1. • Egyptian papyrus - 3000 B.C.
• Celsus (Roman in 1st century A.D.)
Rubor - Tumor - Calor - Dolor
redness - swelling - heat - pain
• Virchow added functio laesa later
History
2. What is inflammation?What is inflammation?
Inflammation –Inflammation –
Protective response intended to eliminate the initialProtective response intended to eliminate the initial
cause of cell injury and the necrotic cells and tissuescause of cell injury and the necrotic cells and tissues
arising from the injuryarising from the injury
Inflammation is intimately associated with theInflammation is intimately associated with the
repair process which includes parenchymal cellrepair process which includes parenchymal cell
regeneration and scarringregeneration and scarring
3. Acute - minutes to daysAcute - minutes to days
Characterized by fluid and proteinCharacterized by fluid and protein
PMN’sPMN’s
Exudate SG > 1.020Exudate SG > 1.020
Chronic - weeks to yearsChronic - weeks to years
Lymphocytes and macrophagesLymphocytes and macrophages
ACUTE Inf - PMN’s (ACUTE Inf - PMN’s (PolyPolymorphonuclear Cells)morphonuclear Cells)
CHRONIC Inf -CHRONIC Inf - MonoMononuclear Cellsnuclear Cells
InflammationInflammation
EXUDATE
4. Acute inflammation
“The immediate and early response to an
injurious agent”
Chronic inflammation
“Inflammation of prolonged duration (weeks
or months) in which active inflammation,
tissue destruction, and attempts at repair are
proceeding simultaneously“
5. Exudate
• ↑ vascular permeability
• high protein & cell debris
• SG > 1.020
Transudate
• normal vascular permeability
• hydrostatic pres. → plasma ultrafiltrate
• low protein (mostly albumin)
• SG < 1.012
Edema
• exudate or transudate ; interstitium or
cavity
6. Acute inflammationAcute inflammation
major componentsmajor components
Transient vasoconstrictionTransient vasoconstriction
VasodilatationVasodilatation
Endothelial permeabilityEndothelial permeability
Extravasation of PMNsExtravasation of PMNs
7. Five classic local signs of acuteFive classic local signs of acute
inflammationinflammation
HeatHeat
RednessRedness
SwellingSwelling
PainPain
Loss of functionLoss of function
Calor – vasodilatationCalor – vasodilatation
Rubor – vasodilatationRubor – vasodilatation
Tumor – vascular permeabilityTumor – vascular permeability
Dolor – mediator release/PMNsDolor – mediator release/PMNs
Functio laesa – loss of functionFunctio laesa – loss of function
8. Vascular changesVascular changes
you need to know thisyou need to know this
Transient vasoconstrictionTransient vasoconstriction
VasodilationVasodilation
Exudation of protein rich fluidExudation of protein rich fluid
Blood stasisBlood stasis
MarginationMargination
Emigration/TransmigrationEmigration/Transmigration
9. Vascular changes
Protein exits vessels :
↓ intravascular osmotic
pressure
↑ intravascular hydrostatic
pressure
Endothelial gaps at intercellular
junctions:
* immediate transient response
* histamine, bradykinin,
leukotrienes, substance P
10.
11. Vascular permeabilityVascular permeability
Vasodilation – increased blood flowVasodilation – increased blood flow
Increased intravascular hydrostatic pressureIncreased intravascular hydrostatic pressure
TransudateTransudate - ultrafiltrate blood plasma (contains little- ultrafiltrate blood plasma (contains little
protein)protein)
Again, this is very transient and just gets the process started.Again, this is very transient and just gets the process started.
Think acute inflammation, think EXUDATEThink acute inflammation, think EXUDATE
ExudateExudate - (protein-rich with PMNs)- (protein-rich with PMNs)
Exudate is the characteristic fluid of acute inflammationExudate is the characteristic fluid of acute inflammation
Intravascular osmotic pressure decreasesIntravascular osmotic pressure decreases
Osmotic pressure of interstitial fluid increasesOsmotic pressure of interstitial fluid increases
Outflow of water and ions -Outflow of water and ions - edemaedema
12.
13. How do endothelial cellsHow do endothelial cells
become permeable?become permeable?
Endothelial cell contractionEndothelial cell contraction
Junctional retractionJunctional retraction
Direct endothelial injury (immediate sustainedDirect endothelial injury (immediate sustained
response)response)
Leukocyte-dependent endothelial injuryLeukocyte-dependent endothelial injury
Increased transcytosis of fluidIncreased transcytosis of fluid
14. Direct endothelial injuryDirect endothelial injury
(immediate sustained response)(immediate sustained response)
Endothelial cell necrosis and detachmentEndothelial cell necrosis and detachment
Result of severe injury or burnResult of severe injury or burn
Occurs immediately and lasts until vesselOccurs immediately and lasts until vessel
repairedrepaired
15. Occurs at sites of leukocyte accumulationOccurs at sites of leukocyte accumulation
Due to leukocyte activation which releasesDue to leukocyte activation which releases
proteolytic enzymes and toxic oxygenproteolytic enzymes and toxic oxygen
Leukocyte-dependent endothelialLeukocyte-dependent endothelial
injuryinjury
16. Leukocyte Cellular EventsLeukocyte Cellular Events
Margination and RollingMargination and Rolling
Adhesion and TransmigrationAdhesion and Transmigration
Migration into interstitial tissueMigration into interstitial tissue
20. MarginationMargination
Normal flow - RBCs and WBCs flow in theNormal flow - RBCs and WBCs flow in the
center of the vesselcenter of the vessel
AA cell poorcell poor plasma is flowing adjacent toplasma is flowing adjacent to
endotheliumendothelium
As blood flow slows, WBCs collect along theAs blood flow slows, WBCs collect along the
endotheliumendothelium MarginationMargination
21. Endothelial ActivationEndothelial Activation
The underlying stimulus causes release ofThe underlying stimulus causes release of
mediators which activate the endotheliummediators which activate the endothelium
causing selectins and other mediators to becausing selectins and other mediators to be
moved quickly to the surfacemoved quickly to the surface
22. SelectinsSelectins
Selectins bind selected sugarsSelectins bind selected sugars
SeSelected +lected + LectinsLectins (sugars) = Selectins(sugars) = Selectins
Some selectins are present on endothelial cells (E-Selectin)Some selectins are present on endothelial cells (E-Selectin)
Some selectins are present on leukocytes (L-Selectin)Some selectins are present on leukocytes (L-Selectin)
Some selectins are present on platelets (P-Selectin)Some selectins are present on platelets (P-Selectin)
Weak & transient bindingWeak & transient binding
Results inResults in rollingrolling
24. RollingRolling
Selectins transiently bind to receptorsSelectins transiently bind to receptors
PMNs bounce or roll alongPMNs bounce or roll along RollingRolling
28. TransmigrationTransmigration
Mediated/assisted by PECAM-1 & ICAM-1 (Integrins)Mediated/assisted by PECAM-1 & ICAM-1 (Integrins)
Diapedesis (cells crawling)Diapedesis (cells crawling)
Primary in venulesPrimary in venules
Collagenases degrade BMCollagenases degrade BM ↑↑ PermeabilityPermeability
29.
30. ChemotaxisChemotaxis
Movement toward the site of injury along aMovement toward the site of injury along a
chemical gradientchemical gradient
Chemotactic factors includeChemotactic factors include
Complement components (20 serum proteins)Complement components (20 serum proteins)
Arachadonic acid (AA) metabolitesArachadonic acid (AA) metabolites
Soluble bacterial productsSoluble bacterial products
Chemokines, cytokinesChemokines, cytokines
31. Phagocytosis & DegranulationPhagocytosis & Degranulation
Phagocytosis (engulf and destroy)Phagocytosis (engulf and destroy)
Degranulation and the oxidative burst destroyDegranulation and the oxidative burst destroy
the engulfed particlethe engulfed particle
Recognition & attachmentRecognition & attachment
Opsonins coat target and bind to leukocytesOpsonins coat target and bind to leukocytes
EngulfmentEngulfment
Killing/degradationKilling/degradation
OO22 dep: Reactive Odep: Reactive O22 species in lysosomes & ECspecies in lysosomes & EC
OO22 indep: Bactericidal permeability agents,indep: Bactericidal permeability agents,
lysozyme, MBP, lactoferrinlysozyme, MBP, lactoferrin
32. Leukocyte-induced tissueLeukocyte-induced tissue
injuryinjury
Lysosomal enzymes are released into theLysosomal enzymes are released into the
extracellular space during phagocytosis causingextracellular space during phagocytosis causing
cell injury and matrix degradationcell injury and matrix degradation
Activated leukocytes release reactive oxygenActivated leukocytes release reactive oxygen
species and products of arachidonic acidspecies and products of arachidonic acid
metabolism which can injure tissue andmetabolism which can injure tissue and
endothelial cellsendothelial cells
These events underlie many human diseases (e.g.These events underlie many human diseases (e.g.
Rheumatoid arthritis)Rheumatoid arthritis)
34. Leukocyte adhesion deficiency 1Leukocyte adhesion deficiency 1
(LAD-1)(LAD-1)
Recurrent bacterial infectionsRecurrent bacterial infections
Inflammatory lesions lack neutrophil infiltrateInflammatory lesions lack neutrophil infiltrate
High numbers of neutrophils in the circulationHigh numbers of neutrophils in the circulation
Neutrophils from patients can roll but do not stickNeutrophils from patients can roll but do not stick
ΒΒ chain of CD11/CD18 integrinchain of CD11/CD18 integrin
Transfuse patients with normal neutrophils and theyTransfuse patients with normal neutrophils and they
can emigratecan emigrate
35. Mechanism of leukocyteMechanism of leukocyte
adhesion deficiency 1 (LAD -1)adhesion deficiency 1 (LAD -1)
Absence of integrins on neutrophilsAbsence of integrins on neutrophils
Mutation in n-terminal region of the integrinMutation in n-terminal region of the integrin ββ chainchain
inhibits proper integrin assemblyinhibits proper integrin assembly
Normal function is restored following transfection ofNormal function is restored following transfection of
patient cells with cDNA forpatient cells with cDNA for ββ chainchain
36. Chediak-Higashi SyndromeChediak-Higashi Syndrome
This syndrome has been on every board test sinceThis syndrome has been on every board test since
NoahNoah
Defect in chemotaxis and lysosomal degranulationDefect in chemotaxis and lysosomal degranulation
into phagosomesinto phagosomes
37.
38. Chronic Granulomatous DiseaseChronic Granulomatous Disease
Defect in NADPH oxidase systemDefect in NADPH oxidase system
Marked decrease in ability to kill microorganismsMarked decrease in ability to kill microorganisms
39. Chemical mediators of inflammationChemical mediators of inflammation
Plasma-derivedPlasma-derived
Circulating precursorsCirculating precursors
Have to be activatedHave to be activated
Cell-derivedCell-derived
Sequestered intracellularSequestered intracellular
Synthesized de novoSynthesized de novo
Most mediators bind to receptors on cell surface butMost mediators bind to receptors on cell surface but
some have direct enzymatic or toxic activitysome have direct enzymatic or toxic activity
Mediators are tightly regulatedMediators are tightly regulated
40.
41. Chemotactic
factors (eg. c5a)
Chemotactic
factors (eg. c5a)
Tissue
injury
Tissue
injury
Vasoactive
mediators
(eg. histamine)
Vasoactive
mediators
(eg. histamine)
Increased vascular
permeability
Increased vascular
permeability
Recruitment of inflammatory
cells
Recruitment of inflammatory
cells
EdemaEdema PMNsPMNs MonosMonos
Production of
inflammatory
mediators
Production of
inflammatory
mediators
Acute
inflammation
Acute
inflammation
Chronic
inflammation
Chronic
inflammation
45. Kinin cascadeKinin cascade
Leads to formation of bradykininLeads to formation of bradykinin
Bradykinin causesBradykinin causes
Increased vascular permeabilityIncreased vascular permeability
Arteriolar dilatationArteriolar dilatation
Smooth muscle contractionSmooth muscle contraction
Bradykinin is short lived (kininases)Bradykinin is short lived (kininases)
Vascular actions similar to histamineVascular actions similar to histamine
46. Complement systemComplement system
Role in immunity (C5-9 complex)Role in immunity (C5-9 complex)
Membrane Attack Complex (MAC C5-9)Membrane Attack Complex (MAC C5-9)
Punches a hole in the membranePunches a hole in the membrane
47. Complement systemComplement system
Role in inflammation (c3a and c5a)Role in inflammation (c3a and c5a)
Vascular effectsVascular effects
Increase vascular permeability and vasodilationIncrease vascular permeability and vasodilation
Similar to histamineSimilar to histamine
Activates lipoxygenase pathway of arachidonic acidActivates lipoxygenase pathway of arachidonic acid
metabolism (c5a)metabolism (c5a)
48. Complement systemComplement system
Leukocyte activation, adhesion and chemotaxis (c5a)Leukocyte activation, adhesion and chemotaxis (c5a)
PhagocytosisPhagocytosis
c3b acts as opsonin and promotes phagocytosis by cellsc3b acts as opsonin and promotes phagocytosis by cells
bearing receptors for c3bbearing receptors for c3b
49. Inflammatory Mediators fromInflammatory Mediators from
ComplementComplement
AnaphylatoxinsAnaphylatoxins::
C3a, C5a, & C4aC3a, C5a, & C4a trigger mast cells to release histaminetrigger mast cells to release histamine
and cause vasodilatationand cause vasodilatation
C5aC5a also activates the lipoxygenase system in PMNsalso activates the lipoxygenase system in PMNs
and monocytesand monocytes →→ release of inflammatoryrelease of inflammatory
mediatorsmediators
Leukocyte activation, adhesion, & chemotaxisLeukocyte activation, adhesion, & chemotaxis::
C5aC5a activates leukocytes, promotes leukocyte bindingactivates leukocytes, promotes leukocyte binding
to endothelium via integrins and is chemotactic forto endothelium via integrins and is chemotactic for
PMNs, monos, eos, & basosPMNs, monos, eos, & basos
50. Inflammatory Mediators fromInflammatory Mediators from
ComplementComplement
PhagocytosisPhagocytosis::
C3b and C3biC3b and C3bi are opsoninsare opsonins
ControlControl::
Convertases are destabilized by "decay acceleratingConvertases are destabilized by "decay accelerating
factor" (DAF)factor" (DAF)
Inability to express DAF causesInability to express DAF causes paroxysmal nocturnalparoxysmal nocturnal
hemoglobinuriahemoglobinuria
C1 inhibitor (C1INH) deficiency causesC1 inhibitor (C1INH) deficiency causes hereditaryhereditary
angioneurotic edemaangioneurotic edema
51.
52. Vasoactive aminesVasoactive amines
HistamineHistamine
Found in mast cells, basophils and plateletsFound in mast cells, basophils and platelets
Released in response to stimuliReleased in response to stimuli
Promotes arteriolar dilation and venularPromotes arteriolar dilation and venular
endothelial contractionendothelial contraction
results in widening of interendothelial cell junctionsresults in widening of interendothelial cell junctions
with increased vascular permeabilitywith increased vascular permeability
SerotoninSerotonin
Vasoactive effects similar to histamineVasoactive effects similar to histamine
Found in plateletsFound in platelets
Released when platelets aggregateReleased when platelets aggregate
54. Arachidonic Acid (AA)Arachidonic Acid (AA)
Where is it located?Where is it located?
AA is a component of cell membrane phospholipidsAA is a component of cell membrane phospholipids
The breakdown of AA into its metabolitesThe breakdown of AA into its metabolites
produces a variety of biologic effectsproduces a variety of biologic effects
55. Arachidonic acid metabolitesArachidonic acid metabolites
Metabolites of AA - short-range hormonesMetabolites of AA - short-range hormones
AA metabolites act locally at site of generationAA metabolites act locally at site of generation
Rapidly decay or are destroyedRapidly decay or are destroyed
56. Arachidonic AcidArachidonic Acid
AA is released from the cell membrane byAA is released from the cell membrane by
phospholipasesphospholipases which have themselves beenwhich have themselves been
activated by various stimuli and/oractivated by various stimuli and/or
inflammatory mediatorsinflammatory mediators
AA metabolism occurs via two major pathwaysAA metabolism occurs via two major pathways
named for the enzymes that initiate thenamed for the enzymes that initiate the
reactions;reactions; lipoxygenaselipoxygenase andand cyclooxygenasecyclooxygenase
61. Arachidonic Acid PathwaysArachidonic Acid Pathways
you need to know thisyou need to know this
LipoxygenaseLipoxygenase
5-HETE, 5-HPETE,5-HETE, 5-HPETE,
LeukotrienesLeukotrienes
Spasm (Vaso, Broncho)Spasm (Vaso, Broncho)
LipoxygenaseLipoxygenase
5-HETE, 5-HPETE,5-HETE, 5-HPETE,
LeukotrienesLeukotrienes
Spasm (Vaso, Broncho)Spasm (Vaso, Broncho)
CyclooxygenaseCyclooxygenase
Prostaglandins - EDEMAProstaglandins - EDEMA
Prostacyclin vs TXA2Prostacyclin vs TXA2
Vasodilatation vs.Vasodilatation vs.
VasoconstrictionVasoconstriction
Platelet aggregationPlatelet aggregation
Inhibits vs. promotesInhibits vs. promotes
CyclooxygenaseCyclooxygenase
Prostaglandins - EDEMAProstaglandins - EDEMA
Prostacyclin vs TXA2Prostacyclin vs TXA2
Vasodilatation vs.Vasodilatation vs.
VasoconstrictionVasoconstriction
Platelet aggregationPlatelet aggregation
Inhibits vs. promotesInhibits vs. promotes
62. Arachidonic Acid MetabolitesArachidonic Acid Metabolites
Participate in every aspect of acute inflammationParticipate in every aspect of acute inflammation
Effective Anti-inflammatory agents act on AA pathwaysEffective Anti-inflammatory agents act on AA pathways
Aspirin and Non-Steroidal Anti-inflammatory DrugsAspirin and Non-Steroidal Anti-inflammatory Drugs
(NSAID’s) - Cyclooxygenase path(NSAID’s) - Cyclooxygenase path
Steroids act, in part, by inhibiting Phospholipase A2Steroids act, in part, by inhibiting Phospholipase A2
63. Platelet-Activating FactorPlatelet-Activating Factor
(PAF)(PAF)
Another phospholipid-derived mediator released byAnother phospholipid-derived mediator released by
phospholipasesphospholipases
Induces aggregation of plateletsInduces aggregation of platelets
Causes vasoconstriction and bronchoconstrictionCauses vasoconstriction and bronchoconstriction
100 to 1,000 times more potent than histamine in100 to 1,000 times more potent than histamine in
inducing vasodilation and vascular permeabilityinducing vasodilation and vascular permeability
Enhances leukocyte adhesion, chemotaxis,Enhances leukocyte adhesion, chemotaxis,
degranulation and the oxidative burstdegranulation and the oxidative burst
It does everything!It does everything!
64. CytokinesCytokines
Polypeptides that are secreted by cellsPolypeptides that are secreted by cells
Act to regulate cell behaviorsAct to regulate cell behaviors
Autocrine, paracrine or endocrine effectsAutocrine, paracrine or endocrine effects
These “biological response modifiers” are beingThese “biological response modifiers” are being
actively investigated for therapeutic use inactively investigated for therapeutic use in
controlling the inflammatory response.controlling the inflammatory response.
65. 1. Macrophages make IL-1 & TNF-α
2. T-cells make TNF-β (lymphotoxin)
3. Can be autocrine, paracrine, endocrine
4. IL-1, TNF, IL-6 acute phase responses,
fever, (appetite, slow wave sleep, ↑ circ.
pmn,↑ ACTH, ↑ corticosteroids)
5. TNF notable for role in septic shock and
maintenance of body mass (cachexia in cancer
from ↑ ↑ TNF-α )
Lymphocyte function
68. Nitric OxideNitric Oxide
NO is a soluble free radical gasNO is a soluble free radical gas
Made by nitric oxide synthetase (NOS) inMade by nitric oxide synthetase (NOS) in
endothelium (eNOS), macrophages (iNOS),endothelium (eNOS), macrophages (iNOS),
and specific neurons in the brain (nNOS)and specific neurons in the brain (nNOS)
Broad range of functions and effects that areBroad range of functions and effects that are
short rangeshort range
Vasodilatation by relaxing smooth muscle.Vasodilatation by relaxing smooth muscle.
↓↓ platelet aggregationplatelet aggregation
Inhibits mast cellsInhibits mast cells
Regulates leukocyte recruitmentRegulates leukocyte recruitment
69. Outcomes of Acute InflammationOutcomes of Acute Inflammation
ResolutionResolution
FibrosisFibrosis
Abscess formationAbscess formation
Progression to chronic inflammationProgression to chronic inflammation