Principle of Principle of Inflammation Inflammation

and Repairand Repair

NatapolNatapol SupanatsetakulSupanatsetakul MD, PhD.MD, PhD.Dept. of Pathology and Forensic MedicineDept. of Pathology and Forensic MedicineFaculty of Medicine, Faculty of Medicine, NaresuanNaresuan UniversityUniversity

TOPICSTOPICS

InflammationInflammation–– Acute inflammationAcute inflammation–– Chronic inflammationChronic inflammation

Tissue repairTissue repair

INFLAMMATIONINFLAMMATION

Complex reactions to injurious agent Complex reactions to injurious agent that consists of that consists of –– Vascular responsesVascular responses–– Migration and activation of leukocytesMigration and activation of leukocytes–– Systemic responsesSystemic responses

Closely intertwined with the process of Closely intertwined with the process of repairrepair

Inflammation is fundamentally a protective Inflammation is fundamentally a protective response, but may be potentially harmfulresponse, but may be potentially harmful

Inflammation consists of two componentsInflammation consists of two components–– Vascular reactionVascular reaction–– Cellular reactionCellular reaction

Vascular and cellular reactions are mediated Vascular and cellular reactions are mediated by by chemical factorschemical factors, derived from plasma , derived from plasma proteins or cells (Cytokines) and are proteins or cells (Cytokines) and are produced in response to or activated by the produced in response to or activated by the stimuli stimuli

Inflammation is divided intoInflammation is divided into–– Acute inflammationAcute inflammation–– Chronic inflammationChronic inflammation

ACUTE INFLAMMATIONACUTE INFLAMMATION

Rapid response to an injurious agentRapid response to an injurious agentthat serves to deliver mediators of host that serves to deliver mediators of host defense (leukocytes and plasma proteins) defense (leukocytes and plasma proteins) to the site of injury to the site of injury

Three majors components:

1. Alterations on vascular caliber that lead to an increase in blood flow

2. Structural change that permit plasma protein (fibrin, complement) and leukocytes to leave the circulation

3. Emigration of the leukocytes from the microcirculation to the stimulated site

Stimuli for Acute inflammationStimuli for Acute inflammation

Infections and microbial toxinsInfections and microbial toxinsTraumaTraumaPhysical and chemical agentsPhysical and chemical agentsTissue necrosisTissue necrosisForeign bodiesForeign bodiesImmune reactionsImmune reactions

Vascular ChangesVascular Changes

Changes in vascular flow and caliberChanges in vascular flow and caliber–– Vasodilation Vasodilation –– Earliest manifestationEarliest manifestation of acute inflammationof acute inflammation–– Stasis Stasis increased blood viscosity increased blood viscosity –– Quickly followed by increased vascular Quickly followed by increased vascular

permeabilitypermeability

Increased vascular permeabilityIncreased vascular permeability–– Hallmark of acute inflammationHallmark of acute inflammation–– Protein and fluid leakage from the lumenProtein and fluid leakage from the lumen

ExudateExudate : extravascular fluid that has : extravascular fluid that has high protein concentrationhigh protein concentration

TransudateTransudate : extravascular fluid that : extravascular fluid that has low protein concentrationhas low protein concentration

PusPus or or purulent exudatepurulent exudate : leukocytes: leukocytes--rich rich exudateexudate with cellular debriswith cellular debris

Cellular EventsCellular Events

Margination Margination Rolling Rolling AdhesionAdhesionTransmigration (diapedesis)Transmigration (diapedesis)Migration Migration chemotaxischemotaxis

CHEMICAL MEDIATORS OF CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION

Mediators or originate either from plasma from cellsMediators or originate either from plasma from cellsThe production is triggers by microbial products or The production is triggers by microbial products or by host proteins, other chemical mediatorsby host proteins, other chemical mediatorsMediators perform activity by binding their specific Mediators perform activity by binding their specific receptorsreceptorsOne mediator can stimulate the release of other One mediator can stimulate the release of other mediatorsmediatorsMediators have different effects on different cell Mediators have different effects on different cell typestypesMost mediators are shortMost mediators are short--livedlived

Chemical mediatorsChemical mediators

VasoactiveVasoactive aminesamines: : HistamineHistaminePlasma proteinsPlasma proteins: complement system, : complement system, kininkinin system, clotting and system, clotting and fibrinolyticfibrinolytic systemsystemArachidonicArachidonic acid metabolitesacid metabolites: prostaglandins, : prostaglandins, leukotrienesleukotrienes, , thromboxanesthromboxanesCytokines and Cytokines and chemokineschemokines: Interleukin: Interleukin--1(IL1(IL--1), 1), Tumor necrotic factor (TNF)Tumor necrotic factor (TNF)Nitric oxide (NO)Nitric oxide (NO)

Effects of Chemical mediatorsEffects of Chemical mediators

Pain: Prostaglandin, Pain: Prostaglandin, bradykininbradykininIncreased vascular permeability, edemaIncreased vascular permeability, edemaVasodilationVasodilation: histamine, NO : histamine, NO Fever, acute phase symptoms: ILFever, acute phase symptoms: IL--1, TNF1, TNFTissue damageTissue damageChemotaxisChemotaxis, leukocyte recruitment and , leukocyte recruitment and activationactivation

OUTCOME OF ACUTE OUTCOME OF ACUTE INFLAMMATIONINFLAMMATION

Complete resolutionComplete resolution

Healing by connective tissue replacementHealing by connective tissue replacement(Fibrosis, scar)(Fibrosis, scar)

Chronic inflammation Chronic inflammation

MORPHOLOGIC PATTERN OF MORPHOLOGIC PATTERN OF ACUTE INFLAMMATIONACUTE INFLAMMATION

Serous inflammationSerous inflammation–– BurnBurn–– Inflammation in the body cavityInflammation in the body cavity

Fibrinous inflammationFibrinous inflammation–– Severe injury, results in greater vascular Severe injury, results in greater vascular

permeabilitypermeability–– Leakage of fibrinogen (plasma protein)Leakage of fibrinogen (plasma protein)

Suppurative or purulent inflammationSuppurative or purulent inflammation–– Inflammation with pus or purulent exudate Inflammation with pus or purulent exudate

formationformation–– Acute appendicitisAcute appendicitis–– Acute meningitisAcute meningitis–– Abscess : localized collections of purulent Abscess : localized collections of purulent

inflammatory tissueinflammatory tissue–– FibrinopurulentFibrinopurulent inflammation inflammation

Ulcers Ulcers –– Local defect or excavation of the surface of Local defect or excavation of the surface of

an organ or tissue an organ or tissue –– Most common encounter inMost common encounter in

Oral mucosaOral mucosaSubcutaneous tissueSubcutaneous tissue

CHRONIC INFLAMMATIONCHRONIC INFLAMMATION

Inflammation of prolonged duration Inflammation of prolonged duration (weeks or months) in which active inflammation, (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are tissue destruction, and attempts at repair are proceeding simultaneously. proceeding simultaneously.

Cause of chronic inflammationCause of chronic inflammation

Persistent infectionPersistent infection

Prolonged exposure to potentially toxic Prolonged exposure to potentially toxic agents, either exogenous or endogenousagents, either exogenous or endogenous

Autoimmunity Autoimmunity

Morphologic featuresMorphologic features

Infiltration with mononuclear cells, including Infiltration with mononuclear cells, including macrophages, lymphocytes and plasma cells macrophages, lymphocytes and plasma cells (Acute inflammation = (Acute inflammation = NeutrophilsNeutrophils))

Tissue destructionTissue destruction

Healing by connective tissue replacement of Healing by connective tissue replacement of damaged tissue (fibrosis, scar)damaged tissue (fibrosis, scar)

AbscessAbscess

Focal collection of pus (consisting of Focal collection of pus (consisting of neutrophilsneutrophils, necrotic cells, and edema fluid), necrotic cells, and edema fluid)

Abscess has a central, largely necrotic Abscess has a central, largely necrotic region rimmed by a layer of preserved region rimmed by a layer of preserved neutrophilsneutrophils, and completely walled off by , and completely walled off by connective tissueconnective tissue

GranulomaGranuloma

GranulomatousGranulomatous inflammationinflammationA distinctive pattern of chronic inflammationA distinctive pattern of chronic inflammationCharacterized by central Characterized by central caseouscaseous necrosis, necrosis, activated activated epithelioidepithelioid macrophage, macrophage, multinucleated giant cells, and peripheral multinucleated giant cells, and peripheral lymphocyteslymphocytesMycobacterium tuberculosisMycobacterium tuberculosis infection, infection, leprosy, Syphilis, leprosy, Syphilis, SarcoidosisSarcoidosis

REPAIRREPAIR

Maintenance of normal structure and Maintenance of normal structure and function and survival of the organism function and survival of the organism

RegenerationRegeneration

Healing: scar formation and fibrosisHealing: scar formation and fibrosis

RegenerationRegeneration : growth of cells and tissue to : growth of cells and tissue to replace lost structurereplace lost structure–– Tissue with high proliferative activity : Tissue with high proliferative activity :

hematopoietic tissue (bone marrow), hematopoietic tissue (bone marrow), epithelium (epidermis, GI)epithelium (epidermis, GI)

–– Intact connective scaffoldIntact connective scaffold

HealingHealing : restore original structures : restore original structures involving involving collagen deposition and scar collagen deposition and scar formationformation–– Wound, inflammation, necrosisWound, inflammation, necrosis

TISSUETISSUE--PROLIFERATIVE ACTIVITYPROLIFERATIVE ACTIVITY

Labile tissue (continuous dividing tissue)Labile tissue (continuous dividing tissue)–– EpitheliumEpithelium–– Hematopoietic cells in bone marrowHematopoietic cells in bone marrow

Stable tissue (quiescent tissue)Stable tissue (quiescent tissue)–– LiverLiver–– Kidney Kidney –– Mesenchymal tissue : fibroblasts, smooth Mesenchymal tissue : fibroblasts, smooth

musclemusclePermanent tissue (Permanent tissue (nondividingnondividing tissue)tissue)–– Brain Brain –– Cardiac and striated muscleCardiac and striated muscle

HEALING, SCAR FORMATION HEALING, SCAR FORMATION AND FIBROSISAND FIBROSIS

Induction of an inflammatory processesInduction of an inflammatory processes

Proliferation and migration of parenchymal and Proliferation and migration of parenchymal and connective tissue cellsconnective tissue cells

Formation of new blood vessels and granulation Formation of new blood vessels and granulation tissuetissue

Hallmark of healing : proliferation of fibroblasts Hallmark of healing : proliferation of fibroblasts and endothelial cells to form granulation tissueand endothelial cells to form granulation tissue

CUTANEOUS WOUND CUTANEOUS WOUND HEALINGHEALING

Inflammatory processInflammatory processGranulation formation and reGranulation formation and re--epithelializationepithelializationExtracellular matrix deposition, wound Extracellular matrix deposition, wound contracture and tissue remodelingcontracture and tissue remodeling

First intention woundFirst intention woundSecond intention woundSecond intention wound

HEALING BY FIRST INTENTIONHEALING BY FIRST INTENTION

24 hr : migration of neutrophils, re24 hr : migration of neutrophils, re--epithelializationepithelialization

Day 3 : migration of macrophages, Day 3 : migration of macrophages, granulation tissue formation, collagen granulation tissue formation, collagen synthesissynthesis

Day 5 : more granulation tissue Day 5 : more granulation tissue formation and collagen synthesis, formation and collagen synthesis, bridge in the incision, epidermis recover bridge in the incision, epidermis recover normal thicknessnormal thickness

Week 2 : continue proliferation of Week 2 : continue proliferation of fibroblasts and collagen depositionfibroblasts and collagen deposition

1 month : complete scar formation1 month : complete scar formation

HEALING OF SECOND INTENTIONHEALING OF SECOND INTENTIONMore inflammatory processMore inflammatory processMore granulation tissue formationMore granulation tissue formationMore wound contracture : More wound contracture : myofibroblastsmyofibroblastsThinning of new epitheliumThinning of new epithelium

WOUND STRENGTHWOUND STRENGTH1 week : 10%1 week : 10%3 months : 703 months : 70--80%80%

COMPLICATION IN CUTANEOUS COMPLICATION IN CUTANEOUS WOUND HEALINGWOUND HEALING

Inadequate formation of granulation Inadequate formation of granulation tissue and scar formationtissue and scar formation

Excessive formation of the repair Excessive formation of the repair componentscomponents–– Hypertrophic scar Hypertrophic scar –– Keloid Keloid

Formation of contractureFormation of contracture

ReferencesReferences

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