innate immunity: inflammation chapter 6 mosby items and derived items © 2010, 2006 by mosby, inc.,...

Innate Immunity: InflammationInnate Immunity: Inflammation

Chapter 6Chapter 6

Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

2Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

ImmunityImmunity First line of defenseFirst line of defense

Innate resistanceInnate resistance Second line of defenseSecond line of defense

InflammationInflammation Third line of defenseThird line of defense

Adaptive (acquired) immunityAdaptive (acquired) immunity


First Line of DefenseFirst Line of Defense Physical and mechanical barriersPhysical and mechanical barriers

SkinSkin Linings of the gastrointestinal, genitourinary, and Linings of the gastrointestinal, genitourinary, and

respiratory tractsrespiratory tracts• Sloughing off of cellsSloughing off of cells

• Coughing and sneezingCoughing and sneezing

• FlushingFlushing

• VomitingVomiting

• Mucus and ciliaMucus and cilia


First Line of DefenseFirst Line of Defense

Biochemical barriersBiochemical barriers Synthesized and secreted saliva, tears, earwax, Synthesized and secreted saliva, tears, earwax,

sweat, and sebumsweat, and sebum Antimicrobial peptidesAntimicrobial peptides

• Cathelicidins, defensins (Cathelicidins, defensins (α α defensins in neutrophil granules), defensins in neutrophil granules), and collectins (lungs)and collectins (lungs)

Normal bacterial floraNormal bacterial flora• Vaginal: lactobacillusVaginal: lactobacillus

• Intestinal: produce ammonia, phenols, indols, etc. that inhibit Intestinal: produce ammonia, phenols, indols, etc. that inhibit colonization by pathogenscolonization by pathogens


Second Line of DefenseSecond Line of Defense Inflammatory responseInflammatory response

CausesCauses• Infection, mechanical damage, ischemia, nutrient Infection, mechanical damage, ischemia, nutrient

deprivation, temperature extremes, radiation, etc.deprivation, temperature extremes, radiation, etc.

Local manifestationsLocal manifestations Vascular responseVascular response

• Blood vessel dilation, increased vascular permeability Blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the and leakage, WBC adherence to the inner walls of the vessels and migration through the vesselsvessels and migration through the vessels


InflammationInflammation GoalsGoals

Limit and control the inflammatory processLimit and control the inflammatory process Prevent and limit infection and further damagePrevent and limit infection and further damage Control bleedingControl bleeding Interact with components of the adaptive immune Interact with components of the adaptive immune

systemsystem Prepare the area of injury for healingPrepare the area of injury for healing


Plasma Protein SystemsPlasma Protein Systems

Protein systemsProtein systems Complement systemComplement system Coagulation systemCoagulation system Kinin systemKinin system

All contain inactive enzymes (proenzymes)All contain inactive enzymes (proenzymes) Sequentially activatedSequentially activated

• First proenzyme is converted to an active enzymeFirst proenzyme is converted to an active enzyme• Substrate of the activated enzyme becomes the next Substrate of the activated enzyme becomes the next

component in the seriescomponent in the series


Plasma Protein SystemsPlasma Protein Systems Complement systemComplement system

Can destroy pathogens directlyCan destroy pathogens directly Activates or collaborates with every other Activates or collaborates with every other

component of the inflammatory responsecomponent of the inflammatory response PathwaysPathways

• ClassicalClassical

• LectinLectin

• AlternativeAlternative


Plasma Protein SystemsPlasma Protein Systems Coagulation (clotting) systemCoagulation (clotting) system

Forms a fibrinous meshwork at an injured or Forms a fibrinous meshwork at an injured or inflamed site inflamed site • Prevents the spread of infectionPrevents the spread of infection

• Keeps microorganisms and foreign bodies at the site of Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activitygreatest inflammatory cell activity

• Forms a clot that stops bleedingForms a clot that stops bleeding

• Provides a framework for repair and healingProvides a framework for repair and healing

Main substance is an insoluble protein called fibrinMain substance is an insoluble protein called fibrin


Plasma Protein SystemsPlasma Protein Systems Kinin systemKinin system

Functions to activate and assist inflammatory cellsFunctions to activate and assist inflammatory cells Primary kinin is bradykininPrimary kinin is bradykinin Causes dilation of blood vessels, pain, smooth Causes dilation of blood vessels, pain, smooth

muscle contraction, vascular permeability, and muscle contraction, vascular permeability, and leukocyte chemotaxisleukocyte chemotaxis


Plasma Protein SystemsPlasma Protein Systems


Cellular Mediators of Cellular Mediators of InflammationInflammation

Cellular componentsCellular components Granulocytes, platelets, monocytes, and Granulocytes, platelets, monocytes, and

lymphocyteslymphocytes Cell surface receptorsCell surface receptors

Pattern recognition receptors (PRRs)Pattern recognition receptors (PRRs) Pathogen-associated molecular patterns (PAMPs)Pathogen-associated molecular patterns (PAMPs) Toll-like receptorsToll-like receptors Complement receptorsComplement receptors Scavenger receptorsScavenger receptors


Mast CellsMast Cells Cellular bags of granules located in loose Cellular bags of granules located in loose

connective tissues close to blood vesselsconnective tissues close to blood vessels Skin, digestive lining, respiratory tractSkin, digestive lining, respiratory tract

ActivationActivation Physical injury, chemical agents, immunologic Physical injury, chemical agents, immunologic

processes, Toll-like receptorsprocesses, Toll-like receptors Chemical release in two waysChemical release in two ways

• Degranulation and synthesis of lipid-derived chemical Degranulation and synthesis of lipid-derived chemical mediatorsmediators


Mast Cell DegranulationMast Cell Degranulation HistamineHistamine

Vasoactive amine that causes temporary, rapid Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the constriction of the large blood vessels and the dilation of the postcapillary venulesdilation of the postcapillary venules

Retraction of endothelial cells lining the capillariesRetraction of endothelial cells lining the capillaries ReceptorsReceptors

• HH11 receptor (proinflammatory) receptor (proinflammatory)

• HH22 receptor (anti-inflammatory) receptor (anti-inflammatory)


HistamineHistamine ReceptorsReceptors

HH11 receptor receptor

• Proinflammatory Proinflammatory

• Present in smooth muscle cells of the bronchiPresent in smooth muscle cells of the bronchi

HH22 receptor receptor

• Anti-inflammatoryAnti-inflammatory

• Present on parietal cells of the stomach mucosaPresent on parietal cells of the stomach mucosa Induces the secretion of gastric acidInduces the secretion of gastric acid


Mast CellsMast Cells


Mast Cell DegranulationMast Cell Degranulation Chemotactic factorsChemotactic factors

Neutrophil chemotactic factorNeutrophil chemotactic factor• Attracts neutrophilsAttracts neutrophils

Eosinophil chemotactic factor of anaphylaxis Eosinophil chemotactic factor of anaphylaxis (ECF-A)(ECF-A)• Attracts eosinophilsAttracts eosinophils


Mast Cell Synthesis of Mediators: Mast Cell Synthesis of Mediators: Late ResponseLate Response

LeukotrienesLeukotrienes Product of arachidonic acid from mast cell membranesProduct of arachidonic acid from mast cell membranes Similar effects to histamine in later stagesSimilar effects to histamine in later stages

ProstaglandinsProstaglandins Similar effects to leukotrienes; they also induce painSimilar effects to leukotrienes; they also induce pain

Platelet-activating factorPlatelet-activating factor Similar effect to leukotrienes and platelet activationSimilar effect to leukotrienes and platelet activation


Mast CellsMast Cells


PhagocytosisPhagocytosis Process by which a cell ingests and disposes Process by which a cell ingests and disposes

of foreign materialof foreign material Production of adhesion moleculesProduction of adhesion molecules Margination (pavementing)Margination (pavementing)

Adherence of leukocytes to endothelial cellsAdherence of leukocytes to endothelial cells DiapedesisDiapedesis

Emigration of cells through the endothelial Emigration of cells through the endothelial junctionsjunctions


PhagocytosisPhagocytosis


PhagocytosisPhagocytosis StepsSteps

Opsonization, recognition, and adherenceOpsonization, recognition, and adherence Engulfment Engulfment Phagosome formationPhagosome formation Fusion with lysosomal granulesFusion with lysosomal granules Destruction of the targetDestruction of the target


PhagocytesPhagocytes NeutrophilsNeutrophils

Also referred to as polymorphonuclear neutrophils Also referred to as polymorphonuclear neutrophils (PMNs)(PMNs)

Predominate in early inflammatory responsesPredominate in early inflammatory responses Ingest bacteria, dead cells, and cellular debrisIngest bacteria, dead cells, and cellular debris Cells are short lived and become a component of Cells are short lived and become a component of

the purulent exudatethe purulent exudate


PhagocytesPhagocytes Monocytes and macrophagesMonocytes and macrophages

Monocytes produced in bone marrow, enter Monocytes produced in bone marrow, enter circulation, and migrate to the inflammatory site, circulation, and migrate to the inflammatory site, where they develop into macrophageswhere they develop into macrophages

Macrophages typically arrive at inflammatory site 3 Macrophages typically arrive at inflammatory site 3 to 7 days after neutrophilsto 7 days after neutrophils

Macrophage activation results in increased size, Macrophage activation results in increased size, plasma membrane area, glucose metabolism, plasma membrane area, glucose metabolism, number of lysosomes, and secretory productsnumber of lysosomes, and secretory products


PhagocytesPhagocytes EosinophilsEosinophils

Mildly phagocyticMildly phagocytic DutiesDuties

• Defense against parasites and regulation of vascular Defense against parasites and regulation of vascular mediatorsmediators

BasophilsBasophils Role uncertainRole uncertain


PhagocytesPhagocytes Natural killer (NK) cellsNatural killer (NK) cells

Function: recognize and eliminate cells infected Function: recognize and eliminate cells infected with viruses and some function in eliminating with viruses and some function in eliminating cancer cellscancer cells

PlateletsPlatelets Activation results in degranulation and interaction Activation results in degranulation and interaction

with components of the coagulation systemwith components of the coagulation system


CytokinesCytokines InterleukinsInterleukins

Produced primarily by macrophages and Produced primarily by macrophages and lymphocytes in response to a pathogen or lymphocytes in response to a pathogen or stimulation by other products of inflammationstimulation by other products of inflammation

Many typesMany types ExamplesExamples

• IL-1 is a proinflammatory cytokineIL-1 is a proinflammatory cytokine

• IL-10 is an anti-inflammatory cytokineIL-10 is an anti-inflammatory cytokine


CytokinesCytokines InterferonInterferon

Protects against viral infectionsProtects against viral infections Produced and released by virally infected host Produced and released by virally infected host

cells in response to viral double-stranded RNAcells in response to viral double-stranded RNA TypesTypes

• INF-INF-αα and INF- and INF-ßß Induce production of antiviral proteinsInduce production of antiviral proteins

• INF-INF-γγ Increases microbiocidal activity of macrophagesIncreases microbiocidal activity of macrophages


CytokinesCytokines


CytokinesCytokines

Tumor necrosis factor-Tumor necrosis factor-αα Secreted by macrophages in response to PAMP and Secreted by macrophages in response to PAMP and

Toll-like receptor recognition (i.e., in response to Toll-like receptor recognition (i.e., in response to pathogens)pathogens)• Induces fever by acting as endogenous pyrogenInduces fever by acting as endogenous pyrogen

• Increases synthesis of inflammatory serum proteinsIncreases synthesis of inflammatory serum proteins

• Causes muscle wasting (cachexia) and intravascular Causes muscle wasting (cachexia) and intravascular thrombosis thrombosis


ChemokinesChemokines Induce WBC chemotaxisInduce WBC chemotaxis Produced by macrophages, fibroblasts, Produced by macrophages, fibroblasts,

endothelial cellsendothelial cells


Results from vascular changes and Results from vascular changes and corresponding leakage of circulating corresponding leakage of circulating components into the tissuecomponents into the tissue HeatHeat RednessRedness SwellingSwelling PainPain

Local Manifestations of Local Manifestations of InflammationInflammation


Vascular ResponseVascular Response Transient vasoconstriction—secondsTransient vasoconstriction—seconds VasodilationVasodilation Increased capillary permeabilityIncreased capillary permeability Exudation of fluid and cellsExudation of fluid and cells Cellular migration (margination/adherence, Cellular migration (margination/adherence,

migration)migration)


Exudative FluidsExudative Fluids

Serous exudateSerous exudate Watery exudate: indicates early inflammationWatery exudate: indicates early inflammation

Fibrinous exudateFibrinous exudate Thick, clotted exudate: indicates more advanced Thick, clotted exudate: indicates more advanced

inflammationinflammation Purulent exudatePurulent exudate

Pus: indicates a bacterial infectionPus: indicates a bacterial infection Hemorrhagic exudateHemorrhagic exudate

Exudate contains blood: indicates bleedingExudate contains blood: indicates bleeding


Systemic Manifestations of Systemic Manifestations of InflammationInflammation

FeverFever Caused by exogenous and endogenous pyrogensCaused by exogenous and endogenous pyrogens Act directly on the hypothalamusAct directly on the hypothalamus

LeukocytosisLeukocytosis Increased numbers of circulating leukocytesIncreased numbers of circulating leukocytes Left shift, increase in immature cells (bands)Left shift, increase in immature cells (bands)

Increased plasma protein synthesisIncreased plasma protein synthesis• Acute-phase reactantsAcute-phase reactants

C-reactive protein, fibrinogen, haptoglobin, amyloid, C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc. ceruloplasmin, etc.


Control of InflammationControl of Inflammation Carboxypeptidase—inhibits C3a and C5aCarboxypeptidase—inhibits C3a and C5a Histaminase—inhibits histamineHistaminase—inhibits histamine Arylsulfatase—inhibits histamineArylsulfatase—inhibits histamine C-1 esterase inhibitor—inhibits complementC-1 esterase inhibitor—inhibits complement Kinins and clottingKinins and clotting


Chronic InflammationChronic Inflammation Inflammation lasting 2 weeks or longerInflammation lasting 2 weeks or longer Often related to an unsuccessful acute Often related to an unsuccessful acute

inflammatory responseinflammatory response Other causesOther causes

High lipid and wax content of microorganismHigh lipid and wax content of microorganism Ability to survive inside the macrophageAbility to survive inside the macrophage ToxinsToxins Chemicals, particulate matter, or physical irritantsChemicals, particulate matter, or physical irritants


Chronic InflammationChronic Inflammation


Chronic InflammationChronic Inflammation CharacteristicsCharacteristics

Dense infiltration of lymphocytes and macrophagesDense infiltration of lymphocytes and macrophages Granuloma formationGranuloma formation Epithelioid cell formationEpithelioid cell formation Giant cell formationGiant cell formation


Resolution and RepairResolution and Repair RegenerationRegeneration ResolutionResolution

Returning injured tissue to the original structure Returning injured tissue to the original structure and functionand function

RepairRepair Replacement of destroyed tissue with scar tissueReplacement of destroyed tissue with scar tissue Scar tissueScar tissue

• Composed primarily of collagen to restore the tensile Composed primarily of collagen to restore the tensile strength of the tissuestrength of the tissue


Resolution and RepairResolution and Repair DébridementDébridement

Cleaning up dissolved clots, microorganisms, Cleaning up dissolved clots, microorganisms, erythrocytes, and dead tissue cellserythrocytes, and dead tissue cells

HealingHealing Filling in the woundFilling in the wound Sealing the wound (epithelialization)Sealing the wound (epithelialization) Shrinking the wound (contraction)Shrinking the wound (contraction)


HealingHealing Primary intentionPrimary intention

Wounds that heal under conditions of minimal Wounds that heal under conditions of minimal tissue losstissue loss

Secondary intentionSecondary intention Wounds that require a great deal more tissue Wounds that require a great deal more tissue

replacementreplacement• Open woundOpen wound


HealingHealing Reconstructive phaseReconstructive phase

Fibroblast proliferationFibroblast proliferation Collagen synthesisCollagen synthesis EpithelializationEpithelialization ContractionContraction

• MyofibroblastsMyofibroblasts

Cellular differentiationCellular differentiation


HealingHealing Maturation phaseMaturation phase

Continuation of cellular differentiationContinuation of cellular differentiation Scar tissue formationScar tissue formation Scar remodelingScar remodeling


HealingHealing


Dysfunctional Wound Healing Dysfunctional Wound Healing Dysfunction during inflammatory responseDysfunction during inflammatory response

HemorrhageHemorrhage Fibrous adhesionFibrous adhesion InfectionInfection Excess scar formationExcess scar formation Wound sepsisWound sepsis HypovolemiaHypovolemia HypoproteinemiaHypoproteinemia Anti-inflammatory steroidsAnti-inflammatory steroids


Dysfunctional Wound Healing Dysfunctional Wound Healing Dysfunction during reconstructive phaseDysfunction during reconstructive phase

Impaired collagen matrix assemblyImpaired collagen matrix assembly• Keloid scarKeloid scar

• Hypertrophic scarHypertrophic scar

Impaired epithelializationImpaired epithelialization• Anti-inflammatory steroids, hypoxemia, and nutritional Anti-inflammatory steroids, hypoxemia, and nutritional

deficienciesdeficiencies

Impaired contractionImpaired contraction• Contracture Contracture


Dysfunctional Wound Healing Dysfunctional Wound Healing


Dysfunctional Wound Healing Dysfunctional Wound Healing Wound disruptionWound disruption

DehiscenceDehiscence• Wound pulls apart at the suture lineWound pulls apart at the suture line

Excessive strain and obesity are causesExcessive strain and obesity are causes

• Increased risk of wound sepsisIncreased risk of wound sepsis


Pediatrics Pediatrics Neonates have transiently depressed Neonates have transiently depressed

inflammatory and immune functioninflammatory and immune function Neutrophils not capable of efficient chemotaxisNeutrophils not capable of efficient chemotaxis Neonates express complement deficiencyNeonates express complement deficiency Deficient in collectins and collectin-like Deficient in collectins and collectin-like

proteinsproteins


Older Adults Older Adults Impaired inflammation likely a result of Impaired inflammation likely a result of

chronic illnesschronic illness Diabetes, cardiovascular disease, etc.Diabetes, cardiovascular disease, etc.

Chronic medication intake decreases the Chronic medication intake decreases the inflammatory responseinflammatory response

Healing response is diminished due to loss of Healing response is diminished due to loss of the regenerative ability of the skinthe regenerative ability of the skin

Infections are more common in older adultsInfections are more common in older adults

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