Acute inflammation

Question 1

What do we mean by inflammation?

Answer 1

The reaction of living, vascularised tissue to injury

Question 2

How do we recognise infection?

Answer 2

Cutaneous inflammation- skin

Red, warm, swollen, tender, loss of function

Question 3

Name examples of inflammation

Answer 3

Obstructions- gallstone cholecystitis, appendicitis
Reaction to infection- pneumonia, shingles
Burns, ulcer, Gout,
After necrosis- stroke, myocardial infarction

Question 4

What does inflammation do?

Answer 4

Deliver concentrated, activated defensive materials to the innate immune system in fluid- phagocytes, plasma proteins

Question 5

What is exudate?

Answer 5

Delivered cells, protein, fluid

Question 6

What is inflammation?

Answer 6

Delivery and battle

Question 7

Name tissue sentinel cells

Answer 7

Pericytes, mast cells, tissue macrophages, DC

Question 8

Name blood sentinel cells

Answer 8

Monocytes, NK cells, resident liver macrophages

Question 9

What danger signals trigger inflammation by activating the innate immune response?

Answer 9

Mild physical trauma
Specific molecular patterns
Perturbed cellular homeostasis
Missing self molecules

Question 10

What does mild physical trauma cause?

Answer 10

Degranulates mast cells (secretion of cytoplasmic granules)

short-lived Histamine released

Question 11

What are specific molecular patterns?

Answer 11

PAMPS

DAMPS

Question 12

What is perturbed cellular homeostasis?

Answer 12

Surveillance of vital systems/ effector triggered immunity

Phosphorylation status, ion balance, mitochondrial status- signals converge to activate a cytoplasmic PRR

Question 13

What are missing self molecules?

Answer 13

Cell surface molecules that prevent immune attack

MHC Class 1, Complement inhibitors

Question 14

What are the vascular changes in inflammation?

Answer 14

Accelerated by active changes in small blood vessels- dilation of arteriole, leakiness of capillary bed

Question 15

What does arteriole dilation do?

Answer 15

Vasoactive mediators initiate and sustain response (nitric oxide from endothelium/ cytokines)
Capillary bed opens fully, fluid leak= fluid slows/ more viscous and concentrated= stasis/ more oxygen delivery

Question 16

What causes local tissue swelling?

Answer 16

Fluid leaving leaky vessels, caused by active structural changes to endothelium in venules in response to vasoactive mediators

Question 17

What are the vasoactive mediators that cause the leaky vessels?

Answer 17

Endothelial contraction opens gap
Initial- histamine
Rapid- bradykinin
Delayed- cytokines
Transcytosis channels- VEGF

Question 18

What is the clot protein that escapes with the fluid?

Answer 18

Fibrinogen- made in liver, forms insoluble polymer that clots, scaffolding for cells

Question 19

How do passive leaks occur?

Answer 19

At sites of epithelial injury until endothelium regenerates
(sunburn/ leucocyte transmission)
Angiogenesis- new leaky capillaries

Question 20

What limits tissue swelling?

Answer 20

The space around the swelling- more= more swelling
Exudate in soft brain tissue- necrosis, no space (pressure)
Extra fluid reduces joint stability
Skin- lots of compartments

Question 21

What are the types of exudate in clinical practice?

Answer 21

Pus
Fibrinous
Serous
Haemorrhagic

Question 22

What is pus?

Answer 22

Neutrophil and enzyme rich

Opaque, greenish, chemotactic microorganisms

Question 23

What is fibrinous exudate?

Answer 23

Few cells
Greyish sticky fibrin coating- polymer
Restricts escape of infecting agents

Question 24

What is serous exudate?

Answer 24

Few cells, watery exudate
Serum-like, little fibrinogen/ platelets
Burn blister

Question 25

What is haemorrhagic exudate?

Answer 25

Vascular destruction

Question 26

How do circulating neutrophils get to an injury site?

Answer 26

Leucocytes passively marginate (roll along) on passing into venules, pushed by haemodynamic of blood flow Slow= more neutrophils contact endothelium Change in cell adhesion molecules expressed Transmigration

Question 27

How are circulating neutrophils and vascular endothelium activated?

Answer 27

DAMP, cytokines and chemokines from DAMP activated cells like pericytes

Question 28

How do neutrophils exit into the tissue?

Answer 28

Contact, capture and rolling- histamine, DAMP and cytokines TNF/ IL1 cause endothelium to expose sticky selectins on surface Firm adhesion, spreading, crawling- cytokines increase endothelial surface adhesion molecules firmly bind to neutrophils Transmigration- crawling neutrophils encounter platelets, mover to endothelial junction to exit using proteases

Question 29

What is the process of transmigration?

Answer 29

Crossing basement membrane Pericyte guides molecules Extravasated neutrophils have transcriptional burst (ATP mitochondria) releasing cytokines, chemokines and growth factors- screen perivascular tissue Move by chemotaxis along fibrin matrix scaffold to injury site

Question 30

Name self agents that cause neutrophil chemotaxis

Answer 30

Coagulation products Complement C5a and C3a Cytokine IL-8

Question 31

Name foreign agents that cause neutrophil chemotaxis

Answer 31

``` Bacterial endotoxin (LPS) f-met-leu-phe peptides- tag on peptides ```

Question 32

How do resident macrophages shield trivial injury?

Answer 32

Sporadic- cloak tissue microlesions, single muscle fibre | Above density of tentacles= neutrophils activated and swarm initiated

Question 33

How does the nature of the exudate change with time?

Answer 33

Fluid then Neutrophil peak then macrophage peak Extravasating neutrophils leave trail of granule proteins along endothelium and extravasating tissue, recognised by monocytes coming next Neutrophils secrete tenderising proteins, engage process of repair

Question 34

What is the nociceptive system?

Answer 34

Noxious stimuli are processed by specialised neural pathways (pain)

Question 35

What are the types of pain processed?

Answer 35

Direct physical stimulation Chemical mediators- bradykinin, ATP, serotonin, histamine Itching- histamine and proteases Reduced pain threshold (hyperalgesia)- prostaglandin, amines, cytokines Deep visceral pain- autonomic/ more complex than somatic pain

Question 36

How does pain and stress stimulate the autonomic nervous system?

Answer 36

Adrenaline/ noradrenaline Indirect pain- capsular stretch, secondary inflammation No pain nerve fibres= no pain innervation/ psychological

Question 37

How are the lymphatics involved in inflammation?

Answer 37

Terminal lymphatics proliferate and drain some of the exudate- carry guide molecules that lead into dendritic cells/ post-phagocytic macrophages/ neutrophils Draining lymph rich in immune cells, cytokines and proteins

Question 38

What are the systematic effects of inflammation?

Answer 38

Hormonal cytokine effects distant to the injury - Fever (prostaglandin synthesis in hypothalamus) - Acute phase proteins (fibrinogen, C-reactive proteins, serum amyloid A) - Leucocytosis (accelerated neutrophilia release from marrow) - Sickness behaviours

Question 39

What are the sickness behaviours?

Answer 39

Listlessness, fatigue, decreased appetite, irritability and social withdrawal, heightened pain sensitivity, anhedonia (inability to feel pleasure) Cytokine-induced depression- inflammatory cytokines alter CNS neurotransmitter (serotonin and dopamine) availability