2.1 acute inflammation
TRANSCRIPT
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SECTION 2.1
ACUTE INFLAMMATION
Pathology CourseChapter 2
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Topics
y Introduction
Definition ofInflammation
Acute vs. Chronic
Cardinal Signs ofAcute Inflammationy Causes ofAcute Inflammation
y The Events ofAcute Inflammation
Vascular Changes
Cellular Changes
y Morphology ofAcute Inflammation
y Outcome ofAcute Inflammation
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D E F I N I T I O N O F I N F L A M M A T I O N
A C U T E V S . C H R O N I C
C A R D I N A L S I G N S O F A C U T E I N F L A M M A T I O N
Introduction
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What is inflammation?
Inflammation is a response by the body to injury,intended to remove the injurious agent,remove dead cells, and repair the area.
It is indicated by the suffix -itis (e.g. pericarditis).
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Acute vs. Chronic
The basic difference between the two is that in acute inflammation the removal of injurious agent
and repair can be done fast and easy, but in chronic inflammation they cant.
Fewhours
up to fewdays...
AcuteInflammation
More thanthat...
up toyears!!!
ChronicInflammation
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Cardinal Signs ofAcute Inflammation
Redness ofthearea because ofvasodilationRubor
Warmth ofthearea because ofvasodilationCalor
Swelling ofthearea because ofedemaTumor
Pain due to stimulatnion ofnerveendingsDolor
Loss offunction in thearea because ofedemaand painFunctio laesa
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I N F E C T I O N S
T I S S U E N E C R O S I S
F O R E I G N B O D I E S
I M M U N E R E A C T I O N S
Causes ofAcute Inflammation
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Infections
Immune cells recognize microbes by many receptors, such as Toll-like receptors and many
cytoplasmic receptors. This recognition triggers signal transduction pathways, leading to releaseof mediators, and initiation of inflammation.
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Tissue Necrosis
This is a sample from the heart, showing extensive inflammation after an infarction. Tissue necrosis from any
cause will induce inflammation. This is due to many materials released from necrotic cells (e.g. uric acid,adenosine, etc.) that induce inflammation.
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Tissue Necrosis
This is an example of inflammation due to tissue necrosis from a frostbite [Frostbite occurs when there is
extreme cold, causing constriction of peripheral blood vessels, leading to ischemia and necrosis.]
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Foreign Bodies
Foreign bodies can cause inflammation because they are foreign! They may even do it by causing traumaticnecrosis, or by carrying microbes.
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Immune Reactions
Pencillin rash (left) and hay fever (right) are cases of immune-related inflammation. The immune system will
attack anything that is foreign. Sometimes even things that are not foreign! Inflammation in this case is due tocytokines released by activated T cells.
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V A S C U L A R C H A N G E S
C E L L U L A R C H A N G E S
L E U K O C Y T E - I N D U C E D D A M A G E
S T O P P I N G I N F L A M M A T I O N
The Events ofAcuteInflammation
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Vascular Changes
Vasoconstriction
Vasodilatation
IncreasedPermeability
Stasis
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Vascular Changes
The main mediators for vasodilatation are histamine and nitric oxide (released from nearby
cells). This causes fluid loss, hence stasis of the blood.
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Increased Vascular Permeability
Mediated by histamineand other mediatorsreleased at the site
Immediateand short-lived (immediate transientresponse)
Endothelial cellcontraction
Ifthe injurious agent also damaged blood vessels Can either be immediateand prolonged
(immediate sustained response) or delayed andprolonged (delayed prolonged response)
Endothelialinjury
When theleukocytes arrivelater on, they caninjure the vessels by their enzymes.
Leukocyte-mediated damage
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Increased Vascular Permeability
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Edema
Transudate is accumulation of fluid with little protein content and low specific gravity outside
blood vessels. Exudate has higher protein content and specific gravity.
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Lymphatic Involvement
Lymphatic drainage increases during inflammation. If the offending agent is also carried away, inflammation can
even involve the lymphatic vessels (lymphangitis) or even the lymph nodes (lymphadenitis). Red streaks on the arm
emanating from a wound indicate lymphangitis.
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Cellular Changes
y Theaim ofbringing neutrophilsto thearea is to:
kill infectious agents ifpresent
removeanyforeign material present remove necrotic tissue
produce growth factors that aid inrepair
y The price is: normal tissuemay be damaged
inflammation may get prolonged
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Cellular Changes
Marginationand Rolling
Adhesion Transmigration Chemotaxis
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Margination
y Normal blood flowhas:
centralaxialflowofRBCs
more peripheralflowofneutrophils
y In inflammation: stasis ofblood flow(because offluid transudation) will
allowmore peripheralmovement ofleukocytes and more
contactwith endothelium this is called margination
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Rolling
y As leukocytes marginate, they start binding to anddetaching from theendothelium bya set ofcomplementaryadhesion molecules called
selectins
y Thereare three types ofselectins:
L-selectin: on leukocytes
E-selectin: on endothelium P-selectin: on endothelium (and platelets)
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Selectins
y Normally the selectins arenot active; they get activatedduring inflammation
y
During inflammation the offending agent and necroticcell debriswill come into contactwith macrophages,mast cells, and endothelial cells
y
These cellswill secrete cytokines likeTNF, IL-1, andchemokines
y These cytokines activate the selectins
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Selectins
y TNF and IL-1willactivate E-selectin and theligandfor L-selectin on the nearby venular endothelium
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Selectins
y P-selectins are normally sequestered in Weibel-Palade bodies in endothelial cells
y Histamine and thrombin stimulate their re-
distribution to the cell surface
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Adhesion
y The tumbling leukocytes can nowbind morefirmlyto theendothelium using their integrin receptors
y Expression ofintegrin ligands on theendothelium is
stimulated byTNF and IL-1
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Adhesion
y The integrin receptors on theleukocytes arenormallylow-affinity
y Chemokines that haveentered theendothelial cells
during inflammation bind theleukocytes and changetheir integrins to high-affinitystate
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Transmigration
y After firmadehsion, chemokines will stimulate themigration oftheadhered leukocytes between theendothelial cells (diapedesis) to the outside
y Themovement is mediated by binding to moleculeson theendothelial cells, such as PECAM-1
y On reaching the basement membrane oftheendothelial cells, theleukocyteswill secretecollagenases to break them down and move on
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Chemotaxis
y After leaving the blood vessel, theleukocytescontinuemoving toward the injury site under theeffect ofmany substances
y During this part ofthe journey, theleukocytesremain localized to the injured tissueby usingtheir integrins and CD44 molecules to bind to
matrix proteins likefibronectin
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Cellular Changes
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Chemotaxis
y Howchemotaxis occurs:
Chemoattractansbind toreceptors on theleukocyte
This initiates asignaltransduction pathway
The result is rearranging the cell'scontractileelements to increasepolymerized actin at theleading
end and myosin at the back Leukocyte begins moving by
extending filopodia
Direction ofmovement depends onchemoattractant gradient
filopodium
trailing tail
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Chemotaxis
y Chemoattractants for leukocytes include:1. Bacterial products 2. C5a complement product
3. Chemokines 4. Leukotriene B4
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Type ofRecruited Cell
y Neutrophils predominate in 6 to 24 hours because theyaremore numerous in blood
respond better to chemokines
bind more strongly to selectins
are short-lived and die soon
y Macrophages predominateat 24 to 48 hours because theyaremorelong-lived
y Exceptions! Pseudomonas infections call neutrophils for days
Viral infections calllymphocytes
Eosinophils predominate in hypersensitivity reactions
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Type ofRecruited Cell
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Type ofRecruited Cell
Mainly neutrophils (early phase) Mainlymacrophages (late phase)
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TNF Inhibitors
y TNF is amajor cytokineinvolvedin recruiting leukocytes
y TNF inhibitors can reduceinflammation in inflammatorydiseases like rheumatoid arthritis
y Sideeffectwould obviously includeincreased riskfor infections
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Activation ofLeukocyte
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Phagocytosis
y After theleukocyte has arrived at the injury siteandcomes into contactwith the offending agent, it startsphagocytosing it in three steps:
Recognition Engulfment
Destruction
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Recognition and Engulfment
y Recognition ofamicrobe or aforeign antigen is donethrough receptors like:
Mannosereceptors (which only recognize bacterial sugarsand not mammalian sugars)
Scavengerreceptors (binding microbes, aswellas anotherrole in binding oxidized LDL in atherosclerosis)
Opsonin receptors (receptors for opsonins like IgG, C3b,and mannan-binding lectin)
y Engulfment ofthe offending agent into a phagosomeis due to arearrangement ofactin filaments
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Recognition and Engulfment
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H2O2-MPO-Halide System
y Superoxide is spontaneously converted into H2O2y Meanwhile, alysosome fuseswith the phagosome
so that MPO (myeloperoxiase) nowcan be released
from thelysosome into the phagosomey MPO uses chloride to convert H2O2 into
hypochlorite (OCl.), which is also found in bleach
y Hypochlorite is a powerful destructiveagent
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Killing the Offending Agent
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Other Weapons
y Theleukocytes also use otherweapons to fightmicrobes:
Elastase
Defensins Cathelcidins
Lysozyme (for bacterial cellwalls)
Lactoferrin
Major basic protein (for parasites)
Bactericidal/permeability increasing protein (for gram-negative bacteria)
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Activating Tissue Repair and Stopping Inflammation
Macrophages can enhance inflammation, or stop it and induce tissue repair,
depending on the stimulus they receive.
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TissueDamagefrom Leukocytes
y Activation ofleukocytes during inflammation candamage selftissues in a number ofsettings:
Normal inflammatory response to a harmfulforeign agent
Autoimmune diseases where the target is selftissue Excessive inflammatory response to a harmless foreign agent
y Selftissue damage occurs fromenzymes released
from theleukocyte due to: Inability to phagocytose the target agent (frustrated
phagocytosis)
Formation ofphagolysosomebefore closure ofphagosome
Damage to phagolysosome membranefrom urate crystals
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Chdiak-Higashi Syndrome
y Defectivefusion ofphagosome andlysosome
y This delays microbial killing and
causes susceptibilityto infections
y Giant granules seen inmacrophages fromaberrant
phagolysosome formation
y Patients also havealbinism, nervedefects, andbleeding
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Chronic Granulomatous Disease
y Defect in phagocyteoxidase(different variants depending ontheaffected enzyme subunit)
y Susceptibility to recurrentbacterial infections
y As neutrophils cannot control thesituation, macrophages comeandformgranulomas
Granuloma
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Acquired LeukocyteDeficiency
y This is themost common scenarioofleukocyte defect, and is due to
bonemarrowsuppression
y Marrowsuppressionwilldecrease the production ofleukocytes
y It could befromdrugs, cancerradiotherapy or chemotherapy,or tumors in themarrow(e.g.leukemia, metastasis, etc.)
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Stopping Inflammation
y Inflammation slows down and stops due to:
on-demand release (froma stimulus) and very short half-life ofinflammatorymediators
short half-life ofneutrophils
production oflipoxins, TGF-B, IL-10, resolvins, and protectinslater in the inflammatory response
cholinergic neural inhibition ofTNF production inmacrophages
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Morphology ofAcute Inflammation
y In general, acute inflammation is manifested bycongested blood vessels, stasis, edema, andleukocytic infiltratein tissues
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Morphology ofAcute Inflammation
y Special patterns ofmorphology can be recognizeddepending on the siteand cause involved:
Serous inflammation
Fibrinous inflammation
Purulent inflammation
Ulcers
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Serous Inflammation
y This type ofinflammation showsaccumulation of
serous fluid, eitherderived from plasmaor from mesothelialsecretions (when inone of the three body
cavities, called aneffusion). Examplesare viral and burn
blisters.
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Serous Inflammation
serous fluid separatingepidermis from dermis
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Fibrinous Inflammation
y This occurswhen there isexudation oflarge amount offibrinogen (due to large
vascular leak) orwhen there is
localprocoagulant stimulifrom cancer cells
y This usually occurs inmeninges, pericardium, andpleura
y Persistence offibrin canstimulatefibroblast and blood
vessel ingrowth, leading toorganization
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Fibrinous Inflammation
Fibrinouspericarditis can
result from 6general causes,including acutemyocardialinfarction,
infections,cardiacsurgery, andothers
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Purulent Inflammation
y Characterized byformationofpus,which is a collectionofdead neutrophils,liquefactive necrosis,
and edema fluid
y Caused by pyogenic (pus-forming) bacterialikeStaphylococcus species
y Ifthe pus isburied deepin a tissue, organ, orconfined space, it is calledabscess
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Purulent Inflammation - Abscess
Coreofnecrotic
tissue cells andleukocytes
Outer zoneofpreservedneutrophils
Outermost zoneofvasculardilation, andparenchymaland fibroblasticproliferation
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Ulcers
y Ulcer is adefect in thesurface ofa tissue or organdue to thesloughing ofnecrotic inflamed tissue
y Seen in themucosa ofGIT (e.g. gastric ulcer,
duodenal ulcer, etc) and GUT
uod nal ulcer
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Ulcers
y Seen in theskin and subcutaneous tissueoflowerextremities in diabetics (because ofextensive ischemic necrosis)
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Outcome ofAcute Inflammation
y Acute inflammation can end in:
Resolution: the injurious stimulus is removed, cellular debrisis removed, parenchyma regenerates, and function is regained
Fibrosis (organization): ifthere is substantial damage, or
parenchyma cannot regenerate, or therewas largeamount ofexudate, therewill be collagen deposition in theareaand lossoffunction
Progression to Chronic Inflammation: this occurswhenthe injurious stimulus cannot be removed easily. Examplesinclude pneumonialeading to chronic lung abscess,tuberculosis, etc.
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How
resolutionoccurs
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