Inflammation Flashcards
Features of acute inflammation?
- Initial RAPID response to tissue injury, mins-hrs to develop, lasts short while hrs-days
- INNATE response
- NON-SPECIFIC
Features of chronic inflammation?
-Long LASTING weeks-months
may follow acute or slow insidious onset
-↑tissue DESTRUCTION
-Attempts to repair damaged tissue –>fibrosis
Causes of acute inflammation?
-Infections
-Tissue damage∵
Physical agents= frost bites, burns, ionising UV
Chemical agents= chemical burns, irritants
Mechanical injury + ischaemia= trauma, tissue crush, reduced blood flow
-Foreign bodies
Causes of chronic inflammation?
- Failure to close inflammatory reactions= constant infections
- Misdirected inflammatory reaction= harmless environmental substances (allergies) + self antigens (autoimmune diseases)
- Cancer, atherosclerosis, Alzheimer, Type 2= directed against endogenous substances: crystals -> cholesterol, urate (gout)
Why acute inflammation?
Alert body ↓ spread of infection + damage Protect injured site from infection Eliminate dead cells/tissue Create conditions needed for healing
If acute didn’t exist?
No control of infections, impaired wound healing, tissue wouldn’t be repaired
5 R’s of acute?
Recognition of injury Recruitment of leukocytes Removal of agent Regulation (closure of response) Resolution/repair
Signs of acute?
Red∵ ↑blood flow-hyperaemia Swell∵ fluid accumulation ∵ ↑ vessel permeability Heat∵ ↑blood flow + metabolic activity Pain∵ ⇶pain mediators, ↑p on nerve ends Loss of function∵ ↑ swelling + pain
What are systemic changes of acute?
Fever
Neutrophilia
Acute phase reactants
Why fever?
endogenous pyrogens - IL-1, TNF-α
exogenous pyrogens - microbial components
Why neutrophilia?
G-CSF stimulates bone marrow⇶immature neutrophils to replenish dead
Why acute phase reactants?
IL-6, IL-1, TNF-α induces liver to produce:
C-reactive protein CRP
fibrinogen
complement
serum amyloid A protein SAP
↑ fibrinogen–> stacking of🔴(rouleaux)–> 🏃sedimentation rate
Form of Systemic Inflammatory Response Syndrome SIRS?
Sepsis
Vascular events of acute?
Vasodilation in small vessels
↑blood flow
↑vessel permeabilty (microvessels)
Overall effect of vascular events of acute?
ⓦ+plasma🐟 exit vessels ➩ site
How vasodilation happens?
Injured cells, macrophages, mast cells ⇶ HISTAMINE, serotonin
Why ↑blood flow ➩ site?
So influx of ⓦ, fluid, O2, nutrients
How vessels ↑ permeabilty?
- Contraction of endothelial cells∵histamine,serotonin –>leakage of fluid + cells in site
- endothelial cell activation–> ↑adhesion ∞
What’s inflammatory exudate?
H2O, salts, plasma🐟(fibrinogen), inflammatory cells, 🔴 get out of vessels + enter tissues/ serous cavities ∵ ↑ vessel permeabilty
What’s transudate
- fluid leaks∵ altered osmotic/hydrostatic p
- normal vessel permeability
Cellular events of acute?
Migration + accumulation of cells
Removal of pathogens/dead cells
Migration + accumulation of monocytes
How cells migrate + accumulate?
Neutrophils arrive 1st via complex process to exit from vessels
How dead cells + pathogens removed
Neutrophils phagocytose–> live briefly –> die–> pus
How monocytes migrate + accumulate?
Monocytes (in blood) differentiate→ macrophages(at tissue)–>phagocytosis–>clearance of site + tissue repair factors TGF-β
Neutrophil recruitment?
Adherence to endothelial lumen surface, migrates via vessel wall
Steps of neutrophil recruitment?
- Margination + rolling
- Integrin activation by chemokines
- Firm adhesion to endothelium
- Transmigration via endothelium ➩tissue
- Chemotaxis to site
Function of adhesion ∞ + eg
Involved in neutrophil recruitment
Selectins
Integrins
Ig superfamily cell adhesion molecules CAM
What are Selectins + diff types?
Expressed by activated endothelium, mediate rolling of neutrophils
P,E,L
What’s P-selectin?
in pre-formed granules
What’s E-selectin?
induced by IL-1 + TNF-α (cytokines produced by macrophages, mast cells, endothelial cells at site)
What’s L-selectin?
expressed by ⓦ, ligands on endothelium
What are ligands?
carbs PSGL-1, sialyl-Lewis
How do selectins work?
Endothelial selectins bind to ligands on neutrophis–> low affinity interaction–> disrupted by flowing blood –> repetitive binding + detaching –> slow rolling
What are Integrins?
(LFA-1) expressed by rolling neutrophils - low affinity state ∴ can’t bind to ligands
How do integrins have high affinity state?
Activated endothelial cells produce chemokines –> bind to receptors on neutrophils –> integrin activation –>
How do integrins work?
bind to ligands on endothelium∴ adhesion of neutrophils to endothelium
What are the integrin ligands?
induced by IL-1 and TNF-α (cytokines produced by macrophages, mast cells, endothelial cells at site)
ICAM-1 (intracellular)
VCAM-1 (vascular)
How neutrophils transmigrate?
via interendothelial spaces –> pass via vessel wall + enter tissue –> chemotaxis via tissue towards site
What guides migration via tissues?
Gradient of chemoattractants
What are chemoattractants?
Produced at site, diffuses ➩ adjacent tissues + form gradient
- 🐛 components (peptides containing N-formyl-methionine-leucine-phenylalanine; lipids)
- chemokines IL-8
- complement components C5a
- leukotriene B₄ (LTB₄)
Time of neutrophils at site?
short lived 6-24hrs
dies in tissue 24-48hrs
Time of monocytes at site?
lives longer 24-48hrs, profilerate
at tissue → macrophage
Pathogen destruction mechanisms?
⇶granule content
Phagocytosis
Generation of reactive O2/N species
Formation of Neutrophil Extracellular Traps NETs (netosis)
What’s NETs?
mesh of chromatin - traps microbes, contains anti-microbial ∞
Types of neutrophil granules?
Specific (small) : lysozyme, collagenase, gelatinase, lactoferrin, alkaline phosphatase
Azurophil (large) : myeloperoxidase, lysozyme, defensins, acid hydrolases, proteases (elastase, cathepsin G, collagenases, proteinase 3)
How to terminate acute?
Anti-microbial mechanisms via inflammatory mediators
Inflammatory mediators :(
Non specific ∴ normal tissues damaged
Termination of acute?
neutrophils die
inflammatory mediators degraded
regulatory mechanisms - anti-inflammatory
repair mechanisms - tissue regeneration/connective tissue
Outcomes of acute
Resolution-affected tissue restored to normal
Repair-lost tissue replaced by connective tissue,fibrosis
Chronic-if acute unresolved
How resolution happens?
damaging agent removed
injured tissue replaced by same cell type∴ no change in tissue structure/function
restoration of normal tissue structure only if residual tissue’s structurally intact
How repair happens?
scarring alters tissue function
macrophages⇶ TGF-β -promotes fibrosis
How chronic happens after acute?
Abscess formed by mass of necrotic tissue caused by pyrongenic 🐛.. if not drained/reabsorbed→
What type of tissues have high regeneration ability + eg?
Labile tissues- ÷ continuously
epithelial cells eg 🏼, airways, gut, blood cells
What type of tissues have intermediate regeneration ability + eg?
Stable tissues
normal state: quiescent cells (G0/G1) injury –> ÷
eg liver, kidney, pancreas. endothelial cells, fibroblasts
What type of tissues have no/little regeneration ability + eg?
Permanant tissues
eg neurons, myocardium, skeletal muscle
Factors that favour tissue regeneration?
minimal cell death + destruction
good regeneration ability of tissue
🏃♂️ removal of debris + clearance of infection
removal of foreign matierial - sutures, bone frag
immboilisation of wound edges - sutures
Factors that prevent tissue regeneration?
extensive injury + haemorrhage infection old age diabetes poor health/nutrition - 🐟, vit C deficiency 💊 - corticosteroids poor vascular supply foreign bodies dehiscence - p/torsion/movement on wound edges
Cells involved in chronic?
Macrophages Lymphocytes - T + B Eosinophils Mast cells Neutrophils
Role of macrophage?
-act as sentinels present in:
kupuffer cells (liver), microglia (brain), alveolar macrophages (lungs)
-produce growth factors–> tissue repair
-take up dead microbes,cells –> elimination
-activate T cells
-⇶ inflammatory cytokines - TNF-α , IL-1, chemokines
Role of lymphocytes
- granulomatous inflammation, autoimmunity, allergy
- T produce cytokines –> recruit + activate macrophages
- B –> plasma cells –> produce antibodies
How are lymphocytes activated?
microbes, dead cells
How are lymphocytes recruited?
from macrophages TNF-α , IL-1
What’s tertiary lymphoid tissue /TLO + eg?
clusters of lymphocytes, macrophages, plasma cells similar to lymphoid tissue in lymph nodes eg rheumatoid arthritis
Role of eosinophils?
parasite infections, Ig-E mediated allergies
MBP Major Basic 🐟 destroys parasites/tissues
Where are mast cells found?
connective tissue close to vessels - in acute + chronic
What type of chronic inflammation are neutrophils present in?
suppurative inflammation -abscess, osteomyelitis
lung disease -🚬/irritants
How are neutrophils recruited?
macrophages, T cells⇶ chemokines IL-8
What does ‘acute on chronic inflammation’ mean?
neutrophil-rich infiltrate
Role of cytokines?
soluble mediator for cell-cell communication used in acute +/or chronic
How are cytokines produced?
macrophages, lymphocytes, dendritic cells
endothelial, epithelial cells, connective tissue
What are the soluble mediators for chronic?
cytokines : IFN-γ Interferon-gamma, TNF-α, IL-17, IL-12
Role of IFN-γ?
activates macrophages–> ↑microbicidal activity
How’s IFN-γ produced?
T cells + NK cells
Types of chronic inflammation?
Non-specific
Autoimmune
Chronic suppurative
Chronic granulomatous
Inflammatory cells of non-specific inflammation?
lymphocytes, plasma cells
Why does non-specific inflammation happen?
when acute FAILS to remove causative agent
How does non-specific inflammation happen?
caused by Helicobacter pylori or NSAIDs
tissue destruction - gastric/duodenal peptic ulcers
Ulceration?
loss of dead cells–>local defect/excavation of surface eg oral mucosa, stomach, intestine, GU tract–>granulation tissue fills ulcer–>scar
Where’s Helicobacter pylori located?
stomach lumen
How does chronic gastris happen?
-neutrophil infiltration in stomach wall doesnt harm H.pylori
-neutrophils damage epithelial cells
-antibodies against H.pylori ineffective
∴infection persists –>
Inflammatory cells of autoimmune inflammation?
lymphocytes, macrophages
What’s autoimmune inflammation + why does it happen?
immune response to self antigens
no acute
progressive, persistent, tissue damage
What’s rheumatoid arthritis?
Joint synovium expanded by macrophage, lymphocyte infiltrate + fibrin deposition - pannus
Bone + joint destruction
70% patients have IgM antibodies anti-Fc portion of IgG
Inflammatory cells of chronic suppurative inflammation?
NEUTROPHILS, eosophils
What’s chronic suppurative inflammation?
persisting pus-forming inflammation
How does chronic suppurative inflammation happen?
acute purulent inflammation by pyrogenic (pus forming) 🐛 eg Staphilococci –> pus accumulates–> abscess
How to remove abscess?
surgery- incision + drainage clears pus
What’s an abscess + areas?
fibrosis walls off of acute–> localised purulent inflammation
central area: necrotic Ⓦ + tissue cells
zone: neutrophils, fibroblast proliferation
fibrotic area
What’s chronic granulomatous inflammation + why does it happen?
Causative agent not removed –> granuloma formation to isolate + prevent agent spreading
What are granulomas made of?
macrophages, lymphocytes (T, b), fibroblasts, sometimes necrotic tissue
What causes immune granulomas?
Persistent T cell activation ∵ Infection: 🐛-TB, leprosy, syphilis Parasitic- Schistosomiasis Autoimmune diseases: Crohn's disease Rheumatoid arthritis
What causes foreign body granulomas?
inert materials: talc, sutures, fibres, silica
What’s Sarcoidosis?
disease which causes granulomas
unknown etiology
Inflammatory cells of chronic granulomatous inflammation?
epitheliod cells, giant cells, lymphocytes
How chronic granulomatous inflammation happens?
macrophage responds to agent (INNATE)–> can’t remove it–> ADAPTIVE ∴ T cell activates–> activates macrophages–> change in macrophage appearance:
epitheloid cells-↑ cyroplasm
macrophage fusion- multinucleate giant cells
–>sig tissue destruction
How does granuloma look 🔬?
- Centre: cluster of epitheloid cells
- Infectious agent/ foreign body may be visible
- Periphery: rim of lymphocytes, fibroblasts, connective tissue
- Multinucleated giant cells 40-50 μm
- neutrophils, lymphocytes ~10 μm
- macrophages ~20 μm
- Central necrosis area = caseous necrosis seen in TB
Why central necrosis area in TB?
hypoxia, ROS that damage tissue
mixture of coagulative + liquefactive necrosis
What are non-caseating granulomas + where is it seen?
no central necrosis area
Crohn’s, sarcoidosis, foreign body granulomas
How do multinucleate giant cells arise from macrophages?
adjacent macrophages phagocytose same hard to destroy particle eg silica, mycobacterium, Schistosoma ova
How do multinucleate giant cells look like?
horseshoe nuclei arrangement
40-50 μm
Granulomatous inflammation outcomes?
agent removed: tissue healing–>fibrosis + Calcium deposition in scarred tissue- x-ray visible
agent persists: 'walled off' by fibrosis tissue, calacium deposition, infection kept in check by T cells + macrophages compromised immunity (steroids, HIV)--> TB reactivation
What’s tissue repair used for?
parencymal + connective tissue
What’s tissue healing used for?
surface epithelia
Types of tissue repair?
Regeneration + replacement
What’s regeneration?
proliferation of residual healthy cells
proliferation + maturation of tissue resident stem cells
What’s replacement?
replaced w connective tissue–> scar
How healing starts?
Organisation (ingrowth of capillaries + fibroblasts) form granulation tissue
How healing ends?
Resolution or REPAIR–>scar
How can wounds heal?
1 or 2ᵒ intention
What’s 1ᵒ intention?
injury to epithelial layer–>resolution
if wound edges can be apposed
What’s 2ᵒ intention?
extensive tissue loss–>regeneration+scarring
deep gaping wounds
epithelium regenerates–>normal
adnexal structures–> scar–> restrict function
Process of 1ᵒ intention + ⌚?
-wound–>activation of coagulation–>clot–>clot surface dehydrates–>wound scab …⌚24hrs…–> neutrophils infiltrate wound margins⇶proteolytic 𝔼–>clear microbe/debris
-24-48hrs : migration + profileration of epithelial cells at wound edges, deposit extracellular matrix components, meet in midline below scab, thin layer to close wound
-Day 3 : macrophages replace neutrophils to clear debris, fibrin, promote angiogenesis, ECM deposition + granulation tissue invades wound space
-Day 5 : granulation tissue fills wound; neovessels + edema –> fibroblast proliferation–> produce collagen–>deposits in wound
-2nd week : fibroblast profileration + collagen deposition continues, vessel regeneration, ↓ inflammatory infiltrate–>scar blanching
-1m : scar made of connective tissue w/o inflammatory cells, normal epidermis, dermal appendages lost permanently ∵ incisions, wound strength ↑:
well sutured=70% strength
sutures removed 1 week=10%
3m=70-80%
then no further improvement
Diff between clot vs thrombus?
extravascular blood coagulation vs intravascular
Process of 2ᵒ intention + ⌚?
-Larger wounds ∵ big clot, ↑exudate
-Granulation tissue more extensive–> big scar
pale avascular scar= fibroblasts, dense collagen, no inflammatory cells
dermal appendages lost permanently ∵ incisions
epidermal layer recovers
-Wound contraction
helps close wound + ↓ wound surface
myofibroblasts= modified fibroblasts w smooth muscle cell features
6 weeks : 5-10% of original size + ↓ defects
Types of abnormal tissue repair?
Wound dehiscence/rupture + ulceration
Hypertrophic scars + keloids
⇧ Wound contraction
When does wound dehiscence/rupture+ulceration happen?
abdominal surgery–>
inappropriate vascularisation–> (ischemic necrosis)
When does hypertrophic scars + keloids happen?
excessive collagen deposition–> raised scar–>
scar grows beyond margins–> 🍇
keloid predisposition to Afro-caribbean
When does ⇧ wound contraction happen?
after severe 🔥
contractures (palms, sores, 𝔸 thorax)
impair joint movements
