InflammationInflammation
Dr. Najla Aldaoud, MDDr. Najla Aldaoud, MD
School of Medicine, JUSTSchool of Medicine, JUST
InflammationInflammation
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.
InflammationInflammation
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.
InflammationInflammation
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
InflammationInflammation
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
InflammationInflammation
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).
Acute InflammationAcute InflammationVascular ChangesVascular Changes
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.
Acute InflammationAcute InflammationVascular ChangesVascular Changes
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).
Acute InflammationAcute InflammationVascular ChangesVascular Changes
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.)
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
Effects of Chemotactic Effects of Chemotactic Factors on Endothelial CellsFactors on Endothelial Cells
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.
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
Effects of Chemotactic Effects of Chemotactic Factors on LeukocytesFactors on Leukocytes
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
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
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.
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))
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
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 inflammationChronic inflammation
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).
Chronic inflammationChronic inflammation
• 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