5 - Acute Inflammation

Front 1

Purpose of acute inflammation:

Back 1

Sentinel cells found microbial insult and/or tissue damage, and need reinforcement

1. Delivery of leukocytes and plasma proteins to site of injury

- vasodilation

- vascular permeability

- emigration, activation and chemotaxis of leukocytes (leave blood and go into tissues)

2. Elimination of agent (effector processes)

3. Trigger acquired immunity

4. Initiate tissue repair

5. Systemic responses - fever, leukocytosis etc.

Front 2

5 signs of acute inflammation

Back 2

1. Rubor (redness)

2. Tumor (swelling)

3. Calor (heat)

4. Dolor (pain)

5. Functio Laesa (loss of function)

*mainly consequences of local vascular changes

Front 3

Initiators of acute inflammation:

Back 3

Infections:

- bacteria

- viruses

- parasites

- microbial toxins

Trauma

Physical and Chemical injury:

- cold (frostbite)

- burns

- irradiation

Tissue Necrosis

Foreign body:

- dirt

- suture

Immune Reactions:

- hypersensitivities

- autoimmune diseases

Front 4

What happens when sentinel cells detect microbial or parasitic products in the host tissues?

Back 4

Sentinel cells such as macrophages express PRRs so they can monitor tissues for PAMPS/DAMPS

When they find a PAMP, it leads to signaling cascades within the macrophage, which activates it

The macrophage then synthesizes and releases proinflammatory cytokines (ILs, TNF) or chemokines that act as signals for other inflammatory cells (to release even more) and blood vessels in the area

These chemokines/cytokines set up a concentration gradient as they move away from the macrophage and that helps to direct other luekocytes like neutrophils to the site of insult = chemokine-directed chemotaxis

Front 5

How are mast cells involved in acute inflammation?

Back 5

Cytokines produced by macrophages activate the mast cell to rapidly amplify proinflammatory signals

Mast cells sit near blood vessels and nerves and contain granules with histamine and serotonin (vasoactive compounds), associated with type 1 hypersensitivities (allergies)

the degranulation of mast cells (ie. release of serotonin and histamine) causes changes to local vasculature

Front 6

How are eicosanoids and cytokines different?

Back 6

Cytokines are proteins, can travel further distances

Eicosanoids (leukotrienes and prostaglandins) are oxidized derivatives of fatty acids - short half life and act locally on vasculature and endothelium

Front 7

What are the vascular changes that occur in acute inflammation?

Back 7

1. Vasodilation and local stasis of blood flow

2. Increased vascular permeability

3. Expression of cell-adhesion molecules on vascular endothelium

Front 8

What are the mediators of local vascular changes?

Back 8

1. Histamine, serotonin

2. Nitric Oxide

3. Prostaglandins and leukotrienes

Front 9

Histamine:

Back 9

Mast cell degranulation adjacent to blood cells

Induced by:

- trauma/cold/heat

- immune reactions (IgE)

- C3a and C5a (from complement activation pathway)

- Histamine releasing proteins from leukocytes

- Neuropeptides (substance P)

- Cytokines (IL-1 and IL-8)

Binds to H1 receptors on endothelial cells

Dilation of arterioles and increased permeability of venules

Front 10

Nitric Oxide:

Back 10

- Released from endothelial cells and macrophages

- Induces relaxation of vascular smooth muscle

- Also anti-inflammatory role (reduces leukocyte recruitment)

- NO is microbicidal

Front 11

Prostaglandins and leukotrienes

Back 11

NSAIDs block COX1&2 for prostaglandin production

Front 12

What do leukotrienes increase?

Back 12

1. Vascular permeability

2.Smooth muscle contraction

3.Neutrophil Chemotaxis

Front 13

What do Prostaglandins increase?

Back 13

1.Vascular permeability

2. Vasodilation

3. Hyperalgesia (pain receptors)

Front 14

Why is vasodilation and stasis of blood flow important in acute inflammation?

Back 14

- Increased blood to area

- Expansion of capillary beds

- Decreased velocity of flow

- Increased permeability (fluid loss)

All allow more leukocytes to travel to site of injury/infection, blood slows down enough so that the leukocytes can exit the blood into the tissues

Front 15

What do NSAIDs block?

Back 15

COX-1&2

ie. meloxicam, phenylbutazone, etc

Local effects- anti-inflammatory and analgesic

Central effects - can temporarily reduce the bodys set point (anti pyretic)

Front 16

What is the action of prostaglandin E2 and what is its primary source?

Back 16

Action: Vasodilation, vascular permeability, pain

Source: Leukocytes (mast cells)

Front 17

What are some other major mediators of inflammation?

Back 17

Cytokines and chemokines

Interleuken, TNF-alpha

Plasma proteins

Leukotrienes

Eicosanoids

Histamine and serotonin

Front 18

What is vasodilation?

Back 18

Vascular smooth muscle contraction

-increased blood to area,

-expansion of capillary beds,

-Decreased velocity of flow,

-Increased permeability (fluid loss)

Front 19

What is vasodilatation mediated by?

Back 19

Histamine

Nitric Oxide

Prostaglandins

Front 20

Increased vascular permeability physically is?

Back 20

-Gaps between endothelial cells due to endothelial contraction or trauma

Front 21

Increased vascular permeability causes what?

Back 21

-transport of plasma through endothelial cells (transcytosis)

-High protein fluid accumulates in tissue = edema

-Edema activates endothelia cells to make inflammatory mediators

Front 22

What is increase vascular permeability mediated by?

Back 22

Histamine

Leukotrienes

Protaglandins

Front 23

Why is there a decrease blood velocity?

Back 23

-Vasodilation (expansion of capillary beds)

-Increased permeability (fluid loss)

Front 24

What can cause vascular changes?

Back 24

-Endothelial contraction

-Increased Transcytosis

-Direct Injury

-Leukocyte dependent injury

Front 25

What are the four phases of leukocyte extravasation? (blood to tissue)

Back 25

1. Leukocyte margination (tethering) and rolling

2. Firm endothelial adhesion (pavementing)

3. Diapedesis (transmigration)

4. Migration in interstitial tissues - chemotactic gradient (chemotaxis)

Front 26

Migration and rolling...

-Can be normal in blood vessels but do not adhere to epithelium

-Vasodilation and increased _________, _________, and slows blood flow

Back 26

-Can be normal in blood vessels but do not adhere to epithelium

-Vasodilation and increased vascular permeability, hemoconcentrates and slows blood flow

Front 27

What causes the activation of endothelial cells to be able to tether leukocytes cis 'selections'?

Back 27

TNF-alpha, IL-1, and histamine

Front 28

Migration and rolling causes leukocytes to transiently adhere to the endothelium (rolling). This allows for what?

What does the presence of chemokines activate?

Back 28

-Close association between endothelium and leukocytes

-High affinity integrins on the leukocyte that allow them to adhere

Front 29

What is a disease that lacks the ability to for leukocytes to adhere?

Back 29

Bovine leukocyte adhesion deficiency

-Holstein cattle (autosomal recessive) - gene B2-integrin

-Impaired expression of LFA-1 on neutrophils thats required for firm adhesion

-Rolling neutrophils cannot adhere = unable to extravasate

**re-occuring bacterial infections and premature death

Front 30

Describe firm adhesion (pavementing) ...

Back 30

-chemokines and rolling leukocytes causes change from low to high affinity integrin surface expression

-firm integrin-mediated binding of leukocytes to endothelium at infection site

=leukocytes spread out along endothelial surfaces (pavementing)

Front 31

Describe Diapedesis….

Back 31

-predominantly in venules

-basement membrane is compromised by leukocytes secretion of collagenases (digest membrane)

Front 32

Describe Chemotaxis...

Back 32

-moves along chmoattractant gradient

-Extended cytoplasmic tag, then pulls trailing edge (polymerization of actin then pseudopodia formation)

Front 33

What are the two types of chemoattractant gradients?

Back 33

Exogenous: N-formyl-methionine and bacterial lipids

Endogenous: C3a C5a (complement), leukotrienes, IL-8

Front 34

Main cell in pus?

Back 34

Neutrophils

Front 35

Main cell with parasites? Mechanism?

Back 35

Eosinophils

(cells with red cytoplasmic granules)

Mechanism: combination of chemokines and cytokines, type adhesion molecules on endothelia

Front 36

Appearance of leukocytes during inflammation

Back 36

Front 37

What are some systemic effects of acute inflammation?

Back 37

-loss of appetite

-slow wave sleep

-lethargy

-cachexia (muscular wasting)

-Hemodynamic changes (shock): decreased vascular resistance (vasodilation) and increased heart rate

-Leukocytosis (neutrophilia)

-metabolic acidosis (low blood pH)

-Acute phase protein alterations

-Fever (pyrexia)

Front 38

What is the purpose of the systemic effects?

Back 38

To conserve energy and mobilize reserves

Front 39

What are the 3 organs that produce acute inflammation?

Back 39

-Bone marrow = leukocytosis

-Liver = acute phase proteins

-Hypothalamus = Fever (can have affect on liver)

Front 40

Leukocytosis…

Back 40

-Initial increase in circulating neutrophils (IL-1 and TNF increase release of stored neutrophils in bone marrow)

-Prolonged infection induces production of colony stimulation factors

Front 41

Prolonged infection induces production of colony stimulation factors which do what?

Back 41

Release of immature (band) neutrophils (left shift)

-Neutrophilia with left shift is the most common in change in acute inflammation

Front 42

Acute phase proteins (APP) are synthesized where?

Back 42

In the liver in response to cytokines in fist 24 - 48 hours

Front 43

What are the actions of acute phase proteins?

Back 43

-homeostasis of tissue

-reduces tissue damage

-aids in propagating inflammatory reaction

-Regulation of immune response

-Protection against infection

-Aids in tissue repair

Front 44

Examples of acute phase proteins

Back 44

C-Reactive Protein (CRP): Dog and pig, not cats

Serum Amyloid A: Dogs, cats, pigs, and cattle

Haptoglobin:Pigs, cattle, sheep

-moderate in cats and dogs

Front 45

Acute phase proteins - Positive APP and negative APP examples

Back 45

Positive

-C-Reactive Protein

-Serum Amyloid A (SAA)

-Haptoglobin

-Alpha-1-acid glycoprotein (AGP)

-Ceruloplasmin

-Fibrinogen

Negative

-Albumin

-Transferin

Front 46

Fever: Pyrogens stimulate prostaglandin systhesis in vascular and perivascular cells of the ______

Pyrogens include:???

Back 46

Hypothalamus

Pyrogens = LPS (exogenous)

-IL-1 and TNF (endogenous)

Front 47

Function of fever….

Back 47

-Induction of heat shock proteins (enhance leukocyte response)

-Increase expression of cytokines

-Enhance phagocytosis

-Increased t cell proliferation

-Inhibition of growth of some microbes

Front 48

Thermoregulation of body - overview

Back 48

Cutaneous and deep receptors or monoamines => stimulate anterior hypothalamic area of brain => Heat gain or Heat loss

Front 49

Heat gain

Back 49

Heat production - Catecholamines, thyroxine, or shivering

Heat loss - vasoconstriction, piloerection, postural changes, behavioural changes

Front 50

Heat loss

Back 50

Panting

Vasodilation

Postural changes

Perspiration

Behavioural changes

Front 51

What does fever feel like?

Back 51

1. Body's thermostat is set to a higher temperature (body is lower than thermostat): patient is cold -> shivers

2. Temperature reaches set point (not hot or cold): high temperature measured -> fever

3. Body brings temperature back down and thermostat is at a lower temp (body is higher than thermostat): patient is hot 'breaking the fever' -> sweating **infection under control

Front 52

Signs of acute inflammation...

Back 52

1. redness: increased vasodilation due to vasoactive mediators dilating vessels

2. Heat: vasodilation and blood flow increase

3. Swelling: leakiness of blood vessels causes plasma to leak from blood to produce edema

4. Pain: prostaglandins, neuropeptides, cytokines

5. Loss of function

Front 53

Test used for mastitis?

Back 53

California mastitis test (agglutination of DNA)

OR automated cell counting

Front 54

Mastitis...

Back 54

Usually bacterial infection

-PAMPs, sentinel cells, acute inflammation

-Mediators, vascular changes, leukocyte recruitment

-systemic effects

Blood: left shift, haptoglobin, SAA