Path Fall 3 Acute Inflammation

Front 1

we know the 3 components of acute inflammation are increased blood flow, capillary changes to allow plasma proteins and leukocytes to leave and the emmigration of these things into the tissues. what is the physical sign that blood flow has increased? what mediators act?

Back 1

red (rubar) , hot

histamine and NO

Front 2

so with acute inflammation we get
1. increased blood flow (red, hot)
2. Protein leakage
3. PMN emmigration

what are some reasons proteins leak? what is this leak called

Back 2

leakage of protein rich fluid into tissue- EXUDATE edema

Reasons:
1. retraction of endothelium: histamine/NO mediated
2. endothelial cell injuury
3. leukocyte mediated endo damage
4. transcytosis

Front 3

whats the role of lymph in acute inflamm?

Back 3

clean the extravascular tissue and drain excess fluid, can contain some of the same leukocytes, cell debris, and microbes that is in the exudate

**recall the junk got in the tissue to begin with bc of 1. endo retraction 2. endo damage 3. endo damage by leukocytes 4. transcytosis

Front 4

what is the role of a leukocyte in acute inflamm

Back 4

1, leave vessel and enter tissue
2. recognize the microbe or necrosis
3. remove the microbe or necrosis

Front 5

if a pt has high neutrophiles what mught you think

Back 5

acute inflammation

Front 6

whats the fx of inflammation?

Back 6

1. remove damaged/necrotic tissue
2. remove foerign invaders

Front 7

how can you ID inflammation

Back 7

inflammation ID by pain (dalor), redness (rubar), heat (calor), swelling (tumor) and loss of fx.

Front 8

we know that leakage of proteins into tissue causes edema and is a major component of inflammation. How does leakage occur?

Back 8

1. retraction of endo cells
2. Endo cell injury
3. transcytosis

Front 9

what are the 3 major components of acute inflammation

Back 9

ncreased BF, Leakage of plasma protein (edema), PMN emmigration

1. change in vessels, increased blood flow

2. structural change in capillary allows plasma protein and leukocytes to leave circulation

3. once they have left blood they need to get into the tissue: emigration, accumulation, and activation of leukocytes to remove offending agent

I

Front 10

exudate
transudate
edema
pus

Back 10

Exudate: extracellular fluid in the tissues due to inflammation lots of protein, cell debris. Specific gravity >3

Transudate:Little protein, little cell debris, low specific gravity, ultrafiltrate of plasma due to imbalance in hydrostatic/osmotic gradient. no change in vessel permiability.

Edema: excess fluid in serous cavity or tissue, can be trans or exudate. ex pleural effusion, fluid in the lung

Pus: exudate that has leukocytes (PMN), cell debris and microbes.

Front 11

if you have fluid leaking into tissue what kind of edema?

if you have fluid and protein leaking into tissue what kind of edema?

Back 11

transudate
exudate

Front 12

what are the 4 mechs of increased vascular permiability

Back 12

**recall increased perm occurs as a major component of acute inflammation

1. endothelium cells move apart bc of NO and histamine

2. Endo are damaged

3. Endo are damaged by leukocytes (chronic inflamm

4. Transcytosis

**under normal circumstances the endo that lines BV are close together and no leukocytes can pass through, when there is acute inflamm these 4 things happen so that leukocytes can go through

Front 13

how does a leukocyte migrate from the BV into the tissue/.

Back 13

1. endothelium cells move apart bc of NO and histamine

2. Endo are damaged

3. Endo are damaged by leukocytes (chronic inflamm

4. Transcytosis

**under normal circumstances the endo that lines BV are close together and no leukocytes can pass through, when there is acute inflamm these 4 things happen so that leukocytes can go through

Front 14

what are the endo/leukocyte adhesion molecules

Back 14

adhesion occurs after margination and rolling of the leukocyte in the lumen of the BV, adhesion is the last step before the leukocyte diapodesis across the BV

The Leukocytes try integrating but the endo does the selectin.

Leukocytes have integrins and the Endo has selectin

Front 15

whats the dif btwn the early and late cellular infiltrate in inflammation

Back 15

acute: we first see edema, and then within the first day PMN come and die by day 2. After 2 or so days monocytes come and PROLIFORATE


Chronic: lymphocytes, macrophages

Front 16

what are teh receptors found on leukocytes

Back 16

1. G Protein: adhesion, migration into tissue

2. TLR: amplify the inflammation process

3. Cytokine: amplify the inflammatory process, kill microbes

4. Phagocytotic R: kill microbe

Front 17

why do leukocytes have G protein, TLR, cytokine, and phagocytic R

Back 17

so that a microbial product, opsonin, or cytokine can bind to it and acivate it

1. G Protein: adhesion, migration into tissue

2. TLR: amplify the inflammation process

3. Cytokine: amplify the inflammatory process, kill microbes

4. Phagocytotic R: kill microbe

Front 18

what are the 2 ways macrophages are activated and whats the result?

Back 18

1. Clasically Activated: kill bugs
2. Alternatly Activated: repair and fibrosis

Front 19

so leukocytes typically act to help adhere, migrate, kill, amplify inflammation but sometimes things get out of control and we get "leukocyte mediated tissue injury" its seen in

Back 19

aitoimmune disorders, excess response to a normally harmless thing, when tissue gets collateral damage bc of a normal process. examples include asthma, ARDS, transplant rejection, pulm fibrosis etc.

Front 20

3 steps of phago

Back 20

1. recognition and attachment of the bug to the leukocyte. Opsinins like IgG and C3b coat the bug to help ID and increase affinity for phago

2. engulfment: leukocyte eats bug and forms phagosome which fuses with lysosome and forms phagolysosome. lysosome granules do the destruction (the granule can get out and damage the extracellular space)

3. Killing and Degradation: happens IN the macro and PMN. mainly ROS and RNS do the killing. respiratory burst. know MYLOPEROXIDASE is part of this process.

Front 21

what are some of the things we have to prevent ROS damage

Back 21

1. superoxide dismutase
2. catalase
3. glutathione peroxidase
4. ceruloplasm (bind Cu)
5. transferrin (bind Fe)

Front 22

what are the genetic diseases associated with leukocyte dysfx

Back 22

LAD (leukocyte adhesion deficiency): problem with either integrins on leukocyte or selectins on endo

CGD (chronic granulomatous disease): decreased oxidative burst so cant kill bugs

MPO deficiency: cant kill bugs bc of defect in myeloperoxidase

Acagashi: decreases leukocyte fx bc of defective lysosomal trafficking

**all are aquired
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Front 23

what is Acagashi

Back 23

: decreases leukocyte fx bc of defective lysosomal trafficking

Front 24

what is LAD

Back 24

(leukocyte adhesion deficiency): problem with either integrins on leukocyte or selectins on endo

Front 25

what is CGD

Back 25

CGD (chronic granulomatous disease): decreased oxidative burst so cant kill bugs

Front 26

what is MPO

Back 26

MPO deficiency: cant kill bugs bc of defect in myeloperoxidase

Front 27

name the disease:
: cant kill bugs bc of defect in myeloperoxidase



decreased oxidative burst so cant kill bugs


problem with either integrins on leukocyte or selectins on endo

decreases leukocyte fx bc of defective lysosomal trafficking

Back 27

MPO deficiency

CGD

LAD

Acagashi:

Front 28

leukocytes may release Lysosomal enzymes, ROS, and AA metabolites into the extracellular space. release can occur as a result of:

Back 28

1 regurgitation
2 frustrated phago,
3 cytotoxic release, or
4 exocytosis.


We also have lots of leukocyte defects: adhesion, phago, microbicidial activity (myleoperoxidase). Any dysfx leads to disease. lots of examples.

Front 29

why does inflammation decline?

Back 29

mediators that caused it only live a little while, they are degraded

Front 30

what are the major products of AA metabolism:

Back 30

Cyclooxygenase Path
1. PG: vasodilate
2. Thromboxine: vasoconstrict

Lipoxygenase Path
1. Lipoxin: inhibits chemotaxis and adhesion
2. 5 HETE: chemotasis and adhesion
3. Leukotrienes: CDE, vasoconstrict and increase vascular perm. B, chemotaxis and adhesion

Front 31

what AA metabolite does...

1. Vasodilation:

2. Vacosonstriction:

3. Increase Vascular Permiability:

4. Chemotaxis, leukocyte Adhesion:

5. Inhibit Chemotaxis and Adhesion:

Back 31

1. Vasodilation: PG

2. Vacosonstriction: Thromboxine, Leukotrienes CDE

3. Increase Vascular Permiability: leukotriene CDE

4. Chemotaxis, leukocyte Adhesion: leukotriene B, HETE

5. Inhibit Chemotaxis and Adhesion: lipoxin

Front 32

what inhibits AA metabolism

Back 32

1. Steroids: inhibits both cycloxygenase and lipoxygenase paths so NO products are made

2. COX1/2 inhibitors, Asprin (NSAIDS), Indomethacin: inhibit cycloxygenase path so no PGI PGD PGE or Thromboxine are made (all dilation is knocked out!)

3. Lipoxygenase Inhibitors:
-inhibit leukotriene (CDE constriction, B chemotaxis & adhesion) production
-block leukotriene Receptors
-corticosteroids that are broad spectrum inhibitors
-increase fish oil so phospholipids in the plasma membranes are less attractive substrates

Front 33

how do NSAIDS work?

Back 33

they inhibit cycloxygenase path so no PG or thromboxine is made. this greatly decreases the amt of vasodilation that occurs

Front 34

why is it the big thing to take fish oils.

Back 34

it changes the plasma membrane composition such that the phospholipids are no longer attractive substrates for AA metabolism and both paths are decreased. BUT the new phospholipids are good substrates for anti-inflammatory things like resolvins and protectins

Front 35

what are the 2 vasoactive amines?

Back 35

Histamine from mast
Serotonin from platelets

**both dilate

Front 36

what does it do...?

1. Histamine:
2. serotonin:
3. PG:
4. LT (leukotrienes):
5. NO:
6. TNF/IL1:
7. Chemokines:

8. compliment:
9. kinins:
10. coagulation proteases:

Back 36

what does it do...?

1. Histamine: made in mast cells. dilation via H1 receptor
2. serotonin: platelets. dilation (like histamine)
3. PG: dilation, pain, fever
4. LT (leukotrienes): BV permiability, chemotaxis, adhesion
5. NO: relax BV, kill bugs
6. TNF/IL1:
7. Chemokines: chemotaxis, leukocyte activation

8. compliment: chemotaxix, dilation
9. kinins: dilation, pain
10. coagulation proteases: endothelial activation, leukocyte recruitment

Front 37

what does PAF do?

Back 37

kill bugs
tissue damage

**PAF antagonists inhibit inflammation

Front 38

who plays a role in...

1. Vasodilation:

2. Increased Vascular permiability:

3. Chemotaxis, leukocyte recruitment/activation:

4. Fever:

5. Pain:

6. Tissue Damage:

Back 38

1. Vasodilation: PG, NO, Histamine

2. Increased Vascular permiability: Histamine/seratonin, C3a C5a, bradykinin, Leukotriene CDE, PAF, Substance P

3. Chemotaxis, leukocyte recruitment/activation: TFN, IL1, Chemokines, C3a, C5a, Leukotriene B,

4. Fever: IL1, TNF, PG

5. Pain: PG, bradykinin, Substance P

6. Tissue Damage: junk from leukocyre lysosomes, ROS, NO

Front 39

what do these do?


PG, NO, Histamine

Histamine/seratonin, C3a C5a, bradykinin, Leukotriene CDE, PAF, Substance P

: TFN, IL1, Chemokines, C3a, C5a, Leukotriene B,

IL1, TNF, PG

PG, bradykinin, Substance P

junk from leukocyre lysosomes, ROS, NO

Back 39

1. Vasodilation: PG, NO, Histamine

2. Increased Vascular permiability: Histamine/seratonin, C3a C5a, bradykinin, Leukotriene CDE, PAF, Substance P

3. Chemotaxis, leukocyte recruitment/activation: TFN, IL1, Chemokines, C3a, C5a, Leukotriene B,

4. Fever: IL1, TNF, PG

5. Pain: PG, bradykinin, Substance P

6. Tissue Damage: junk from leukocyre lysosomes, ROS, NO

Front 40

where are IL1 nad TNF made, and what do they do?

Back 40

activated macrophage
chemotaxis, leukocyte recruitment and activation, fever

Front 41

waht happens if ROS leak out?

Back 41

1. endo damage and increased vascular perm
2. antiproteases are inactivated and go wild breaking down proteins
3. other cells are injured

Front 42

tell me about NO

Back 42

made by endo cells, dilation, also inhibits platelet aggregation/adhesion, inhibit mast cell (histamine), inhibits leukocyte recruitment, KILLS bugs (ROS and reactive N species)

Front 43

what are chemokines

Back 43

small proteins that stim leukocytes to move to tissue (chemotaxis)

Front 44

what is the main thing found in lysosomes of PMN and monocytes?

Back 44

granules that kill bugs and can also kill ourselves. we have antiproteases that protect us from the granules destroying our proteins

Front 45

what are the 3 inter-related systems of plasma proteases

Back 45

1. compliment: C3a, C5a important for increased vascular permiability as well as chemotaxis and leukocyte recruitment/activation. MAC mediated cell lysis

2. Kinin: bradykinin increases vascular permiability and pain

3. Clotting system: thrombin and fibri

Front 46

why do you feel sick with acute inflammation

Back 46

IL1 and TNF and IL6 from activated macrophages act systemically (in addition to fibroblasts, endo, and leukocytes) to:
-fever
-leukocytosis
-increased acute phase proteins
-decrease appetite
-increased sleep

Front 47

the major effects of IL1 and TNF are...

Back 47

1. Systemic: fever, appetite, acute phase protein, PMN production
2. Endothelium: inflammation
3. Leukocytes: imflammation via IL1 IL6
4. Fibroblasts: repair

Front 48

when macrophages are activated (usually 2 days into the inflammatory response) what do they release, what are the effects?

Back 48

secrete IL 1 TNF and affects
1. Systemic: fever, sleep, appetite, neutrophilia, hemodynamic shock

2. Endothelium: leukocyte adherance, PG synthesis, increases coagulation, increases IL1, IL8, IL6 PGGF

3. increases fibroblast activity to repair damages

4. Causes leukocytes to increase secretion of IL1 and IL6

Front 49

whats an inflammasome?

Back 49

complex that controls release of IL1 from activated macrophages. Cleave Il1 into an active cytokine so it can
1. Endothelium: inflammation
2. Leukocytes: inflammation
3. Fibroblasts: repair
4. System: fever, sleep, appetite, acute phase protein, neutrophilia, hemodynamic effects (shock)

Front 50

after experiencing an insult that leads to acute inflammation what can happen next...

Back 50

1. complete resolution: all bad stimuli and mediators are cleared, injured cells repaired and normal fx

2. Healing, connective tissue replacement (fibrosis): some loss of Fx

3. Abcess:
4. Chronic Inflammation: new BV are made, mononuclear cells infiltrate, scar (fibrosis), further tissue injury

Front 51

*chronic inflammatory molecules include

Back 51

IL12, IFNg, adn IL17

Front 52

what does sub P do?

what does bradykinin do?

Back 52

pain and increased vascular permiability

pain and vascular permiability

Front 53

TNF:

IL1:
IL6:

CHemokines:

Back 53

TNF:macro secreted TNF in order to stim expression of endotheliam adhesion melecules (chemotaxis, recruitment). allows cells to enter tissue. Fever

IL1: macro and endo cells release this to stim expression of endo adhesion melecules (same as TNF) but ALSO plays a role in fever

IL6: macro make this and causes an acute phase system response

CHemokines: made by macro, endothelial cells, T cells, and mast cells adn causes migration of cells into normal tissue

Front 54

macro secreted TNF in order to stim expression of endotheliam adhesion melecules (chemotaxis, recruitment). allows cells to enter tissue. Fever

macro and endo cells release this to stim expression of endo adhesion melecules (same as TNF) but ALSO plays a role in fever

macro make this and causes an acute phase system response

: made by macro, endothelial cells, T cells, and mast cells adn causes migration of cells into normal tissue

Back 54

TNF:macro secreted TNF in order to stim expression of endotheliam adhesion melecules (chemotaxis, recruitment). allows cells to enter tissue. Fever

IL1: macro and endo cells release this to stim expression of endo adhesion melecules (same as TNF) but ALSO plays a role in fever

IL6: macro make this and causes an acute phase system response

CHemokines: made by macro, endothelial cells, T cells, and mast cells adn causes migration of cells into normal tissue

Front 55

tell me about prostacyclin and thromoboxine?

Back 55

both are from COX path, and have opposite effects

1. Prostacycline: vasodilation, inhibit platelet aggregation

2. Thromboxine: vasoconstriation, activates platelet aggregation

Front 56

what are the 3 things from COX path, what do they do? what are the 3 things from lipoxygenase, what do they do?

Back 56

COX
1. PG: fever, pain, vasodilation, increased vascular perm
2. Prostacyclin: vasodilation, inhibit platelet aggregation
3. THromboxine: vasoconstriction, platelet aggregation

LIPOOXYGENASE
1. Leukotriene CDE: vasoconstriction, increased vascular permiability
Leukotriene B: same as 5 HETE, chemotaxis, leukocyte adhesion
2. 5 HETE: same as leukotriene B, chemotaxis, leukocyte adhesion
3. Lipoxin: inhibits PMN adhesion/chemotaxis

Front 57

so in COX we have prostacyclin and thromboxine that have totally opposite effects, in lipoxygenase we have two with identical effects, what are they

Back 57

Leukotriene B and 5 HETE BOTH do chemitaxix and leukocyte adhesion

Front 58

tell me everything I need to know about histamine

Back 58

1. from mast
2. vasodilate
3. increased vascular perm

**serotonin does the same things but is form platelet

Front 59

whats the histamine wanna be

Back 59

serotonin

**also does vasodilation adn increased vascular perm but serotonin is fro mplatelets

Front 60

tell me about PG

Back 60

f1. from COX
2. Fever
3. Pain
4. vasodilation
5. increased vascular perm

Front 61

tell me about the leukotrienes

Back 61

from lipooxygenase
2 categories

CDE:vasoconstriction and increased vascular permiability

B: same as 5 HETE, chemotaxis and leukocyte adhesion

Front 62

many times we see vasodilation and increased vascular permiability go hand in hand (PG, histamine, serotonin, kinins, ) when do we see vasoCONSTRICT with increased vascular permiability

Back 62

leukotrienes CDE from lipoxygenase path

Front 63

what does PAF do

Back 63

increased vascular permiability

Front 64

what mediator increases vascular perm w/o a change in vessel diameter

Back 64

PAF

Front 65

tell me everything about NO

Back 65

1. made by endo
2. kills bugs
3. vasodilates
4 inhibits infmallation

Front 66

what do TNF IL1 do

Back 66

LOTS, they act locally on fibroblasts, endothelium, and leukocytes and also act systematically

1. Systemic: fever, anorexia, increased sleep increased acute phase proteins

2. Endothelium: increased leukocyte adhesion, increased IL1 production, procoagulant

3. Leukocytes: activation adn production of cytokines

4. Fibroblasts: increased proliforation and increased collagen

Front 67

whats the dif btwn IL1 and TNF and IL6

Back 67

all three have the same SYSTEMIC effects to cause fever, anorexia, and acute phase proteins

BUT the IL1 nad TNF also have locaal effects to:
1. increase proliforation of fibroblasts and increase collagen

2. promote leukocyte activation and production of cytokines

3. cause endothelium to increase leukocyte adhesion, IL 1 produciton and act as a procoagulatn

Front 68

what is responsible for chemotaxix and leukocyte recruitment/.activation

Back 68

1. Chemokines
2. IL1 TNF
3. Complimant
4. Leukotriene B
5. 5HETE

Front 69

what do chemokines do

Back 69

chemotaxis

leukocyte recruitment/activation

Front 70

what are the 3 interrelated plasma proteases?

Back 70

1. Compliment C3a C5a: inflammation, increased vascular permiability, chemotaxis, leukocyte recruitment/activation

2. Kinin: increased vascular permiability, pain, vasodilation

3. Clotting system:

Front 71

what does compliment do/. C3a C5a

Back 71

1. inflammation
2. increased vascular permiability
3. chemotaxis
4. leukocyte recruitment/activation

Front 72

wwhat does bradykinin do

Back 72

increased vascular permiability
vasodilation
PAIN

Front 73

whats involged with pain? fever

Back 73

PAIN:
PG
bradykinin
Sub P

FEVER:
IL1 TNF
PG

Front 74

whats lipoxin

Back 74

from lipoxygenase path

1. inhibit PMN adhesion/chemotaxis

Front 75

what does sub P do

Back 75

1. pain
2. increase vascular permiability

Front 76

what does IL 6 do

Back 76

the same systemic effects as TNF and IL1

1. fever
2. acute phase proteins
3. anorexia
4. sleep

Front 77

in acute inflammation we have vasodilation that leads to a red color, what kinds of things lead to vasodilation

Back 77

1. histamine
2. Serotonin
3. NO
4. PG

Front 78

we knwo that vascular perm is increased with endo retraction, endo injury, endo injury by lymphocytes and also transcytosis, what mediators also will increased vascular permiability.

Back 78

1. Histamine
2. Serotinin
3. C3a C5a
4. Bradykinin
5. Leukotriene CE
6. PAF
7. Substance P

**way more things that increase vascular permiability than vasodilation (vasodilate was PG, NO, histamine and serotonin. only histamine anserotonin were on both lists)

Front 79

ok we we have leukocytes coming to the tissues. what mediators help direct adn recruit the leukocytes?

Back 79

1. TNF IL1
2. Chemokines
3. C3a C5a
4. Leukotriene B
5. 5 HETE

Front 80

what mediators cause tissue damage

Back 80

1. NO
2. ROS
3. the content of lysosomes in leukocytes