2-Acute Inflammation Flashcards
inflammation
definition-general
local reaction of vascularized tissue to injury
inflammation by time
acute = 0-2 days
subacute = 2-14 days
chronic = 14+ days
acute inflamm cells
- neutrophils
- eosinophils if allergic reaction
subacute inflamm cells
neutrophils + monocytes + lymphocytes + plasma cells + fibroblastc elements + angioblastic elements
chronic inflamm cells
mononuclear cells - monocytes + lymphocytes
plasma cells, macrophages
granuloma cells- epithelioid cells + giant cells
monocyte @ vasculature > migrate to macrophage
eosinophils
predominant inflamm cell in allergic reaction and parasitic infestations
plasma derived molecular systems
- immune - Ab, C3, C5 frags
- kinin- bradykinin
- clotting - thrombin
- fibrinolytic - plasmin
- acute phase proteins - CRP, cereuloplasmin, haptoglobin
tissue derived molecular systems
- vasoactive amines- histamine, serotonin
- acidic lipids- prostaglandins, leukotrienes, lipoxins
- cytokines- IL1, TNF, chemokines (IL8, MCP1, MIP-1alpha, lymphotactin)
- others- PAF, NO, free radicals, lysosomal enzymes
inflamm protective response
to get rid of initial cause of cell injury aka microbes, toxins
or consequences of the injury aka necrotic cells and tissues
inflamm harmful response
if
-inflamm rxn underlies common chronic diseases
-uncontrolled lead to life threatening hypersensitivity rxns
-repair produces constrictive scarring and limb immobilization
6 cardinal signs
- heat aka inc blood flow to site
- redness- inc blood flow
- swelling- acc of water and cells
- pain- pressure of fluid and effect of mediators
- loss of function- secondary to 1-4
- systemic changes- release of humoral factors
causes of inflamm
- infection
- trauma
- physical injury (thermal extremes, radiation)
- chemical injury (poisons)
- immunologic injry
- tissue necrosis (inflamm arises in living tissue next to necrotic area)
serous inflamm
morphologic patterns
outpour of watery, protein poor fluid aka effusion
from serum or mesothelilal cell secretions (peritoneal, pleural, pericardial cavities)
OR from skin blisters from burns or viral infections
fibrinous inflamm
morphologic patterns
more severe injuries or inflamm of body cavities but may resolve
inc vascular permeability so leakage of larger molecules (fibrinogen) so extravascular fibrin acc
-if fibrin not completel removed then ingrowth of fibroblasts and blood vessles happen (organization process)
suppurative/purulent inflamm
morphological patterns
large amounts of pus (neutrophils + necrotic cells + edema fluid + microbes maybe) from pyogenic bacteria most likely
abscess is a collection of pus with central necrotic region surrounded by layer of preserved neutrophils
-can be walled off by fibroblasts in chronic
ulceration inflamm
morphologic patterns
local excavation by sloughing of inflamm necrotic tissue on/near a surface of skin and mucosa
most common @ mucosa mouth, GI tract, GU tract, LE
acute or chronic (fibroblasts in base of ulcer with chronic inflamm cells and scarring)
outcomes of acute inflamm
- resolution
- scarring after substantial tissue destruction or tissues that can’t regenerate
- abscess
- chronic
key events
- inc blood flow via vasodilation after initial constriction
- plasma proteins and leukocytes leave circulation, structual changes to microvasculature
- emigration of leukocytes from microcirculation to acc in focus of injury, activation to eliminate offending agent
hemodynamic changes
- vasoconstriction of arterioles, immediate and transient
- vasodilation of arterioles and venules, precapillary sphincters open, inc blood flow
transudate
formed when fluid leaks out of vascular bed from inc hydrostatic pressure or dec oncotic pressure
effusion characteristics- hypocellular/no cells so clear, low protein, low LDH,
exudate
vascular permeability inc as result of inc interendothelial spaces, lymphatic obstruction, inflamm, or malignancy
effusion character- cellular so cloudy, high protein and LDH
mechanisms of inc permeability
aka vascular leakage
- endothelial contraction to widen junctions, capillaries and post cap venules
- direct injury
- leukocyte injury
- new blood vessel leakage
leakage pathway
- leakage of fluid to interstitial space aka edema
- stasis of circulation resulting in inc blood viscosity
- dec absorption of fluid from interstitial space
lymphedema
is initially transudate and causes pitting edema but becomes more proteinaceous/exudate over time and usually fibrotic
leukocyte extravasation
- leukocyte activation
- endothelial activation
- chemotaxis
leukocyte exit from blood vessels at site of inflamm
selectin family
general
calcium dependent lectins @ surface of endothelium, platelets, leukocytes
mediate rolling phase along endothelium at sites of inflamm but not firm adhesion just slow down
selectin molecules
- P selectin = aka CD62P on endo binds with sialyl lewis X on glycoproteins on leuks
- E selectin = CD62E on endo binds sialyl lewis X on glyoproteins on leuks
- L selectin = CD62L on leuks bind with sialyl lewis X on glycoprotein on leuks
immunoglobulin family
Ig family of moles with 3 endothelial adhesion molecules
1. ICAM 1 aka CD54 on endo for tight binding to integrins LFA1 and Mac 1 on neutrophils and macrophages
2. VCAM 1 aka CD106 on endo for tight binding to integrin VLA4 on lymphocytes, monocytes, eosins, basophils
3. PECAM1 aka CD 31 on endo and leuks to bind homophilic and diapedesis of leuk extravastion
integrin family
group of adhesion moles with heterodimers alpha + beta subunits, transmembrane proteins linking exterior stimuli to cytoskeleton
VLA-4
CD49a/CD29
beta1 integrin CD29 > heterodimer with alpha subunit CD49a
only on leuks to bind VCAM1 on endo
LFA-1
CD11/CD18
beta2 integrin CD18 + CD11a mole = heterodimer
‘leukocyte fuction associated antigen-1’ on neutrophils and macrophages
-binds to ICAM-1 on endo with complement receptor 3 and 4 for extravasation
if deficient in beta2 then susceptible to infection
functional responses leukocytes
- modulate leuk adhesion molecules
- activate oxidative burst and degranulation and secretion lysosomal enzymes
- produce arachidonic acid metabolites
- secrete cytokines
phagocytosis
- recognition and attachment: enhanced by opsonins like IgG, C3b, mannonse-binding lectin
- engulfment: pseudopods surround object = phagosome that fuses with lysosome = phagolysosome
- kill microorganisms: oxygen dependent or independent
aerobic pathway killing microorgansims
oxygen dependent aka respiratory burst
1. superoxide radical via NADPH oxidase
2. convert to hydrogen peroxide by superoxide dismutase
3. myelo-peroxidase from neutrophilic granules catalyzes rxn b/t Cl and hydrogen peroxide = hypochlorous acid powerful oxidant and antimicrobial
oxygen independent pathway
killing microorgs
leukocyte granule proteins and enzymes
i.e. lysozymes, acid hydrolases, lactoferrin, cationic proteins
mediators of inflamm rules
- og from plasma as precursor or tissue cells in granules or synthesized
- bind to specific receptors on target cells
- can stimulate release of other or same mediators from target cells
- short lived so quickly decay and inact by enz or inhibited
- potential to cause harmful effects
vasoactive amines
aka histamine and serotonin
bind to H1 receptors on endo to cause inc permeability or postcap venules
-immediate but transient/quick effect
-stored in granules of mast cells, basophils, platelets
dilate ARTERIOLES but constrict LARGE ARTERIES
mast cell release triggers
- trauma, cold, heat
- platelet aggregation
- C3a, C4a, C5a anaphylatoxins
- neuropeptides
- cytokines IL1 and 8
- histamine releasing proteins (cationic) from platelets and neutrophils
- IgE binding
plasma protein systems
- complement system
- kinin system
- clotting system
- fibrinolytic system
1-3 are cascade
complement activation
critical step to cleave C3
- classic pathway: binding of antigen antibody (IgG or IgM) complex to C1
- alternate: C3 directly act by bacterial endotoxins, complex polysaccharides, aggregated globulins
- lectin: C1 act by binding mannose binding lectin to carbs on microbes
important complement fragments
- C3-5a- anaphylatoxins, stim histamine from mast cells = inc vascular permeability and vasodilation
- C5a - chemotaxis of monocytes and granulocytes = inc surface expression of leukocyte CAM to activate lipoxygenase pathway in neutros and monocytes
- C3b - opsonize with recognition by receptors on neutrophils, macros, eosins
- C5-9 - membrane attack complex inserts into lipid bilayer to make pores to inc cell permeability = lysis
hageman factor
aka factor XII of intrinsic clotting system
act by direct contact with activated platelets, endotoxins, collagen, or BM = kinin system and clotting system
will induce bradykinin, fibrin, fibrin split products, anaphylatoxins
kinin system
hageman factor converts
prekallikrein into kallikrein:
amplifies act of hageman factor
cleaves high molecular weight kninogen = kinins like bradykinins
convert plasminogen to plasmin
chemoattractant for neutros and covert C5 to C5a (for leuks)
inc cell adhesion mole expression on endo
bradykinin
short lived vasoactive peptide that
inc vascular permeability
dilates blood vessels
vontracts nonvascular smooth muscle
causes pain
short bc quickly inactivated by plasma kininase
clotting and fibrinolytic system
cascade of reactions = fibrin clot dissolved by fibrinolytic system
thrombin
protease that cleaves circulating soluble fibrinogen to generate insoluble fibrin by binding protease-activated receptors (PARs) on platelets. endo, smooth muscle,
connects coagulation system to inflammation
effects of thrombin
- mobilize P selectin
- produce chemokines, PAF, NO
- stim endo adhesion mole formation
- induce COX2 and production of prostaglandins
- induce change in endothelial shape
plasmin
lyses fibrin clots
formed by cleaving plasminogen by kallikrein or plasminogen activator released by endothelia and leuk
will activate hageman factor > cleave C3 to C3a > degrades fibrin to form fibrin split products that inc permeabilityin skin and lungs
arachidonic acid metabolites
polyunsat fatty acid in cell membrane phospholipids that get released by phospholipases
either COX pathway or lipoxygenase LOX pathway
aspirin inhibits COX, glucocorticoids inhibit phospholipases
COX products
- TXA2 aka thromboxane A2- potent platelet aggregator and vasoconstrictor
- PGI2- vasodilator and inhibit platelet agg
- PGE2- sensitizees skin to painful stimuli and play role in cytokine induced fever, will also vasodilate and agg
- PGD2, PGE2, PGF2a - vasodilation and potentiate edema
LOX products
convert AA into luekotrienes and lipoxins
1. LT B4
2. LT C/D/E4
LT B4
potent chemoattractant causing neutrophils to:
agg
adhesion to EC
generate ROS
release lysosomal enz
LT C/D/E4
intense vasoconstriction
intense bronchospasm
inc vascular permeability without dilation
lipoxins
inhibit leukocyte recruitment and cellular activities of inflamm
A4 and B4 inhibit neutros adhesion to endo and neutro chemotaxis
platelet activating factor
PAF
from stimulated basophils, mast cells, neutrophils, macrophages, platelets, endo cells basically everything
causes platelet agg and release of platelet products (hist, serotonin)
vasoconstriction and bronchoconstriction BUT if low doses then vasodilation and inc venular permeability
-will also stim leuk oxidative burst, inc leuk adhesion to endo, leuk chemotaxis, stim prostaglandin and leukotriene syn
cytokines/chemokines
polypeps like cellular hormones or locally acting cell to cell mediators
-participate in intricate network to achieve effect
strong chemotactic properties called chemokines
cytokines of inflamm effects
IL1 and TNF from macrophages
1. acute phase proteins- induce fever, affect sleep and appetite, neutrophilia, hemodynamic effects in shock
2. endothelial- inc leuk adherence, stim PGI syn, inc procoagulant activity, inc syn of IL1/6/8, PDGF
3. fibroblasts- inc proliferation, collagen syn, and PGE syn, inc protease and collagenase production aka repair
4. leukocyte inc cytokine secretion IL1 and 6
chemokines
- alpha or CXC - act on neutros, i.e. IL8
- beta or CC - attract other cells NOT neutros, i.e. MCP1, MIP1a, eotaxin for eosinophils
- gamma or C - specific for lymphocytes i.e. lymphotactin
- CX3C - fractalkine strong attractant for monocyte and T cells
