Pathology - Inflammation 1

Front 1

Acute inflammation
how long?
which cells?

Back 1

minutes to days; neutrophils

Front 2

Chronic inflammation
how long?
which cells?

Back 2

weeks to months; mononuclear leukocytes

Front 3

Exudation

Back 3

Extravation of fluid, proteins, and blood-cells from vessels to the interstitial tissue and body cavities. Only happens during inflammation!

Front 4

Edema

Back 4

The fluid which left the vessels and accumulates in interstitial tissue. May be transudate or exudate.

Front 5

Transudate

Back 5

Extravascular fluid with low protein content, specific gravity < 1.012; fluid left the vessels due to hydrostatic pressure gradients (no impaired vascular permeability).

Front 6

Exudate

Back 6

Extravascular fluid with high protein content; specific gravity > 1.020, and usually leukocytes. Left the vessels due to vascular hyperpermeability. ONLY IN INFLAMMATION!

Front 7

PUS/Purulent exudate

Back 7

Exudate rich in neutrophils and debris of necrotic cells.

Front 8

Local signs of acute inflammation

Back 8

heat, redness, swelling (edema), pain, impaired function

Front 9

What is the most common mechanism by which permeability is altered in acute inflammation?

Back 9

Enterendothelial gaps in venules, due to histamine and leukotrienes. It is immediate and transient (up to 30 secs).

Front 10

Margination of Leukocytes

Back 10

Following extravasation of fluid and proteins the flow↓ (=stasis), RBC masses flow in the center and leukocytes are pushed to the margins.

Front 11

Following margination, leukocytes roll on epithelium and then _____, which is mediated by what?

Back 11

they stop, and we get adhesion mediated by adhesion proteins

Front 12

Do we find these adhesion proteins on the membrane of the leukocytes or on the endothelium?

Back 12

Haha - trick question. We find them on both.

Front 13

What are the main adhesion proteins (4)?

Back 13

1. Selectins
2. Mucin-like glycoproteins
3. Immunoglobulins
4. Integrins

Front 14

Selectins

Back 14

Responsible for transient adhesions during rolling. E- and P-selectins are on the endothelium and L-selectins are on leukocytes. E- and P-selectins are upregulated by mediators. So, binding of leukocytes is restricted to site of injury (which is where the mediators are produced).

Front 15

Integrins

Back 15

Receptors for adhesion. Normally expressed on leukocyte plasma membranes in low-affinity form and do not adhere to their appropriate ligands until leukocytes are activated by cytokines secreted at site of inflammation.

Front 16

Mucin-like glycoproteins

Back 16

bind to selectins

Front 17

Which cytokines are responsible for the stimulation of binding of integrins to endothelium?

Back 17

IL-1
TNF

Front 18

What are VCAM-1 and ICAM-1?

Back 18

Both are present on endothelium, and are ligands for integrin receptors on leukocytes. They are stimulated by IL-1 and TNF-alpha.
ICAM-1 = Inter-cellular Adhesion Molecule;
VCAM-1 = Vascular Cell Adhesion Molecule

Front 19

What role do cytokines play in rolling and adhesion?

Back 19

1. They mobilize selectins from the cytoplasm to the membranes of leukocytes in minutes.
2. They stimulate the production of adhesion molecules (hours). IL-1 and TNF induce appearance of E-selectin and increase ICAM and VCAM on endothelium
3. They change the protein architecture, which inreases affinity for receptor. Ex: activated leukocyte integrin will adhere to endothelial ICAM.

Front 20

What happens after rolling and adhesion?

Back 20

Transmigration via diapedesis

Front 21

What is transmigration?

Back 21

Leukocytes, after tight adhesion, adhere to CD31, extend pseudopodia and pass through gaps between endothelial cells. Proteins, found on the leukocyte and endothelial cell surfaces, interact and effectively pull the cell through the endothelium. The leukocytes secrete proteases that degrade the basement membrane, allowing them to escape the blood vessel. Once in the interstitial fluid, leukocytes migrate along a chemotactic gradient towards the site of injury or infection.

Front 22

What is diapedesis

Back 22

When leukocytes secrete proteases that degrade the basement membrane, allowing them to escape the blood vessel during transmigration.

Front 23

What is chemotaxis?

Back 23

Movement of leukocytes along a chemical gradient.

Front 24

List four chemotactic molecules for leukocytes.

Back 24

1. bacterial products
2. C5a
3. Leukotriene B4
4. Chemokines (IL-8)

Front 25

How does chemotaxis work, if I may ask?

Back 25

Chemotactic molecules bind to specific cell surface receptors, which stimulates a G-protein signal transduction. This increases calcium levels, and activates assembly of contractile elements. Leukocytes move via pseudopods that anchor to the ECM.

Front 26

Describe the recognition and attachment phase of phagocytosis.

Back 26

Opsonins bind to the bacteria. Neutrophils and macrophages have receptors for IgG, C3b, and collectins (opsonin receptors).

Front 27

What happens after recognition and attachment?

Back 27

Phagocytic vacuole fuses with lysosome.

Front 28

Killing and degradation can happen one of two ways:

Back 28

1. H2O2 myeloperoxidase system (MAJOR mechanism) in the phagolysosome.
2. Non-O2 dependent, which is far less efficient. Lysosomal contents: lysozyme, lactoferrin, cationic proteins, defensins, etc break down the bacteria.

Front 29

Which of the two degradation methods in the phagolysosome is more efficient?

Back 29

Oxygen pathway is far more efficient.

Front 30

What happens after the microbe is dead?

Back 30

Acid proteases degrade the bacteria.

Front 31

Can leukocyte products cause damage to the tissue?

Back 31

Yes. Spillage out of the leukocyte of lysosomal enzymes.
1. During feeding via regurgitation.
2. Reverse endocytosis= frustrated phagocytosis.
3. Damage to phagolysosome membrane
4. Massive neutrophil destruction.

Front 32

Sialyl Lewis X determinant

Back 32

An E-selectin ligand with a carbohydrate structure that is constitutively expressed on granulocytes and monocytes and mediates inflammatory extravasation of these cells. Defective synthesis of the sialyl lewis X antigen results in immunodeficiency.

Front 33

What are the two main defects in leukocyte adhesion?

Back 33

1. Defective production (genetic) of leukocyte integrins.
2. Genetic absence of Sialyl-Lewis X oligosaccharide on leukocytes that bind selectins..

Front 34

What can cause a defect in leukocyte chemotaxis?

Back 34

C5a deficiency

Front 35

What can cause defects in phagocytosis?

Back 35

1. Severe G6PD deficiency (lack of NADPH)
2. Deficiency or dysfunction of NADPH-oxidase, depleting microbicidal activity.

Front 36

Classify each of the following as local, preformed; systemic; local, newly synthesized:
1. vasoactive amines
2. lysosomal proteins
3. plasma proteases
4. arachidonic acid metabolites
5. cytokines

Back 36

Local, preformed: 1&2
Systemic: 3
Local, newly synthesized: 4&5

Front 37

Histamine is a vasoactive amine. Where is it stored, when is it released, and what is its function?

Back 37

Stored in mast cells.
Released upon trauma/heat, IgE binding, C3a/C5a, neuropeptides.
Causes arteriolar vasodilation and increased permeability (immediate and transient).

Front 38

What is the major source of plasma proteases?

Back 38

Liver

Front 39

Phospholipase A2

Back 39

Regulator of many inflammatory processes. Catalytically hydrolyzes a phopholipid bond, releasing arachidonic acid and lysophospholipids.

Front 40

Arachidonic Acid

Back 40

Is freed from phospholipid molecule by phospholipase A2, which cleaves off the fatty acid. Arachidonic acid is a precursor in the production of eicosanoids: prostaglandins, prostacyclin, and thromboxanes.

Front 41

Prostaglandins

Back 41

Prostaglandins are found in virtually all tissues and organs, and are produced by all nucleated cells except lymphocytes. They are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine and mast cells, among others. They are synthesized in the cell from the essential fatty acids, and have a wide variety of functions, including the regulation of inflammatory mediation.

Front 42

Thromboxanes

Back 42

Thromboxanes are produced in platelets by cyclooxygenase (COX) enzyme from arachidonic acid. They are vasoconstrictors and potent hypertensive agents. They also facilitate platelet aggregation.

Front 43

Leukotrienes

Back 43

Leukotrienes are eicosanoid lipid mediators, produced in the body from arachidonic acid. They act principally on a subfamily of G protein coupled receptors, and are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. They also have a powerful effect in broncho-constriction, and increase vascular permeability.

Front 44

COX1/COX2

Back 44

Cyclooxygenase (COX) is an enzyme that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain; this is the method of action of non-steroidal anti-inflammatory drugs, such as the well-known aspirin and ibuprofen. The name "prostaglandin synthase" is still sometimes used to refer to the COX enzyme.
* COX-1 is responsible for the baseline levels of prostaglandins.
* COX-2 produces prostaglandins through stimulation.

Front 45

What activates phospholipase A2, and what inhibits it?

Back 45

Phospholipase A2 is activated by chemical/physical stimuli, mediators (C5a) and is inhibited by steroids!

Front 46

Two types of lysosomes:

Back 46

1. Large-azurophilic granules: MPOX, cationic proteins, acid and neutral proteases.
2. Specific-secondary granules: lactoferrin, alkaline phosphatase, neutral proteases.

Front 47

What is the function of acid proteases?

Back 47

Degrade bacteria in phagolysosome.

Front 48

What are neutral proteases?

Back 48

Collagenase, elastase, cathepsin: cause tissue destruction.

Front 49

Function of cytokines?

Back 49

Activate endothelium for production of adhesion proteins, cytokines, chemokines, GFs, AA metabolites.

Front 50

Where are IL-1, TNF-alpha, and TNF-beta produced?

Back 50

IL-1 and TNF-alpha are produced by activated macrophages.
TNF-beta is produced by activated T cells.

Front 51

What is IL-8?

Back 51

A chemokine produced by macrophages and other cell types such as epithelial cells. Primary function of IL-8 is the induction of chemotaxis in its target cells (e.g. neutrophil granulocytes).

Front 52

Prostaglandins, NO, and histamines all cause vaso____.

Back 52

dilation

Front 53

Histamine, bradykinins, leukotrieness, and platelet activating factor all cause_____.

Back 53

Hyperpermeability.

Front 54

What is the function of PAF?

Back 54

It causes platelets to aggregate and blood vessels to dilate.

Front 55

C5a, LTB4, Bacterial products, and IL-8 are all involved in:

Back 55

Chemotaxis and leukocytic activation.

Front 56

IL-1, TNF, IL-6, and prostaglandins are all involved in:

Back 56

fever

Front 57

Prostaglandins, and bradykinin are both involved in:

Back 57

pain

Front 58

What is the first stage of the inflammatory process?

Back 58

Vasodilation