Chronic tissue injury and infection

Question 1

How do recognise chronic inflammation?

Answer 1

injury, inflammation, repair
Macrophages and granulation tissue, new blood vessels
Usually adaptive response
e.g. gallbladder- red pus lining, cholesterol gallstones, thick and pale with fibrosis tissue wall

Question 2

What is granulation tissue?

Answer 2

New connective tissue- (formed by) fibroblasts, vessels (allows circulation to continue delivering exudate), lymphatics, collagen eventually
Surround dead tissue, pus or irritants- protects and delivers

Question 3

What are the types of monocytes?

Answer 3

Sentinel- (CD16+) patrol in vessels, survey and support endothelium
Migratory- emigrate steadily

Question 4

What occurs to monocytes during inflammation?

Answer 4

Enhanced migration, activation- activated interstitial monocytes acquire APC ability, secrete TNF and NO (antimicrobial)
Become interstitial monocytes- initially pro-inflammatory, later restorative
Monocytes exit by lymphatics/ death

Question 5

How are macrophages created?

Answer 5

Monocytes in blood (from yolk sac/ bone marrow) enlarge and undergo mitochondrial, lysozyme and ER changes

Question 6

Why are macrophages useful?

Answer 6

Highly plastic and capable cells- enhanced killing (IFN gamma), immune modulation (cytokine, chemokines, antigen presentation), acute phase reaction, clearance, new or remodelled tissue
Homeostatic and metabolic functions

Question 7

How is NET associated with autoinflammation?

Answer 7

Gout (urate crystal) arthritis

Reaction of crystals activates monocyte inflammasomes, triggers NET release, localised pain

Question 8

How is NET associated with allergy?

Answer 8

Asthma- neutrophil inflammation, rhinovirus increases Netosis, NET DNA intensifies allergic type 2 immune responses in asthmatic airways

Question 9

How is NET associated with autoimmunity?

Answer 9

Systematic lupus erythematosus

NET major source of antigens, immune complexes trigger more NET release, NET injure endothelium

Question 10

What are inflammasomes?

Answer 10

Caspase-rich multiprotein complexes

Assembled by PRR signals in myeloid cells

Question 11

What do caspase enzymes produce?

Answer 11

Inflammatory cytokines (IL-1 beta and IL-18)
Programmed lytic cell death (pyroptosis)- liberates cytokines and inflammasomes, traps bacteria in the corpse, glucocorticoid resistance (cleaves receptor)

Question 12

Why are inflammasomes important?

Answer 12

Antimicrobial defence, inflammatory cell death

Question 13

Name the special types of inflammatory lesions

Answer 13

Inflammatory sinus and fistula
Erosion and ulcer
Abscess and cellulitis
Granuloma
Amyloid deposition

Question 14

What is an inflammatory sinus?

Answer 14

Infected hair follicle, abscess, lined by granulation tissue
Characterised by blind ending pit and tracking
Small hole

Question 15

What is a fistula?

Answer 15

Fistula hole between two surfaces
Painful
Surgical intervention can lead to more
Abnormal link between different epithelial surfaces

Question 16

What is an erosion and ulcer?

Answer 16

Localised defect in epithelial surface
Sloughing of inflammatory necrotic tissue
Full thickness- all the way through surface
Exposes tissue under epithelial
Dermis/ lining of stomach
Not quick fix- no basement membrane
Exposed to acidic juices- expand ulcer, digest submucosa (ulcer deeper/ erosion has basal membrane so potential to regenerate)
Erode through wall of artery- haemorrhage
Perforating gastric ulcer

Question 17

What is an abscess?

Answer 17

Pus accumulates in newly formed cavity- avascular so poor drug penetration
Pus- neutrophil and potassium rich, excretory enzymes- damage tissues. Swarm pushes aside connective tissue
Granulation tissue surrounds to deliver exudate

Question 18

What are abscess outcome?

Answer 18

Persists- scars/ fibrosis (burst)
Discharges- sinus and fistula
Fascial inelastic- tissue swelling limit, pressure increase, same as blood coming in, no blood supply- strangle itself
Drained to relieve pressure

Question 19

What is cellulitis?

Answer 19

Unlocalised subcutaneous spready infection- Strep pyogenes, staph aureus

Question 20

What are granulomas?

Answer 20

Organised clusters of mature macrophages in response to persistent stimuli

Question 21

What are the characteristics of granulomas?

Answer 21

Larger, more organelles, ruffled membranes, avascular
Low turnover (foreign body- inert indigestible material like suture)
High turnover (immune- toxic inciting agent, continual replenishment and Tell cells migrate in then retained)

Question 22

Describe non- immune granulomas

Answer 22

Foreign body reaction to poorly antigenic material
Larger, non-phagocytosable material
Aspirated cooked cellulose food molecule

Question 23

What does a tuberculosis granuloma looks like?

Answer 23

Lots of nuclei, merged cytoplasm, contain mycobacteria

Question 24

What occurs during mycobacterium tuberculosis infection?

Answer 24

Manipulates macrophage response
Granulomas form and spread the infection unrestricted
Specific T cells are required to arrest infection

Question 25

How do they manipulate macrophage responses?

Answer 25

Inhaled bacteria are imported into lung tissue in macrophages Renders them insensitive to T cell help Promotes its phagocytosis (avoiding lysosomes) Promotes m0 chemotaxis and phagocytosis of apoptotic m0/ Mimics complement system/ Waxy coat so cant digest- survives in cytoplasm/ Suppresses adaptive

Question 26

How do granulomas form and spread the infection unrestricted?

Answer 26

Phagocytosis of apoptotic infected m0 infects arriving m0, migration of infected m0 initiates secondary granulomas, m0 necrosis permits exuberant extracellular proliferation- soft caseous necrosis

Question 27

What is the impact of specific T cells being present?

Answer 27

TNF and IFN gamma produced. TNF not necessary for granulomas but increases microbicidal capacity Contribute to lung destruction (cavitation) and so transmission Bacterial population stabilise- some proliferate, others go dormant until immunity dips

Question 28

How is chronic kidney inflammation diagnosed?

Answer 28

Enlarged on ultrasound scan, proteinuria, failed glomerulus, amyloid-fibrils in tissues

Question 29

What is amyloid?

Answer 29

Extracellular accumulation of insoluble fibrils made from a misfolded peptide (plus amyloid P protein) Polymerise- beta pleated sheet Misfolded proteins self-associate- either aggregation-prone mutant or simple overproduction of normal protein (+/- defective degradation)

Question 30

What are the causes of amyloid?

Answer 30

Different disease proteins- local/ multiorgan | amyloid AA/ serum amyloid A in chronic inflammatory disease

Question 31

What are the outcomes of chronic inflammation?

Answer 31

Focal scarring to protect- ulcer, abscess Widespread scarring destroys; organ failure- cirrhosis, chronic pyelonephritis, ischaemic heart disease Persistence promotes cancer- osteomyelitis, cirrhosis