• 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

What is inflammation?What is inflammation?

Inflammation – Inflammation – Protective response intended to eliminate Protective response intended to eliminate

the initial cause of cell injury and the the initial cause of cell injury and the necrotic cells and tissues arising from necrotic cells and tissues arising from the injurythe injury

Inflammation is intimately Inflammation is intimately associated with the repair process associated with the repair process which includes parenchymal cell which includes parenchymal cell regeneration and scarringregeneration and scarring

Acute - minutes to daysAcute - minutes to days Characterized by fluid and protein Characterized 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 morphonuclear Cells)Cells)

CHRONIC Inf - CHRONIC Inf - MonoMononuclear Cellsnuclear Cells

InflammationInflammation

EXUDATE

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“

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

Acute inflammation Acute inflammation major componentsmajor components

Transient vasoconstrictionTransient vasoconstriction VasodilatationVasodilatation Endothelial permeabilityEndothelial permeability Extravasation of PMNsExtravasation of PMNs

Five classic local signs of Five classic local signs of acute inflammationacute inflammation

HeatHeat RednessRedness SwellingSwelling PainPain Loss of Loss of

functionfunction

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

Vascular changes Vascular changes you need to know thisyou need to know this

Transient vasoconstrictionTransient vasoconstriction Vasodilation Vasodilation Exudation of protein rich fluidExudation of protein rich fluid Blood stasisBlood stasis MarginationMargination Emigration/TransmigrationEmigration/Transmigration

Vascular changesProtein exits vessels :

intravascular osmotic pressure

intravascular hydrostatic pressure

Endothelial gaps at intercellular junctions:

* immediate transient response

* histamine, bradykinin, leukotrienes, substance P

Vascular permeabilityVascular permeability Vasodilation – increased blood flowVasodilation – increased blood flow Increased intravascular hydrostatic pressureIncreased intravascular hydrostatic pressure Transudate Transudate - ultrafiltrate blood plasma - ultrafiltrate blood plasma

(contains little protein)(contains little protein) Again, this is very transient and just gets the Again, this is very transient and just gets the

process started. Think acute inflammation, think process started. Think acute inflammation, think EXUDATEEXUDATE

ExudateExudate - (protein-rich with PMNs) - (protein-rich with PMNs) Exudate is the characteristic fluid of acute Exudate is the characteristic fluid of acute

inflammationinflammation 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

How do endothelial cellsHow do endothelial cellsbecome permeable?become permeable?

Endothelial cell contractionEndothelial cell contraction Junctional retractionJunctional retraction Direct endothelial injury Direct endothelial injury

(immediate sustained response) (immediate sustained response) Leukocyte-dependent endothelial Leukocyte-dependent endothelial

injury injury Increased transcytosis of fluidIncreased transcytosis of fluid

Direct endothelial injury Direct endothelial injury (immediate sustained (immediate sustained

response)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 vessel Occurs immediately and lasts until vessel

repairedrepaired

Occurs at sites of leukocyte Occurs at sites of leukocyte accumulationaccumulation

Due to leukocyte activation which Due to leukocyte activation which releases proteolytic enzymes and releases proteolytic enzymes and toxic oxygentoxic oxygen

Leukocyte-dependent Leukocyte-dependent endothelial injuryendothelial injury

Leukocyte Cellular Leukocyte Cellular EventsEvents

Margination and RollingMargination and Rolling Adhesion and TransmigrationAdhesion and Transmigration Migration into interstitial tissueMigration into interstitial tissue

SLOWING CONCENTRATION

Margination Rolling AdhesionTransmigration

Selectins CAMS

Integrins

Mucin-like glycoproteins

(Sialyl-Lewis X PSL-1 & ESL-1)

Weak and transient binding

Results in rolling

Integrins upregulated and activated for increased affinity to CAMS

Results in firm adhesion

MarginationMargination

Normal flow - RBCs and WBCs flow Normal flow - RBCs and WBCs flow in the center of the vesselin the center of the vessel

A A cell poorcell poor plasma is flowing plasma is flowing adjacent to endotheliumadjacent to endothelium

As blood flow slows, WBCs collect As blood flow slows, WBCs collect along the endothelium along the endothelium MarginationMargination

Endothelial ActivationEndothelial Activation

The underlying stimulus causes The underlying stimulus causes release of mediators which activate release of mediators which activate the endothelium causing selectins the endothelium causing selectins and other mediators to be moved and other mediators to be moved quickly to the surfacequickly to the surface

Selectins Selectins

Selectins bind selected sugars Selectins bind selected sugars SeSelected + lected + LectinsLectins (sugars) = Selectins (sugars) = Selectins

Some selectins are present on endothelial cells (E-Some selectins are present on endothelial cells (E-Selectin)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 in Results in rollingrolling

Fig 3-Fig 3-99

RollingRolling

Selectins transiently bind to Selectins transiently bind to receptorsreceptors

PMNs bounce or roll along PMNs bounce or roll along Rolling Rolling

AdhesionAdhesion

Mediated by integrins ICAM-1 and Mediated by integrins ICAM-1 and VCAM-1 VCAM-1

TransmigrationTransmigration

Mediated/assisted by PECAM-1 & ICAM-1 Mediated/assisted by PECAM-1 & ICAM-1 (Integrins)(Integrins)

Diapedesis (cells crawling)Diapedesis (cells crawling) Primary in venulesPrimary in venules Collagenases degrade BM Collagenases degrade BM PermeabilityPermeability

ChemotaxisChemotaxis

Movement toward the site of injury Movement toward the site of injury along a chemical gradientalong a chemical gradient Chemotactic factors includeChemotactic factors include

Complement components (20 serum Complement components (20 serum proteins)proteins)

Arachadonic acid (AA) metabolitesArachadonic acid (AA) metabolites Soluble bacterial productsSoluble bacterial products Chemokines, cytokinesChemokines, cytokines

Phagocytosis & Phagocytosis & DegranulationDegranulation

Phagocytosis (engulf and destroy)Phagocytosis (engulf and destroy) Degranulation and the oxidative Degranulation and the oxidative

burst destroy the engulfed particleburst destroy the engulfed particle Recognition & attachmentRecognition & attachment

Opsonins coat target and bind to Opsonins coat target and bind to leukocytesleukocytes

EngulfmentEngulfment Killing/degradationKilling/degradation

OO22 dep: Reactive O dep: Reactive O22 species in species in lysosomes & EClysosomes & EC

OO2 2 indep: Bactericidal permeability indep: Bactericidal permeability agents, lysozyme, MBP, lactoferrinagents, lysozyme, MBP, lactoferrin

Leukocyte-induced Leukocyte-induced tissue injurytissue injury

Lysosomal enzymes are released into the Lysosomal enzymes are released into the extracellular space during phagocytosis extracellular space during phagocytosis causing cell injury and matrix causing cell injury and matrix degradationdegradation

Activated leukocytes release reactive Activated leukocytes release reactive oxygen species and products of oxygen species and products of arachidonic acid metabolism which can arachidonic acid metabolism which can injure tissue and endothelial cellsinjure tissue and endothelial cells

These events underlie many human These events underlie many human diseases (e.g. Rheumatoid arthritis)diseases (e.g. Rheumatoid arthritis)

Table 3-3Table 3-3GeneticGenetic DefectDefectLAD 1LAD 1 B chain of CD11/CD18 B chain of CD11/CD18

integrinsintegrinsLAD 2LAD 2 Sialylated Sialylated

oligosaccharideoligosaccharideNeutrophil-specific Neutrophil-specific granule deficiencygranule deficiency

Absence of neutrophil-Absence of neutrophil-specific granules specific granules

CGDCGD

X-linkedX-linked

ARAR

Defective chemotaxisDefective chemotaxisNADPH oxidatise NADPH oxidatise (membrane)(membrane)NADPH oxidase NADPH oxidase (cytoplasm)(cytoplasm)

MPO deficiencyMPO deficiency Absent MPO-H2O2 Absent MPO-H2O2 systemsystem

Chediak-Higashi syndromeChediak-Higashi syndrome Lysosomal defectLysosomal defectAcquiredAcquiredThermal injury, DM, CA, Thermal injury, DM, CA, sepsissepsis

ChemotaxisChemotaxis

Dialysis, DMDialysis, DM AdhesionAdhesionLeukemia, anemia, sepsis, Leukemia, anemia, sepsis, DM, neonates, DM, neonates, malnutritionmalnutrition

Phagocytosis & Phagocytosis & microbicidal activitymicrobicidal activity

Leukocyte adhesion Leukocyte adhesion deficiency 1 (LAD-1)deficiency 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 Neutrophils from patients can roll but do not

stickstick chain of CD11/CD18 integrinchain of CD11/CD18 integrin Transfuse patients with normal neutrophils Transfuse patients with normal neutrophils

and they can emigrateand they can emigrate

Mechanism of leukocyte Mechanism of leukocyte adhesion deficiency 1 adhesion deficiency 1

(LAD -1)(LAD -1)

Absence of integrins on neutrophilsAbsence of integrins on neutrophils Mutation in n-terminal region of the Mutation in n-terminal region of the

integrin integrin chain inhibits proper integrin chain inhibits proper integrin assemblyassembly

Normal function is restored following Normal function is restored following transfection of patient cells with cDNA for transfection of patient cells with cDNA for chain chain

Chediak-Higashi Chediak-Higashi SyndromeSyndrome

This syndrome has been on every This syndrome has been on every board test since Noahboard test since Noah

Defect in chemotaxis and lysosomal Defect in chemotaxis and lysosomal degranulation into phagosomes degranulation into phagosomes

Chronic Granulomatous Chronic Granulomatous DiseaseDisease

Defect in NADPH oxidase systemDefect in NADPH oxidase system Marked decrease in ability to kill Marked decrease in ability to kill

microorganismsmicroorganisms

Chemical mediators of Chemical mediators of inflammationinflammation

Plasma-derived Plasma-derived Circulating precursors Circulating precursors Have to be activatedHave to be activated

Cell-derivedCell-derived Sequestered intracellular Sequestered intracellular Synthesized de novoSynthesized de novo

Most mediators bind to receptors on Most mediators bind to receptors on cell surface but some have direct cell surface but some have direct enzymatic or toxic activityenzymatic or toxic activity

Mediators are tightly regulatedMediators are tightly regulated

Chemotacticfactors (eg. c5a)

Chemotacticfactors (eg. c5a)

Tissue injury

Tissue injury

Vasoactivemediators(eg. histamine)

Vasoactivemediators(eg. histamine)

Increased vascularpermeability

Increased vascularpermeability

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

Plasma Mediator Systems - Interaction 

1. Kinin

2. Clotting

3. Complement

4. Fibrinolytic

C5

C5a

Plasminogen Plasmin

C3

C3a

Fibrin FSPs

Prothrombin Thrombin

Fibrinogen

XII

Kinin

Complement

Clotting

Fibrinolytic

Fibrinopeptides

Prekallikrein XIIa Kallikrein

High Mol. Wt. Kininogen Bradykinin

Plasma Mediator Systems - Interaction

Kinin cascadeKinin cascade

Leads to formation of bradykininLeads to formation of bradykinin Bradykinin causes Bradykinin causes

Increased vascular permeabilityIncreased vascular permeability Arteriolar dilatation Arteriolar dilatation Smooth muscle contraction Smooth muscle contraction

Bradykinin is short lived (kininases)Bradykinin is short lived (kininases) Vascular actions similar to histamineVascular actions similar to histamine

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

Complement systemComplement system

Role in inflammation (c3a and c5a)Role in inflammation (c3a and c5a) Vascular effectsVascular effects

Increase vascular permeability and Increase vascular permeability and vasodilationvasodilation

Similar to histamineSimilar to histamine Activates lipoxygenase pathway of Activates lipoxygenase pathway of

arachidonic acid metabolism (c5a)arachidonic acid metabolism (c5a)

Complement systemComplement system

Leukocyte activation, adhesion and chemotaxis Leukocyte activation, adhesion and chemotaxis (c5a)(c5a)

PhagocytosisPhagocytosis c3b acts as opsonin and promotes phagocytosis c3b acts as opsonin and promotes phagocytosis

by cells bearing receptors for c3bby cells bearing receptors for c3b

Inflammatory Mediators Inflammatory Mediators from Complementfrom Complement

AnaphylatoxinsAnaphylatoxins::

C3a, C5a, & C4aC3a, C5a, & C4a trigger mast cells to release trigger mast cells to release histamine and cause vasodilatationhistamine and cause vasodilatation

C5aC5a also activates the lipoxygenase system in also activates the lipoxygenase system in PMNs and monocytes PMNs and monocytes release of release of inflammatory mediatorsinflammatory mediators

Leukocyte activation, adhesion, & chemotaxisLeukocyte activation, adhesion, & chemotaxis::C5aC5a activates leukocytes, promotes leukocyte activates leukocytes, promotes leukocyte

binding to endothelium via integrins and is binding to endothelium via integrins and is chemotactic for PMNs, monos, eos, & basoschemotactic for PMNs, monos, eos, & basos

Inflammatory Mediators Inflammatory Mediators from Complementfrom Complement

PhagocytosisPhagocytosis::

C3b and C3biC3b and C3bi are opsonins are opsonins

ControlControl: :

Convertases are destabilized by "decay Convertases are destabilized by "decay accelerating factor" (DAF) accelerating factor" (DAF)

Inability to express DAF causes Inability to express DAF causes paroxysmal nocturnal hemoglobinuriaparoxysmal nocturnal hemoglobinuria

C1 inhibitor (C1INH) deficiency causes C1 inhibitor (C1INH) deficiency causes hereditary angioneurotic edemahereditary angioneurotic edema

Vasoactive aminesVasoactive amines HistamineHistamine

Found in mast cells, basophils and Found in mast cells, basophils and plateletsplatelets

Released in response to stimuli Released in response to stimuli Promotes arteriolar dilation and venular Promotes arteriolar dilation and venular

endothelial contraction endothelial contraction results in widening of interendothelial cell results in widening of interendothelial cell

junctions with increased vascular junctions with increased vascular permeabilitypermeability

SerotoninSerotonin Vasoactive effects similar to histamineVasoactive effects similar to histamine Found in platelets Found in platelets Released when platelets aggregateReleased when platelets aggregate

Bradykinin: Potent biomolecule

1. Vasodilatation

2. Increased vascular permeability

3. Contraction of smooth muscle

4. Pain on injection

5. Short life, kininase degrades

Bradykinin: Potent biomolecule

1. Vasodilatation

2. Increased vascular permeability

3. Contraction of smooth muscle

4. Pain on injection

5. Short life, kininase degrades

Factor XII activated by:

1. Plasmin

2. Kallikrein

3. Collagen & basement membrane

4. Activated platelets

5. Co-factor = HMWK

Factor XII activated by:

1. Plasmin

2. Kallikrein

3. Collagen & basement membrane

4. Activated platelets

5. Co-factor = HMWK

Vascular Permeability:

- Bradykinin

- Fibrionopeptides

- Fibrin Split Prod.

- Factor Xa

- Leukotrienes

Vascular Permeability:

- Bradykinin

- Fibrionopeptides

- Fibrin Split Prod.

- Factor Xa

- Leukotrienes

Arachidonic Acid (AA)Arachidonic Acid (AA)

Where is it located?Where is it located? AA is a component of cell membrane AA is a component of cell membrane

phospholipidsphospholipids The breakdown of AA into its metabolites The breakdown of AA into its metabolites

produces a variety of biologic effectsproduces a variety of biologic effects

Arachidonic acid Arachidonic acid metabolitesmetabolites

Metabolites of AA - short-range Metabolites of AA - short-range hormoneshormones

AA metabolites act locally at site of AA metabolites act locally at site of generationgeneration

Rapidly decay or are destroyedRapidly decay or are destroyed

Arachidonic AcidArachidonic Acid

AA is released from the cell AA is released from the cell membrane by membrane by phospholipasesphospholipases which which have themselves been activated by have themselves been activated by various stimuli and/or inflammatory various stimuli and/or inflammatory mediatorsmediators

AA metabolism occurs via two major AA metabolism occurs via two major pathways named for the enzymes pathways named for the enzymes that initiate the reactions; that initiate the reactions; lipoxygenaselipoxygenase and and cyclooxygenasecyclooxygenase

AA metabolites (eicosanoids)Cyclooxygenases synthesize

Prostaglandins

Thromboxanes

Lipoxygenases synthesize

Leukotrienes

Lipoxins

PGG2

PGH2

PGI2

ProstacyclinTXA2

Thromboxane

PGD2 ; PGE2 PGF2

Vasodilatation

Inhibits Platelet Aggregation

Vasoconstriction

Promotes Platelet Aggregation

Vasodilatation Edema

PGI2

TXA2

Arachidonic Acid Arachidonic Acid PathwaysPathways

you need to know thisyou need to know this LipoxygenaseLipoxygenase

5-HETE5-HETE ChemotaxisChemotaxis

5-HPETE5-HPETE Leukotriene Leukotriene

generationgeneration LeukotrienesLeukotrienes

VasoconstricitonVasoconstriciton BronchospasmBronchospasm Increased vascular Increased vascular

permeabilitypermeability

LipoxygenaseLipoxygenase 5-HETE5-HETE

ChemotaxisChemotaxis 5-HPETE5-HPETE

Leukotriene Leukotriene generationgeneration

LeukotrienesLeukotrienes VasoconstricitonVasoconstriciton BronchospasmBronchospasm Increased vascular Increased vascular

permeabilitypermeability

CyclooxygenaseCyclooxygenase ProstaglandinsProstaglandins

VasodilatationVasodilatation Increased vascular Increased vascular

permeabilitypermeability ProstacyclinProstacyclin

VasodilatationVasodilatation Inhibits platlelet Inhibits platlelet

aggregationaggregation Thromboxane A2Thromboxane A2

VasoconstrictionVasoconstriction Promotes platlelet Promotes platlelet

aggregationaggregation

CyclooxygenaseCyclooxygenase ProstaglandinsProstaglandins

VasodilatationVasodilatation Increased vascular Increased vascular

permeabilitypermeability ProstacyclinProstacyclin

VasodilatationVasodilatation Inhibits platlelet Inhibits platlelet

aggregationaggregation Thromboxane A2Thromboxane A2

VasoconstrictionVasoconstriction Promotes platlelet Promotes platlelet

aggregationaggregation

Arachidonic Acid Arachidonic Acid PathwaysPathways

you need to know thisyou need to know this LipoxygenaseLipoxygenase

5-HETE, 5-HPETE, 5-HETE, 5-HPETE, LeukotrienesLeukotrienes

Spasm (Vaso, Spasm (Vaso, Broncho)Broncho)

LipoxygenaseLipoxygenase 5-HETE, 5-HPETE, 5-HETE, 5-HPETE,

LeukotrienesLeukotrienes Spasm (Vaso, Spasm (Vaso,

Broncho)Broncho)

CyclooxygenaseCyclooxygenase Prostaglandins - Prostaglandins -

EDEMAEDEMA Prostacyclin vs TXA2Prostacyclin vs TXA2

Vasodilatation vs. Vasodilatation vs. VasoconstrictionVasoconstriction

Platelet aggregationPlatelet aggregationInhibits vs. promotesInhibits vs. promotes

CyclooxygenaseCyclooxygenase Prostaglandins - Prostaglandins -

EDEMAEDEMA Prostacyclin vs TXA2Prostacyclin vs TXA2

Vasodilatation vs. Vasodilatation vs. VasoconstrictionVasoconstriction

Platelet aggregationPlatelet aggregationInhibits vs. promotesInhibits vs. promotes

Arachidonic Acid Arachidonic Acid MetabolitesMetabolites

Participate in every aspect of acute Participate in every aspect of acute inflammationinflammation

Effective Anti-inflammatory agents Effective Anti-inflammatory agents act on AA pathwaysact on AA pathways Aspirin and Non-Steroidal Anti-Aspirin and Non-Steroidal Anti-

inflammatory Drugs (NSAID’s) - inflammatory Drugs (NSAID’s) - Cyclooxygenase pathCyclooxygenase path

Steroids act, in part, by inhibiting Steroids act, in part, by inhibiting Phospholipase A2Phospholipase A2

Platelet-Activating Platelet-Activating Factor (PAF)Factor (PAF)

Another phospholipid-derived mediator Another phospholipid-derived mediator released by phospholipasesreleased by phospholipases

Induces aggregation of plateletsInduces aggregation of platelets Causes vasoconstriction and Causes vasoconstriction and

bronchoconstrictionbronchoconstriction 100 to 1,000 times more potent than 100 to 1,000 times more potent than

histamine in inducing vasodilation and histamine in inducing vasodilation and vascular permeabilityvascular permeability

Enhances leukocyte adhesion, chemotaxis, Enhances leukocyte adhesion, chemotaxis, degranulation and the oxidative burstdegranulation and the oxidative burst

It does everything!It does everything!

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 Autocrine, paracrine or endocrine

effectseffects These “biological response modifiers” These “biological response modifiers”

are being actively investigated for are being actively investigated for therapeutic use in controlling the therapeutic use in controlling the inflammatory response.inflammatory response.

1. Macrophages make IL-1 & TNF-

2. T-cells make TNF- (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- )

Lymphocyte function

Selected Inflammatory Selected Inflammatory Cells & Their Cells & Their ChemokinesChemokines

Target CellTarget Cell Important ChemokinesImportant Chemokines

NeutrophilsNeutrophils IL-8, GroIL-8, Gro, , , , , others, others

MonocytesMonocytes MIP-1MIP-1, MIP-1, MIP-1, MCP-1,2,3, MCP-1,2,3

EosinophilsEosinophils EotaxinEotaxin

LymphocytLymphocyteses

LymphotaxinLymphotaxin

BasophilsBasophils IL-8, MIP-1IL-8, MIP-1, MCP-1,3, , MCP-1,3, RANTESRANTES

Nitric OxideNitric Oxide NO is a soluble free radical gasNO is a soluble free radical gas Made by nitric oxide synthetase Made by nitric oxide synthetase

(NOS) in endothelium (eNOS), (NOS) in endothelium (eNOS), macrophages (iNOS), and specific macrophages (iNOS), and specific neurons in the brain (nNOS)neurons in the brain (nNOS)

Broad range of functions and effects Broad range of functions and effects that are short rangethat are short range

Vasodilatation by relaxing smooth muscle.Vasodilatation by relaxing smooth muscle. platelet aggregationplatelet aggregation Inhibits mast cellsInhibits mast cells Regulates leukocyte recruitmentRegulates leukocyte recruitment

Outcomes of Acute Outcomes of Acute InflammationInflammation

ResolutionResolution FibrosisFibrosis Abscess formationAbscess formation Progression to chronic inflammationProgression to chronic inflammation