Inflammation Dr. Najla Aldaoud, MD School of Medicine, JUST

InflammationInflammation

Dr. Najla Aldaoud, MDDr. Najla Aldaoud, MD

School of Medicine, JUSTSchool of Medicine, JUST


The body is exposed to wide range of The body is exposed to wide range of causes of injury (trauma, infection, causes of injury (trauma, infection, heat / cold, infarction, radiation, heat / cold, infarction, radiation, chemicals).chemicals).

How does the body protect itself How does the body protect itself against injury?against injury?

InflammationInflammation Non-specific mechanisms: Non-specific mechanisms:

Mechanical barriersMechanical barriers skin barrierskin barrier acid in stomachacid in stomach mucus and cilia in lungs mucus and cilia in lungs

InflammationInflammation PhagocytosisPhagocytosis

Specific mechanisms: Specific mechanisms: specific immune response specific immune response

humoral (antibody) mediated humoral (antibody) mediated cell-mediated.cell-mediated.


Definition: A dynamic process of Definition: A dynamic process of chemical and cytological reactions that chemical and cytological reactions that occur in response of vascularized living occur in response of vascularized living tissue to stimuli that cause cell injury. tissue to stimuli that cause cell injury.

Inflammation results in:Inflammation results in: accumulation of leukocytes, and accumulation of leukocytes, and

fluid in extravascular tissue.fluid in extravascular tissue. systemic effects.systemic effects.

Inflammation is a protective response.Inflammation is a protective response.


Inflammation is a protective response Inflammation is a protective response that aims to:that aims to: clear the body of the cause of the cell clear the body of the cause of the cell

injury.injury. destroy, dilute or isolate the destroy, dilute or isolate the

injurious agent (microbes, toxins).injurious agent (microbes, toxins). Eliminate Eliminate the consequences of that the consequences of that

injuryinjury of the of the necrotic cells necrotic cells and tissues.and tissues.

Paves the way for repairPaves the way for repair

ParticipantsParticipants of Inflammation of Inflammation

Inflammatory responses involve an Inflammatory responses involve an interaction of:interaction of: Blood vessels (Blood vessels (endothelial cells and endothelial cells and

smooth muscles of vesselssmooth muscles of vessels) ) White blood cells and plateletsWhite blood cells and platelets

Neutrophils, monocytes, basophils Neutrophils, monocytes, basophils lymphocytes, eosinophils. lymphocytes, eosinophils.

PlasmaPlasma proteins and chemical proteins and chemical mediators: mediators:

Coagulation / fibrinolytic system, Coagulation / fibrinolytic system, kinin system, complement systemkinin system, complement system

ParticipantsParticipants of Inflammation of Inflammation (Cont..)(Cont..)

Inflammatory responses involve also an Inflammatory responses involve also an interaction of:interaction of: Extracellular matrix and stromal cellsExtracellular matrix and stromal cells

Mast cells, fibroblasts, macrophages Mast cells, fibroblasts, macrophages & lymphocytes& lymphocytes

Structural fibrous proteins, adhesive Structural fibrous proteins, adhesive glycoproteins, proteoglycans, glycoproteins, proteoglycans, basement membranebasement membrane

ParticipantsParticipants of Inflammation of Inflammation


Inflammation and repair may have potentially Inflammation and repair may have potentially harmful outcomes such as dharmful outcomes such as digestion of normal igestion of normal tissues, swelling, and inappropriate tissues, swelling, and inappropriate inflammatory responseinflammatory response.. Rheumatoid arthritis. Rheumatoid arthritis. Life threatening hypersensitivity reactions.Life threatening hypersensitivity reactions. Fibrous scarring after pericarditis.Fibrous scarring after pericarditis.

Inflammation Inflammation NomenclatureNomenclature

--itisitis (- after name of tissue) e.g. (- after name of tissue) e.g. AppendixAppendix Appendicitis Appendicitis DermisDermis Dermatitis Dermatitis GallbladderGallbladder Cholecystitis Cholecystitis DuodenumDuodenum Duodenitis Duodenitis MeningesMeninges Meningitis, etc Meningitis, etc


Inflammation is divided into acute and Inflammation is divided into acute and chronic patterns.chronic patterns.

AcuteAcute Inflammation Inflammation

Acute inflammation is a non-specific Acute inflammation is a non-specific immediate and early response to tissue immediate and early response to tissue damage.damage.

It begins within seconds and lasting hours It begins within seconds and lasting hours to several days, or longer if the cause to several days, or longer if the cause persists. persists.

It aims to mediate local defences, destroy It aims to mediate local defences, destroy any infective agents and remove debris.any infective agents and remove debris.

Causes: any cause of cell injury.Causes: any cause of cell injury.

CausesCauses of Acute of Acute InflammationInflammation InfectionsInfections (bacteria, fungal, viruses, and (bacteria, fungal, viruses, and

parasitesparasites).). Physical agents (Physical agents (heat, cold,heat, cold, burns, burns,

radiation, and trauma).radiation, and trauma). Chemicals (Chemicals (acids, alkali, bacterial acids, alkali, bacterial

toxins, metals, and toxins, metals, and caustic substances).caustic substances). Necrotic tissue (Necrotic tissue (infarctioninfarction)) All types of immunologic reactions, i.e., All types of immunologic reactions, i.e.,

hypersensitivity (contact with some hypersensitivity (contact with some substances), autoimmune reactionssubstances), autoimmune reactions

Local Signs of Acute Local Signs of Acute InflammationInflammation

HeatHeat RednessRedness SwellingSwelling PainPain Loss of functionLoss of function

FeaturesFeatures of of Acute Acute InflammationInflammation

Vascular changes Vascular changes Cellular eventsCellular events

Emigration of Emigration of leukocytesleukocytes from microvessels from microvessels

Acute InflammationAcute InflammationVascular ChangesVascular Changes Transient vasoconstrictionTransient vasoconstriction VasodilatationVasodilatation Slowing of the circulation and stasisSlowing of the circulation and stasis Leukocytic marginationLeukocytic margination

Acute InflammationAcute InflammationVascular ChangesVascular Changes

Transient vasoconstriction of arterioles Transient vasoconstriction of arterioles disappears within 3-5 seconds in mild disappears within 3-5 seconds in mild injuries may last several minutes in more injuries may last several minutes in more severe injury (burn).severe injury (burn).


VasodilatationVasodilatation:: 1st involves the arteriole 1st involves the arteriole and it is the cause of heat and redness). and it is the cause of heat and redness). Increased blood volume lead to increased Increased blood volume lead to increased local hydrostatic pressure leading to local hydrostatic pressure leading to transudation of protein -poor fluid into the transudation of protein -poor fluid into the extravascular space.extravascular space.


Slowing of the circulation due to Slowing of the circulation due to increased permeability of the increased permeability of the microvasculature, this leads to microvasculature, this leads to outpouring of protein-rich fluid in the outpouring of protein-rich fluid in the extravascular tissues. extravascular tissues.

This results in concentration of the red This results in concentration of the red cells in small vessels and increased cells in small vessels and increased viscosity of the blood (stasis: dilated viscosity of the blood (stasis: dilated small vessels packed with red cells).small vessels packed with red cells).


Persistence of stasis leads to peripheral Persistence of stasis leads to peripheral orientation of leukocytes (mainly orientation of leukocytes (mainly neutrophils) along the vascular neutrophils) along the vascular endothelium [leukocytic margination]. endothelium [leukocytic margination]. leukocytes 1st stick transiently then leukocytes 1st stick transiently then more strongly, then they migrate more strongly, then they migrate through the vascular wall into the through the vascular wall into the interstitial tissue [emigration].interstitial tissue [emigration].

Features of acute Features of acute inflammationinflammation

Components of exudateComponents of exudate Fluid.Fluid. Fibrin (insoluble): derived from the plasma Fibrin (insoluble): derived from the plasma

protein fibrinogen (soluble), also important in protein fibrinogen (soluble), also important in clottingclotting

Cells: neutrophils predominate (6-72 hours), also Cells: neutrophils predominate (6-72 hours), also macrophages (involved slightly later: 48+ hours)macrophages (involved slightly later: 48+ hours)

Exudate arises in inflammation due to increased Exudate arises in inflammation due to increased vascular permeability and has a high protein vascular permeability and has a high protein content. content.

Transudate results from hydrostatic imbalances Transudate results from hydrostatic imbalances between vessel and extravascular tissues, vascular between vessel and extravascular tissues, vascular permeability is normal, has a low protein content.)permeability is normal, has a low protein content.)

Features of Acute Features of Acute InflammationInflammation

FeaturesFeatures of acute of acute inflammationinflammation

Acute Inflammation Acute Inflammation Leukocyte Cellular EventsLeukocyte Cellular Events

Margination, rolling and adhesion Margination, rolling and adhesion

Transmigration between endothelial cellsTransmigration between endothelial cells

Migration in the interstitium toward the Migration in the interstitium toward the

site of stimulus (chemotaxis and site of stimulus (chemotaxis and

activation) activation) Phagocytosis and degranulationPhagocytosis and degranulation Release of leukocyte productsRelease of leukocyte products

Neutrophil MarginationNeutrophil Margination

Neutrophil MarginationNeutrophil Margination

Effects of Chemotactic Effects of Chemotactic Factors on Endothelial CellsFactors on Endothelial Cells

Effects of Chemotactic Effects of Chemotactic Factors on LeukocytesFactors on Leukocytes

DiapedesisDiapedesis

Leukocyte Cellular EventsLeukocyte Cellular Events

The Process of Extravasation The Process of Extravasation of Leukocytesof Leukocytes

Selectins and their carbohydrate Selectins and their carbohydrate counterligands mediate leukocyte counterligands mediate leukocyte binding and binding and rollingrolling..

Leukocyte integrins and their ligands Leukocyte integrins and their ligands mediate mediate firm adhesionfirm adhesion..

The Process of Extravasation The Process of Extravasation of Leukocytes (Cont..)of Leukocytes (Cont..)

Chemokines play a role in firm Chemokines play a role in firm adhesion by adhesion by activating integrinsactivating integrins on on the leukocyte cell surface.the leukocyte cell surface.

The leukocytes are directed by The leukocytes are directed by chemoattractant gradientschemoattractant gradients to migrate to migrate across the endothelium, and through across the endothelium, and through the extracellular matrix into the the extracellular matrix into the tissue.tissue.

The Process of Extravasation The Process of Extravasation of Leukocytesof Leukocytes

Lobar PneumoniaLobar Pneumonia

ChemotaxisChemotaxis

Migration of cells along a chemical gradientMigration of cells along a chemical gradient Chemotactic factors:Chemotactic factors:

Soluble bacteial products, e.g. N-formyl-Soluble bacteial products, e.g. N-formyl-methionine terminimethionine termini

Complement system products, e.g. C5aComplement system products, e.g. C5a Lipooxygenase pathway of arachidonic Lipooxygenase pathway of arachidonic

acid metabolism, e.g. LTB4acid metabolism, e.g. LTB4 Cytokines, e.g. IL-8Cytokines, e.g. IL-8


Stimulate locomotionStimulate locomotion Degranulation of lysosomal enzymesDegranulation of lysosomal enzymes Production of AA metabolitesProduction of AA metabolites Modulation of the numbers and affinity Modulation of the numbers and affinity

of leukocyte adhesion moleculesof leukocyte adhesion molecules

Effects of Chemotactic Effects of Chemotactic Factors on Endothelial CellsFactors on Endothelial Cells


Generation of AA Generation of AA MetabolitesMetabolites

PhagocytosisPhagocytosis

The process of ingestion and digestion by The process of ingestion and digestion by cells of solid substances, e.g., other cells, cells of solid substances, e.g., other cells, bacteria, necrotic tissue or foreign bacteria, necrotic tissue or foreign material.material.

Steps of phagocytosis:Steps of phagocytosis: Recognition, attachment and binding to Recognition, attachment and binding to

cellular receptors.cellular receptors. EngulfmentEngulfment Fusion of phagocytic vacuoles with lysosomesFusion of phagocytic vacuoles with lysosomes Killing or degradation or ingested materialKilling or degradation or ingested material

PhagocytosisPhagocytosis

How Do Leukocytes Kill How Do Leukocytes Kill Infectious AgentsInfectious Agents

Oxygen burst products (free radical)Oxygen burst products (free radical) Lysosomal enzymesLysosomal enzymes Bactericidal permeability increasing Bactericidal permeability increasing

proteinprotein Major basic proteinMajor basic protein DefensinsDefensins

General principles for chemical General principles for chemical mediatorsmediators Mediators derive from plasma or by local Mediators derive from plasma or by local

production from cells.production from cells. Most mediators perform their activity by Most mediators perform their activity by

initially binding to specific receptors on initially binding to specific receptors on target cells. However, some have direct target cells. However, some have direct enzymatic or toxic activities.enzymatic or toxic activities.

Mediators may stimulate target cells to Mediators may stimulate target cells to release secondary effector molecules, release secondary effector molecules, which may have activities similar which may have activities similar (amplifying) or opposing (counter-(amplifying) or opposing (counter-regulating) the initial stimulus.regulating) the initial stimulus.

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Outcomes of Acute Outcomes of Acute InflammationInflammation

Complete resolutionComplete resolution Healing by scarring or fibrosisHealing by scarring or fibrosis Abscess formationAbscess formation Progression to chronic inflammationProgression to chronic inflammation

Outcomes of Acute Outcomes of Acute InflammationInflammation

Complete resolutionComplete resolution Occurs when the injury is limited or Occurs when the injury is limited or

short-lived and when the tissue is short-lived and when the tissue is capable of regenerationcapable of regeneration

Outcomes of Acute Outcomes of Acute Inflammation (Cont..)Inflammation (Cont..) Scarring or fibrosisScarring or fibrosis

Occurs when Occurs when

there is substantial tissue there is substantial tissue destruction.destruction.

when the inflammation occurs in when the inflammation occurs in tissue not capable of regeneration.tissue not capable of regeneration.

there is extensive fibrinous exudate there is extensive fibrinous exudate that cannot completely absorbed.that cannot completely absorbed.

Outcomes of Acute Outcomes of Acute Inflammation (Cont..)Inflammation (Cont..) Abscess formation: may occur in the Abscess formation: may occur in the

setting of certain bacterial or fungal setting of certain bacterial or fungal infection (pyogenic or “pus forming”)infection (pyogenic or “pus forming”)

Progression to chronic inflammationProgression to chronic inflammation

Morphologic Appearance Morphologic Appearance of Acute Inflammationof Acute Inflammation

Catarrhal Catarrhal Acute inflammation + mucous Acute inflammation + mucous

hypersecretion (e.g. common cold)hypersecretion (e.g. common cold) SerousSerous

Abundant protein-poor fluid with low Abundant protein-poor fluid with low cellular content, e.g. cellular content, e.g. skin blistersskin blisters and body and body cavities cavities

Fibrinous: Fibrinous: Accumulation of thick exudate rich in fibrin, Accumulation of thick exudate rich in fibrin,

may resolve by fibrinolysis or organize into may resolve by fibrinolysis or organize into thick fibrous tissue (e.g. thick fibrous tissue (e.g. pericarditispericarditis))

Burn BlisterBurn Blister

Fibrinous PericarditisFibrinous Pericarditis

Morphologic Appearance of Morphologic Appearance of Acute Inflammation (Cont..)Acute Inflammation (Cont..)

Suppurative (purulent): Suppurative (purulent): Pus: Creamy yellow or blood stained fluid Pus: Creamy yellow or blood stained fluid

consisting of neutrophils, microorganisms consisting of neutrophils, microorganisms & tissue debris e.g. & tissue debris e.g. acute appendicitisacute appendicitis

AbscessAbscess:: Focal localized collection of pus Focal localized collection of pus EmpyemaEmpyema: Collection of pus within a hollow : Collection of pus within a hollow

organorgan UlcersUlcers::

Defect of the surface lining of an organ or Defect of the surface lining of an organ or tissue, mostly GI tract or skintissue, mostly GI tract or skin

Subcutaneous AbscessSubcutaneous Abscess

Lung AbscessLung Abscess

Foot UlcerFoot Ulcer

Chronic inflammationChronic inflammation

Chronic inflammationChronic inflammation Chronic inflammation is a process in Chronic inflammation is a process in

which ongoing inflammation and tissue which ongoing inflammation and tissue damage proceed at the same time as damage proceed at the same time as attempts at healing, seen as scarring. attempts at healing, seen as scarring.

It aims to eradicate and/or contain the It aims to eradicate and/or contain the harmful agent and heal areas of tissue harmful agent and heal areas of tissue damage.damage.

It It last longer duration and last longer duration and can persist, can persist, sometimes for years, until the damaging sometimes for years, until the damaging stimulus is eradicated.stimulus is eradicated.


Chronic inflammation may follow acute Chronic inflammation may follow acute inflammation because of persistence of inflammation because of persistence of the injurious agent or interference with the injurious agent or interference with the normal process of healing.the normal process of healing.

Changes are superimposed upon and/or Changes are superimposed upon and/or replace those of acute inflammation replace those of acute inflammation several days after onset.several days after onset.

In some cases it has an insidious onset:In some cases it has an insidious onset: infections (TB)infections (TB) autoimmune disease (rheumatoid arthritis)autoimmune disease (rheumatoid arthritis) repeated or prolonged exposure to toxic repeated or prolonged exposure to toxic

(asbestos).(asbestos).


• Is characterized histologically by:Is characterized histologically by:

•Infiltration with mononuclear (“chronic Infiltration with mononuclear (“chronic inflammatory”) cells including inflammatory”) cells including macrophages, lymphocytes, and plasma macrophages, lymphocytes, and plasma cellscells

•Tissue destruction (induced mainly by Tissue destruction (induced mainly by inflammatory cells)inflammatory cells)

•Repair involving new vessel formation Repair involving new vessel formation (angiogenesis) and fibrosis.(angiogenesis) and fibrosis.

Causes of Chronic Causes of Chronic InflammationInflammation

Follow acute inflammationFollow acute inflammation Persistence of injurious agentPersistence of injurious agent Interference in the normal process of Interference in the normal process of

healinghealing

Causes of Chronic Causes of Chronic Inflammation (Cont..)Inflammation (Cont..)

Begin insidiously as a slow response to Begin insidiously as a slow response to various agents:various agents: Microorganisms that are intracellular Microorganisms that are intracellular

(viruses) or are of low direct (viruses) or are of low direct pathogenicity, but evoke a delayed pathogenicity, but evoke a delayed immune response (mycobacteria- immune response (mycobacteria- tubercle bacillis)tubercle bacillis)

Prolonged exposure to potentially toxic Prolonged exposure to potentially toxic agents. E.g., (silicosis)agents. E.g., (silicosis)

Autoimmune diseases: immune response Autoimmune diseases: immune response to self antigens and tissues (which are to self antigens and tissues (which are constantly renewed) e.g., rheumatoid constantly renewed) e.g., rheumatoid arthritis. arthritis.

Cell Types in Chronic Cell Types in Chronic InflammationInflammation MacrophagesMacrophages Plasma cellsPlasma cells EosinophilsEosinophils LymphocytesLymphocytes

Chronic InflammationChronic InflammationCell typesCell types

Plasma cells:

Are the terminally differentiated B-cell lymophocytes.

Produce antibodies directed against antigens in the inflammatory site

Lymphocytes: antibodies and cell mediated immunologic reactions non-immune-inflammation reciprocal relationship to macrophages

Chronic InflammationChronic InflammationCell typesCell types Eosinophils:Eosinophils: immunologic reactions mediated by IgE immunologic reactions mediated by IgE

(allergy)(allergy) Seen in parasitic infections Seen in parasitic infections respond to chemotactic agents derived respond to chemotactic agents derived

largely from mast cellslargely from mast cells contain major basic protein: toxic to contain major basic protein: toxic to

parasites and lead to lysis of mammalian parasites and lead to lysis of mammalian epithelial cellsepithelial cells

Chronic Granulomatous Chronic Granulomatous InflammationInflammation

Granulomatous inflammation is a specific type/pattern of chronic inflammation characterised by the presence of activated macrophages that either become ‘epithelioid’ in appearance or become giant multinucleate cells. Tuberculosis, leprosy, schistosomiasis,

sarcoidosis, Crohn’s disease, reactions to foreign material (e.g. suture),

Chronic Granulomatous Chronic Granulomatous InflammationInflammation

Characterized by formation of granulomas: Characterized by formation of granulomas: 0.5 - 2 mm. 0.5 - 2 mm.

Nodules composed of :Nodules composed of : Modified macrophages (epithelioid cells)Modified macrophages (epithelioid cells) Langhan’s or foreign body giant cellsLanghan’s or foreign body giant cells Fibroblasts, plasma cells, lymphocytes, Fibroblasts, plasma cells, lymphocytes,

neutrophilsneutrophils Necrosis is present (necrotizing

granulomatous inflammation) with certain causes e.g TB, but not in sarcoidosis for example. The patterns of granulomatous inflammation vary depending on the cause

Role of lymphatic & Lymph Role of lymphatic & Lymph Nodes in InflammationNodes in Inflammation

Represents a second line of defenseRepresents a second line of defense Delivers antigens and lymphocytes to the Delivers antigens and lymphocytes to the

central lymph nodescentral lymph nodes Lymph flow is increased in inflammationLymph flow is increased in inflammation May become involved by secondary May become involved by secondary

inflammation (lymphangitis, reactive inflammation (lymphangitis, reactive lymphadenitis)lymphadenitis)

Systemic effects of Systemic effects of inflammationinflammation

Fever, chillsFever, chills acute phase reactions:acute phase reactions:

increased slow wave sleepincreased slow wave sleep decreased appetitedecreased appetite increased degradation of proteinincreased degradation of protein hypotension and other hemodynamic hypotension and other hemodynamic

changeschanges synthesis of acute phase proteins by the synthesis of acute phase proteins by the

liver:liver: C-reactive proteins and serum amyloid AC-reactive proteins and serum amyloid A complement and coagulation proteinscomplement and coagulation proteins

Systemic effects of Systemic effects of inflammation (cont.)inflammation (cont.)

leukocytosis (neutrophilia, lymphocytosis, leukocytosis (neutrophilia, lymphocytosis, eosinophilia)eosinophilia)

leukopenia (typhoid fever, viruses, leukopenia (typhoid fever, viruses, rickettsia, &certain protozoa)rickettsia, &certain protozoa)

Role of IL-1, and TNFRole of IL-1, and TNF

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Inflammation Dr. Najla Aldaoud, MD School of Medicine, JUST