2.1 Acute Inflammation

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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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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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2.1 Acute Inflammation