Lecture 2: Inflammation

Question 1

4 classical signs

Answer 1

Redness
Swelling
Heat
Pain

Question 2

Inflammation purpose

Answer 2

Remove pathogens
Remove injured tissues
Promote healing

Eg. Leukocyte adhesion deficiency

Question 3

Acute inflammation

Answer 3

Rapid response with fluid and neutrophils

Question 4

Chronic inflammation

Answer 4

Lymphocytes and macrophages

Deposits of extra cellular matrix

Question 5

Resolution phase of inflammation

Answer 5

Removing agents and repairing tissues

Or abscess to wall off an infection

Or scarring

Question 6

Process of inflammation

Answer 6

• Macrophages have pattern recognition receptors to eat the pathogen and alerts the immune system
• Mast cells are alerted of the pathogen and release histamine. The complement system C5a activates mast cells
• TNF IL-1 and IL-6 cytokines and histamine act in the vasculature to allow for leukocytes to leave and enter the tissues

Question 7

Vasodilation

Answer 7

NO, prostaglandins, histamine

Question 8

Increased vascular permeability

Answer 8

Histamine, bradykinin, leukotrienes and PAF

Question 9

Chemotaxis, leukocyte recruitment and activation

Answer 9

TNF, IL-1, chemokines C3a and C5a, leukotriene B4, bacterial products (PAMPS)

Question 10

Fever

Answer 10

IL-1, TNF, prostaglandins

Question 11

Pain

Answer 11

Prostaglandins and bradykinin

Question 12

Tissue damage

Answer 12

Lysosomal enzymes of leukocytes, reactive oxygen specifies, NO

Question 13

Microbe entry

Answer 13

Activated complement system leading to generation of C5a

Question 14

C5a then …

Answer 14

Acts in the masts cells to release histamine and prostaglandin D2

Question 15

Histamine

Answer 15

Causes contraction of endothelial cells results in plasm leakage into the site. Also promote EC to release of vasodilators (NO)

Heat and redness and swelling

Question 16

Prostaglandin D2

Answer 16

• Lipid mediator of inflammation
  Causes pain
• Bonds to receptors on smooth muscles and acts as a vasodilator
• Synthesis is prevented by NSAIDs

Question 17

Arachidonic acid

Answer 17

Becomes prostaglandins via cyclooxygenase

The target for NSAIDs

Question 18

Hageman factor (factor XII)

Answer 18

Released by the basement membrane via negatively charged collagen.
Acts on the clotting cascade
Acts on kallikrein- produces C5 and C5a and C5b without he complement system
Act on plasminogen–> to release C3, C3aand C3b without the complement system

Activates the kinin system= bradykinin causes pain and swelling

Question 19

The process of chemotaxis and leukocyte recruitments

Answer 19

Microbe activates complement C3a and C5a, also the microbe has PAMP eg LPS and TLR4 resulting in the release of pro-inflammatory cytokines

Question 20

Adhesion molecules are provoked by…

Answer 20

Histamine, TNF and IL-1

Question 21

C3a and C5a…

Answer 21

Stimulate chemotaxis toward the site of inflammation

The WBC then leaves and follows the chemokine gradient towards the infection sites

Question 22

Inflammasomes

Answer 22

NLRP3 inflammasomes forms a complex with caspase 1. Cleaves pro-IL 1 beta then is secreted as IL-1 beta, a pro inflammatory cytokine

Question 23

Autoinflammatory syndromes

Answer 23

Causes by disregulated inflammasomes- gain of function and unregulated IL-1

Question 24

Neutrophil extravasation

Answer 24

Slowing-causes by fluid leaving the vasculature
Rolling-p-selectin and PSGL-1
Binding- LAF-1 and ICAM-1
Extravasate - PECAM-1
Follow chemokine gradient to find bacteria

Question 25

Neutrophil rolling

Answer 25

Mediated by P-selectin on the endothelial cell and PSGL-1 on the neutrophils

Selectins mediate the rolling step. They bind to selectin ligands.

Question 26

Weibel-Palade bodies

Answer 26

Store p-selectin in the endothelium

Question 27

Binding

Answer 27

ICAm-1 is up-regulated on the endothelial surface to create a high affinity bind to LFA-1 on the neutrophils surface. This causes the neutrophils to stop rolling

Question 28

LFA1/ICAM-1

Answer 28

Both are increasingly present after the neutrophil rolling, the LFA-1 on the neutrophils and the ICAM-1 on the EC have a high affinity bind which cause the cell to stop rolling and adhere to the endothelium

These molecules are called integrins and integrin ligands… these create high affinity reactions

Question 29

Extravasation

Answer 29

Mysterious Process….WBC squeezes through the endothelium to go fine the infection…. PECAM-1 is concentrated at the intracellular Junctions, present on neutrophils and the Endothelial cells

Question 30

Monocyte extravasation

Answer 30

Usually occurs on day two after the neutrophils have invaded

Same mechanism but different specific molecule to neutrophils.

EC selectin- ?
Monocyte selectin ligand-?
EC INTEGRIN-?
Monocyte intgegrin ligand- ?

Question 31

Macrophages

Answer 31

Have both anti microbial activity (M1 type releasing IL-1, IL-12 and IL26)
and anti inflammatory activity/pro-resolving activity (M2) producing IL-10 and TGF beta

Question 32

IL-6

Answer 32

Causes the liver to make acute phase proteins

Question 33

TNF, IL-1 and IL-6

Answer 33

Effects the brain to Promote fevers

And causes generation of leukocytes in the bone marrow

Question 34

Fever

Answer 34

Generate by cytokines - IL-1 and TNF, which trigger arachadonic acid then the formation of prostaglandins PGE2 which signals the hypothalamus to produce neurotransmitters cAMP which elevated body temp.

NSAIDs block prostaglandin E synthesis to lower fevers

Question 35

Neutrophilia

Answer 35

TNF and IL-1 increase the release of nuetrophils from the bone marrow. More band cells are present in the blood

Question 36

Acute phase response

Answer 36

IL-6 cytokines aft in livers to produce CRP- a molecule to measure inflammation. Many of these proteins are opsinins.
The result of increased acute phase proteins results in a fast ESR or erythrocytes sedimentation rate

Question 37

Shock

Answer 37

TNF reaches high levels during sepsis or severe injury

May result in hypercoagulation DIC
Or hypotension and shock