Acute inflammation Flashcards
What do we mean by inflammation?
The reaction of living, vascularised tissue to injury
How do we recognise infection?
Cutaneous inflammation- skin
Red, warm, swollen, tender, loss of function
Name examples of inflammation
Obstructions- gallstone cholecystitis, appendicitis
Reaction to infection- pneumonia, shingles
Burns, ulcer, Gout,
After necrosis- stroke, myocardial infarction
What does inflammation do?
Deliver concentrated, activated defensive materials to the innate immune system in fluid- phagocytes, plasma proteins
What is exudate?
Delivered cells, protein, fluid
What is inflammation?
Delivery and battle
Name tissue sentinel cells
Pericytes, mast cells, tissue macrophages, DC
Name blood sentinel cells
Monocytes, NK cells, resident liver macrophages
What danger signals trigger inflammation by activating the innate immune response?
Mild physical trauma
Specific molecular patterns
Perturbed cellular homeostasis
Missing self molecules
What does mild physical trauma cause?
Degranulates mast cells (secretion of cytoplasmic granules)
short-lived Histamine released
What are specific molecular patterns?
PAMPS
DAMPS
What is perturbed cellular homeostasis?
Surveillance of vital systems/ effector triggered immunity
Phosphorylation status, ion balance, mitochondrial status- signals converge to activate a cytoplasmic PRR
What are missing self molecules?
Cell surface molecules that prevent immune attack
MHC Class 1, Complement inhibitors
What are the vascular changes in inflammation?
Accelerated by active changes in small blood vessels- dilation of arteriole, leakiness of capillary bed
What does arteriole dilation do?
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
What causes local tissue swelling?
Fluid leaving leaky vessels, caused by active structural changes to endothelium in venules in response to vasoactive mediators
What are the vasoactive mediators that cause the leaky vessels?
Endothelial contraction opens gap Initial- histamine Rapid- bradykinin Delayed- cytokines Transcytosis channels- VEGF
What is the clot protein that escapes with the fluid?
Fibrinogen- made in liver, forms insoluble polymer that clots, scaffolding for cells
How do passive leaks occur?
At sites of epithelial injury until endothelium regenerates
(sunburn/ leucocyte transmission)
Angiogenesis- new leaky capillaries
What limits tissue swelling?
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
What are the types of exudate in clinical practice?
Pus
Fibrinous
Serous
Haemorrhagic
What is pus?
Neutrophil and enzyme rich
Opaque, greenish, chemotactic microorganisms
What is fibrinous exudate?
Few cells
Greyish sticky fibrin coating- polymer
Restricts escape of infecting agents
What is serous exudate?
Few cells, watery exudate
Serum-like, little fibrinogen/ platelets
Burn blister
What is haemorrhagic exudate?
Vascular destruction
How do circulating neutrophils get to an injury site?
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
How are circulating neutrophils and vascular endothelium activated?
DAMP, cytokines and chemokines from DAMP activated cells like pericytes
How do neutrophils exit into the tissue?
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
What is the process of transmigration?
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
Name self agents that cause neutrophil chemotaxis
Coagulation products
Complement C5a and C3a
Cytokine IL-8
Name foreign agents that cause neutrophil chemotaxis
Bacterial endotoxin (LPS) f-met-leu-phe peptides- tag on peptides
How do resident macrophages shield trivial injury?
Sporadic- cloak tissue microlesions, single muscle fibre
Above density of tentacles= neutrophils activated and swarm initiated
How does the nature of the exudate change with time?
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
What is the nociceptive system?
Noxious stimuli are processed by specialised neural pathways (pain)
What are the types of pain processed?
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
How does pain and stress stimulate the autonomic nervous system?
Adrenaline/ noradrenaline
Indirect pain- capsular stretch, secondary inflammation
No pain nerve fibres= no pain innervation/ psychological
How are the lymphatics involved in inflammation?
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
What are the systematic effects of inflammation?
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
What are the sickness behaviours?
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
