methyl peptides)

88
Q

Fever

Mediators:

A

IL-1, TNF

Prostaglandins

89
Q

Pain

Mediators:

A

Prostaglandins

Bradykinin

90
Q

Tissue damage

Mediators:

A

Lysosomal enzymes of leukocytes
Reactive oxygen species
Nitric oxide

91
Q

PLASMA PROTEIN-DERIVED MEDIATORS

Complement System

A

Proteolysis of C3; can occur in 3 pathways

  1. Classical: trigger by fixation of C1 to IgM or IgG that has combined with an antigen
  2. Alternative: triggered by microbial surface molecules such as endotoxin or LPS, complex polysaccharides, cobra venom
  3. Lectin: plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates
92
Q

PLASMA PROTEIN-DERIVED MEDIATORS

Coagulation and Kinin systems

A
  • Kinins are vasoactive peptides derived from plasma proteins called kininogens by proteases called kallikreins
  • Activated Hageman factor (Factor XIIa) initiates four systems involved in inflammatory response:
    o Kinin system: produces vasoactive kinins
    o Clotting system: thrombin formation
    o Fibrinolytic system: produces plasmin and degrades fibrin
    o Complement system: produces anaphylatoxins
93
Q 
Local effect of TNF/IL-1
Vasular endothelium:
1. Expression of leukocyte adhesion molecules
2. Production of IL-1, chemokines
3. Inc procoagulant, dec anticoagulant
Leukocyte:
1. Activation
2. Production of cytokines
Fibroblasts
1. Proliferation
2. collagen synthesis
A

Systemic effects

  1. Fever
  2. Leukocytosis
  3. Inc acute phase proteins
  4. Dec. appetite
  5. Inc sleep
94
Q

Outcome of Acute Inflammation

A
  1. complete resolution
  2. Healing by connective tissue replacement
  3. Progression of response to chronic inflammation
95
Q

Localized collection of pus (purulent exudent rich in neutrophils, necrotic cells, & edema fluid) buried in tissue, organ or confined space

A

Abscess

96
Q

Hereditary Defects that Impair the Acute Inflammatory Response:

A 
Deficiency of complement components
**Deficiencies of factors C2, C3, and C5
Defects in neutrophils
1. Chronic granulomatous disease of childhood
o X-linked disorder
o Deficiency activity of NADPH oxidase
2. Myeloperoxidase deficiency
o Sometimes associated with recurrent infections but is often of little consequences
3. Chediak-Higashi Syndrome
o Autosomal recessive disorder
o Neutropenia, albinism, cranial, and peripheral neuropathy, & a tendency to repeated infections
o Marked by presence of abnormal WBC
97
Q

Congenital Diseases of Defective Phagocytic Cell Function Characterized by Recurrent Bacterial Infections
Leukocyte Adhesion Deficiency (LAD)
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Leukocyte Adhesion Deficiency (LAD)
Defect:
LAD-1 (defective β2-integrin expression or function) (CD11/CD18)
LAD-2 (defective fucosylation, selectin binding)

98
Q

Function Characterized by Recurrent Bacterial Infections
Hyper-IgE-recurrent infection (Job Syndrome)
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Hyper-IgE-recurrent infection (Job Syndrome)
Defect: Poor chemotaxis

99
Q

Function Characterized by Recurrent Bacterial Infections
Chediak-Higashi Syndrome
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Chediak-Higashi Syndrome
Defect: Defective lysosomal granules, poor chemotaxis

100
Q

Function Characterized by Recurrent Bacterial Infections
Neutrophil-specific Granule Deficiency
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Neutrophil-specific Granule Deficiency
Defect: Absent neutrophil granules

101
Q

Function Characterized by Recurrent Bacterial Infections
Chronic Granulomatous Disease
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Chronic Granulomatous Disease
Defect: Deficient NADPH oxidase, with absent H2O2 production

102
Q

Function Characterized by Recurrent Bacterial Infections
Myeloperoxidase Deficiency
Defect:

A

Function Characterized by Recurrent Bacterial Infections
Myeloperoxidase Deficiency
Defect: Deficient HOCl production

103
Q

Chronic Inflammation

Causes

A
  1. Persistent infection by intracellular microorganism
  2. Prolonged exposure to non-degradable toxic substances
  3. Immune-mediated inflammatory diseases
    - Autoimmune diseases: immune reaction against own tissues evoked by autoantigens (Autoimmune diseases- immune reaction against own tissues evoked by autoantigens)
    - Unregulated immune response against microbes (Inflammatory bowel disease; Crohn’s disease, ulcerative colitis)
    - Immune reaction against environmental allergens
104
Q

Chronic Inflammation

Histologic Hallmarks

A

 Mononuclear cell infiltration (lymphocytes, plasma cells)
 Proliferation of fibroblasts and small blood vessels (angiogenesis, neovascularization)
 Increased connective tissue (fibrosis)
 Tissue destruction

105
Q

REMEMBER

  • Macrophages are important both in inflammation (acute and chronic) and tissue repair/ fibrosis
  • The role of macrophages depends on which inflammatory mediator is involved
A

o Repair: FGF, PDGF, TGF beta, cytokines, angiogenic factors

o Inflammation: ROS, cytokines, proteases

106
Q

Relationship of macrophages to lymphocytes with

regard to chronic inflammation:

A
  • *phagocytic cell engulfed microbe (bacteria) => microbe serves as an antigen => antigen would be presented by macrophage to T-lymphocyte => T-lymphocyte (TH1 and TH17) will be activated => release of IL17 and TNF => leukocyte recruitment and inflammation
  • *There is also secretion of IFN gamma which will act on the macrophage => macrophage would be activated through the classical pathway => activated macrophage in the presence of TNF, IL1, and chemokines will cause leukocyte recruitment and inflammation
107
Q

PATTERNS OF CHRONIC INFLAMMATION

A
  1. Non-Granulomatous

2. Granulomatous

108
Q

Non-Granulomatous

- Diffuse proliferation of chronic inflammation cells (macrophage, lymphocytes, plasma cells), fibroblasts and collagen

A

Granulomatous
 Nodular collections of specialized macrophages referred to as epitheliod cells (modified macrophages resembling epithelial cells) surrounded by a rim of lymphocytes, multinucleate giant cells, +/- caseous necrosis
**Histologically: Epithelioid cells have pale pink granular cytoplasm, indistinct cell boundaries; nucleus: less dense, oval or elongate, folding of nuclear membrane; may fuse to form giant cells

109
Q

How do granulomas arise?

A

o Formation involves activation of macrophages by
interactions with T lymphocytes
o Macrophage present poorly digestible antigen to CD4+ lymphocytes.
o Interaction with the antigen specific T-cell receptor of these cells triggers the release of cytokines (especially interferon), which mediate the transformation of monocytes and macrophages to epithelioid and giant cells

110
Q

2 types of granuloma

A
  1. Foreign Body
    a. Talc, sutures, fibers are large enough to produce phagocytosis by a single macrophage
    b. Do not incite specific inflammatory response
  2. Immune Granuloma
    Unsoluble particles induce cell-mediated immune
    response
111
Q

Causes of Immune granuloma

A
  1. Infectious agents
  2. Inorganic materials and dusts – Silicosis, berylliosis, irritant lipids
  3. Unknown etiology – sarcoidosis (i.e Crohn’s Disease)
112
Q

Diseases with Granulomatous Inflammation
Tuberculosis
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Tuberculosis
Cause: Mycobacterium tuberculosis
Tissue reaction: Caseating granuloma (tubercle): focus of activated macrophages (epitheloid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli

113
Q

Diseases with Granulomatous Inflammation
Leprosy
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Leprosy
Cause: Mycobacterium leprae
Tissue reaction: Acid-fast bacilli in macrophages: noncaseating granulomas

114
Q

Diseases with Granulomatous Inflammation
Syphilis
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Syphilis
Cause: Treponema pallidum
Tissue reaction: Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells necrotic without loss of cellular routine

115
Q

Diseases with Granulomatous Inflammation
Cat-scratch disease
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Cat-scratch disease
Cause: Gram- negative bacillus
Tissue reaction: Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon

116
Q

Diseases with Granulomatous Inflammation
Sarcoidosis
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Sarcoidosis
Cause: Unknown etiology
Tissue reaction: Noncaseating granulomas with abundant activated macrophages

117
Q

Diseases with Granulomatous Inflammation
Crohn’s disease (inflammatory bowel disease)
Cause:
Tissue reaction:

A

Diseases with Granulomatous Inflammation
Crohn’s disease (inflammatory bowel disease)
Cause: Immune reaction against intestinal bacteria self-antigens
Tissue reaction: Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate

118
Q

SYSTEMIC EFFECTS OF INFLAMMATION

Consists of several changes namely:

A

o Fever
o Acute Phase Proteins
o Leukocytosis

119
Q

SYSTEMIC EFFECTS OF INFLAMMATION

Fever

A

 Characterized by an increase in body temperature usually by 1 - 4 °C
 Due to pyrogens that enter the blood and stimulate prostaglandin synthesis on the thermoregulatory center in the vascular and perivascular cells of the hypothalamus
 Bacterial products, such as LPS (exogenous pyrogens) stimulate leukocytes to release cytokines, such as IL-1 and TNF (endogenous pyrogens) that increase the enzymes (cyclooxygenases) that convert Arachidonic acid into Prostaglandin.
 Increase in prostaglandins in the vascular and perivascular hypothalamaus will stimulate the production of neurotransmitters; cAMP which will reset the temperature set point to dissolve the fever
 NSAIDs (Ex: aspirin) diminish fever by inhibiting PG
synthesis

120
Q

Fever causes hypothalamus to:
 Release TSH to increase production of T3 and T4
 Releases ACTH which increases release of glucocorticoids
 Causes increase release of epinephrine
 Decreases ADH production

A

Benefits of Fever:
 Increased temperature kills microorganisms and adversely affects their growth and reproduction
 Decrease serum levels of iron, copper and zinc – needed for bacterial reproduction
 Causes lysosomal breakdown and autodestruction of cells, preventing viral replication in infected cells
 Increased leukocyte motility
 Facilitates the immune response – activation of T cells
 Enhanced phagocytosis

Pathology 1st LE (12 decks)

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