Chronic tissue injury and infection Flashcards
How do recognise chronic inflammation?
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
What is granulation tissue?
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
What are the types of monocytes?
Sentinel- (CD16+) patrol in vessels, survey and support endothelium
Migratory- emigrate steadily
What occurs to monocytes during inflammation?
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
How are macrophages created?
Monocytes in blood (from yolk sac/ bone marrow) enlarge and undergo mitochondrial, lysozyme and ER changes
Why are macrophages useful?
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
How is NET associated with autoinflammation?
Gout (urate crystal) arthritis
Reaction of crystals activates monocyte inflammasomes, triggers NET release, localised pain
How is NET associated with allergy?
Asthma- neutrophil inflammation, rhinovirus increases Netosis, NET DNA intensifies allergic type 2 immune responses in asthmatic airways
How is NET associated with autoimmunity?
Systematic lupus erythematosus
NET major source of antigens, immune complexes trigger more NET release, NET injure endothelium
What are inflammasomes?
Caspase-rich multiprotein complexes
Assembled by PRR signals in myeloid cells
What do caspase enzymes produce?
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)
Why are inflammasomes important?
Antimicrobial defence, inflammatory cell death
Name the special types of inflammatory lesions
Inflammatory sinus and fistula Erosion and ulcer Abscess and cellulitis Granuloma Amyloid deposition
What is an inflammatory sinus?
Infected hair follicle, abscess, lined by granulation tissue
Characterised by blind ending pit and tracking
Small hole
What is a fistula?
Fistula hole between two surfaces
Painful
Surgical intervention can lead to more
Abnormal link between different epithelial surfaces
What is an erosion and ulcer?
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
What is an abscess?
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
What are abscess outcome?
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
What is cellulitis?
Unlocalised subcutaneous spready infection- Strep pyogenes, staph aureus
What are granulomas?
Organised clusters of mature macrophages in response to persistent stimuli
What are the characteristics of granulomas?
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)
Describe non- immune granulomas
Foreign body reaction to poorly antigenic material
Larger, non-phagocytosable material
Aspirated cooked cellulose food molecule
What does a tuberculosis granuloma looks like?
Lots of nuclei, merged cytoplasm, contain mycobacteria
What occurs during mycobacterium tuberculosis infection?
Manipulates macrophage response
Granulomas form and spread the infection unrestricted
Specific T cells are required to arrest infection
How do they manipulate macrophage responses?
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
How do granulomas form and spread the infection unrestricted?
Phagocytosis of apoptotic infected m0 infects arriving m0, migration of infected m0 initiates secondary granulomas, m0 necrosis permits exuberant extracellular proliferation- soft caseous necrosis
What is the impact of specific T cells being present?
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
How is chronic kidney inflammation diagnosed?
Enlarged on ultrasound scan, proteinuria, failed glomerulus, amyloid-fibrils in tissues
What is amyloid?
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)
What are the causes of amyloid?
Different disease proteins- local/ multiorgan
amyloid AA/ serum amyloid A in chronic inflammatory disease
What are the outcomes of chronic inflammation?
Focal scarring to protect- ulcer, abscess
Widespread scarring destroys; organ failure- cirrhosis, chronic pyelonephritis, ischaemic heart disease
Persistence promotes cancer- osteomyelitis, cirrhosis
