Njds Pathology - The Host Response To Injury Iii: Chemical Mediators

Front 1

Endogenous and exogenous sources of chemical mediators

Back 1

Exogenous sources

1. Cell derived mediators are produced de novo in response to inflammatory stimuli and is stored in intracellular granules

2. Plasma-derived mediators circulate in precursor form and require activation

Exogenous sources include bacterial endotoxin and cobra venom

Front 2

How do chemical mediators control inflammatory and wound healing processes?

Back 2

Chemical mediators...

1. are synthesized, released and activated in local area of injury

2. requires interaction w/ specific cell receptors

Durection and intensity regulated by...

1. Postive feedback loop
2. Generation of secondary chemical mediators
3. Rapid decay of meditiators due to short half-life and enzyme inactivators

Front 3

Histamine

Back 3

1. Stored in mast cells, blood basophils, and platelets

2. Involved in early phases of acute inflammation and inactivated by HISTIMINASE

3. Causes ↑ vasodilation and vasopermeabilty

Front 4

Degranulation of mast cells is promoted by...

Back 4

1. Physical agents (e.g. cold, trauma)

2. C3a and C3b

3. IgE mediated hypersensitivity reactions

4. IL-1

Front 5

Platelet aggregation and degranulation promoted by...

Back 5

1. Exposure to subendothelial collagen at the site of vascular injury

2. Exposure to platelet activating factors in IgE mediated reactions

Front 6

Name the 4 systems of plasma proteases and the factor that links them

Back 6

1. Kinin
2. Coagulation
3. Fibrinolytic
4. Complement

- Systems are linked by activation of inactive HAGEMAN FACTOR (FACTOR XII) to activated PREKALLIKREIN ACTIVATOR (FACTOR XIIa).

- Factor XII activated by exposure to subendothelial collagen or basement membrane as sites of vascular damage

Front 7

The kinin system

Back 7

1. Activation of factor XII ⇒ XIIa leads to BRADYKININ formation

2. Bradykinin similar to histamine (vasodilator + vasopermeabilty)

3. Bradykinin degraded by kininase

4. Kallikrein activates factor XII and amplifies effects of initial stimulus

5. Kallikrain converts C5 ⇒ C5a

Front 8

The clotting system

Back 8

1. Activated Hageman factor results in conversion of fibrinogen ⇒ fibrin by thrombin

2. Allows for STABLIZATION of wound

3. Serves as PROTECTION barrier to prevent spread of infection and entering new microbes

4. Creates ATTACHMENT SUBSTRATE for cells

Front 9

The fibrinolytic system

Back 9

1. Kallikrein converts plasminogen proactivator ⇒ plasminogen activator

2. Plasminogen activator converts plasminogen ⇒ plasmin

Plasmin (protease)

1. Lyses fibrin clots
2. Activates Hageman factors to factor XIIa ⇒ amplifying inflammatory response
3. Converts C3 ⇒ C3a

Front 10

The complement system

Back 10

1. Comprised of inactive C1-9 and its active cleavage products

2. Activated by classic or alternative pathways, but C3 activation step is critical

3. C5a ⇒ chemotaxis and regulates leokocyte adhesion molecules

4. C3a, C5a ⇒ bradykinin effects (vasodilation, vasopermeability)

5. C3b ⇒ opsonization

Front 11

Arachadonic acid

Back 11

1. Is a fatty acid that is membrane-bound in inactive esterified phopholipid form

2, Released during inflammation by phospholipase to generate leukotrienes, lipoxins, and prostaglandins in 2 ways:

- Cylcooxygenase pathway
- Lipooxygenase pathway

Front 12

The complement system

Back 12

1. Comprised of inactive C1-9 and its active cleavage products

2. Activated by classic or alternative pathways, but C3 activation step is critical

3. C5a ⇒ chemotaxis and regulates leokocyte adhesion molecules

4. C3a, C5a ⇒ bradykinin effects (vasodilation, vasopermeability)

5. C3b ⇒ opsonization

Front 13

The fibrinolytic system

Back 13

1. Kallikrein converts plasminogen proactivator ⇒ plasminogen activator

2. Plasminogen activator converts plasminogen ⇒ plasmin

Plasmin (protease)

1. Lyses fibrin clots
2. Activates Hageman factors to factor XIIa ⇒ amplifying inflammatory response
3. Converts C3 ⇒ C3a

Front 14

Cylcooxygenase Pathway

Back 14

1. PGI2 (prostacylin) ⇒ vasodilation & ↓ platelet aggregation

2. TXA2 (thromboxane) ⇒ vasoconstriction & ↑ platelet aggregation

3. PGD2, PGE2, PGF2 ⇒ vasodilation

4. PGE2 ⇒ fever, pain sensation, and illicitation

Front 15

Aspirin and NSAIDS

Back 15

Inhibits COX-1 and COX-2

Front 16

Lipoxygenase Pathway

Back 16

1. LTB4 ⇒ chemotaxis
2. LTD4, LTE4, LTC4 ⇒ ↑ vascular permeability and vasoconstriction
3. LXA4, LXB4 ⇒ negative regulation on leukotrienes

Front 17

Vasoconstriction mediators

Back 17

1. Thomboxane A2
2. LTD4, LTE4, LTC4

Front 18

Vasodilation mediators

Back 18

1. Prostaglandins I2, D2, E2, F2
2. NO
3. Platelet activating factor
4. Histamine (C3a, C5a)
5. Bradykinin

Front 19

Vascular permeability mediators

Back 19

1. Histamine (C3z, C5a)
2. Bradykinin
3. Platelet activating factor
4. Substance P
5. Leukotrienes D4, E4, C4

Front 20

Pain mediators

Back 20

1. Bradykinin
2. PGE2

Front 21

Leukocyte recruitment/activation mediators

Back 21

1. C5a
2. Leukotriene B4
3. Bacterial products
4. Chemokines
5. IL-1 and TNF

Front 22

Tissue damaging elements

Back 22

1. Macrophage and neutrophil lysosomal enzymes

2. ROS

Front 23

Cytokines

Back 23

1. Produced by lymphocytes (lymphokines) and monocyte-macrophages (monokines)
2. IL-1 and TNF produced by macrophages; effects fibroblasts, endothelium, and leukocytes and is important in FEVER production
3. TNF important in apoptosis
4. CHEMOKINES - family of cytokines important in chemotaxis

Front 24

T/F: Platelet activating factor is more potent than histamine

Back 24

TRUE: PAF is 100-10000x more potent than histmine in vasodilation and ↑ vascular permeability

Front 25

T/F: Nitric oxide induces vasoconstriction

Back 25

FALSE: Nitric oxide induces vasodilation

Front 26

Neuropeptides

Back 26

1. Example: calcitonin gene-related peptide and substance P

2. Maybe important in mediating vasodilation and ↑ vascular permeability