Inflammation

Question 1

Stages of inflammation

Answer 1

1. Inflammation triggers vasodilation of local blood vessels which leads to excess local blood flow
2. Capillary permeability increases causing fluid to leak out of vascular space into surrounding tissue
3. Large numbers of granulocytes and monocytes migrate into tissues (via diapedesis)
4. Clots form in tissue due to fibrinogen leaking into tissue space

Question 2

Who are the first responders?

Answer 2

• Macrophages
• Neutrophils

Question 3

Vascular changes during inflammation (step 1)

Answer 3

• Vasodilation: subsequent widening of blood vessels, increasing blood flow leading to redness (hyperemia) and heat
• Tissue macrophages are activated and chemokines and cytokines are released promoting further immune response

Question 4

Increased vascular permeability during inflammation (step 2)

Answer 4

• Release of chemokines and cytokines bind to endothelial receptors, triggering intracellular pathways
• Endothelial cells contract leading to increased inter-endothelial gaps which allows for the plasma proteins to move into tissue space and facilitate swelling (and pain)

Question 5

Plasma proteins that play a role in inflammation

Answer 5

• Kinins
• Complement system activation
• Acute phase proteins
• Clotting factors

Question 6

Kinins

Answer 6

• Activated by inflammation
• Plasma proteins that promote vasodilation, and increase permeability
• Contributes to pain sensation

Question 7

Complement system activation

Answer 7

• Groups of proteins with proteolytic activity that are activated by inflammation. Cascade turns on chain of proteins
• Proteins conduct pathogen lysis via Membrane Attack Complex (MAC) where they puncture the pathogens allowing water to enter AND these proteins will also undergo opsonization (markers for phagocytosis) for enhanced phagocytosis.

Question 8

Acute Phase Proteins

Answer 8

• Will mark dead and dying cells that leads to activation of the complement system

Eg. C-reactive protein (CRP)- reliable marker for inflammation

Question 9

Clotting Factors

Answer 9

• Initiate coagulation
• Establish barrier
• Provide a scaffold for healing

Question 10

Transudate

Answer 10

Described the fluid and plasma proteins that leaks into extracellular space (does not include any cells)

Question 11

Exudate

Answer 11

Fluid including plasma and cells that leaks out of the blood vessels into the tissues

Question 12

Movement of granulocytes (neutrophils) into tissue (Step 3)

Answer 12

1. Cells roll along the endothelial cells lining the vasculature
2. Cytokines/chemokines being released by macrophages inside the tissues attracts immune cells (eg. Neutrophils)
3. Endothelial cells have integrin receptors on surface that bind to the selectin ligand of neutrophils allowing them to adhere to the endothelial cells
   - Selectin ligands are only displayed by neutrophils with the presence of cytokines/chemokines
4. Cells undergo diapedesis and move through the gaps in the endothelial cells towards the inflammation site

Question 13

What happens to neutrophils when they enter tissues?

Answer 13

They will walk along the chemokine gradient produced at the inflammation site in an ameboid direction

• Ameboid movement possible because of pseudopodium and the presence of actin/myosin contraction
• Actin subunits will polymerize to extend pseudopodium, and actin/myosin contraction occurs in rear, similar to cross bridge will allow for the movement forward

Question 14

Shift to arrival of eosinophils, basophils, and monocytes into inflammatory site

Answer 14

Neutrophils are first to arrive. Shift to other leukocytes is stimulus dependent

Question 15

What does the presence of Eosinophils mean?

Answer 15

Signify parasitic infections and allergic responses in dogs and horses

Question 16

What does the presence of Basophils mean?

Answer 16

• Less common
• Indicates certain hypersensitivity and chronic inflammatory states

Question 17

What does the presence of monocytes mean?

Answer 17

• Increases monocytes in the blood for prolonged inflammatory response
• Differentiate into macrophages at the site for extended defense and tissues repair

Question 18

When does adaptive immunity kick in?

Answer 18

Approximately 12 hours after injury/infection

Question 19

Activation of adaptive immunity

Answer 19

• Monocytes may increase as they differentiate into macrophages to present antigens
• Lymphocytes also rise as specific B and T cells are activated

Question 20

Adaptive immunity impacts on CBC

Answer 20

• Increase in monocytes
• Won’t see significant lymphocytosis because lymphocytes are mostly present in the lymphoid tissue, not in the blood

Question 21

Resolution after inflammation

Answer 21

• Involves returning to homeostasis where WBCs and acute phase proteins are normalized
• Initiation of tissue repair and healing processes. Can show a return to normal blood parameters
• Bone marrow returns to a steady state

**If homeostasis is not reached, then it will become chronic

Question 22

Chronic inflammation

Answer 22

• Longer than 7 days
• High levels of activated macrophages in tissues (will appear in CBC)
• Formation of granulomas to wall off and isolate lesions. When present they signify persistent inflammation

Question 23

Granulomas

Answer 23

Collection of immune cells that forms to wall off and isolate lesion

Question 24

Hematologic response to inflammation

Answer 24

Inflammation causes release of cytokines and growth factors which:

1. Increase production in the proliferative pool (increase mitosis)
2. Increase release of reserves in maturation and storage pool
3. Increase tissue consumption

Question 25

Neutrophil production vs. tissue utilization

Answer 25

• Neutrophil levels will vary based on the marrow output vs. the tissues demands
• If marrow delivery is higher than tissue consumption then Neutrophilia
• If marrow delivery is lower than tissue consumption then neutropenia

Question 26

What will happen when there is an inflammatory response when bone marrow is keeping up with demand?

Answer 26

• Leukocytosis causes by neutrophilia and left shift
• Interpreted as moderate inflammation

Question 27

What will happen when there is an inflammatory response when bone marrow is not keeping up with demand?

Answer 27

• Leukopenia caused by neutropenia and a left shift
• Interpreted as severe inflammation

Question 28

Bone marrow contribution to neutrophil trafficking during inflammation across species

Answer 28

• Dogs: high marrow reserve, Neutrophilia: 20-120.
• Cow: relatively low reserve, neutrophilia: 10-25
• Therefore if dogs have neutropenia, more severe because they have a high range to start with.

Question 29

Factors modulating the magnitude of neutrophilia in an inflammatory response

Answer 29

1. Acute inflammation is a lesion with increased local blood flow and swelling
   - Small injury if everything is relatively balanced
   - Mild to moderate if neutrophilia with a variable left shift
   - Bigger injury when consumption exceeds production (neutropenia with a prominent left shift)
2. Chronic, walled off inflammatory lesions
   - High neutrophil concentrations because lesions continue to stimulate the marrow to reach maximal production but the rate of consumption is reduced due to closed off area.