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Inflammation - The body’s natural response to injury

Characteristics:Dilation (increase in diameter) & fenestration (increase

in permeability) of the capillariesEdema (swelling, redness)Local rise in temperaturePain, sensitivity to painInflux of leukocytes, esp. Polymorphonuclear leukocytes

(PMNs), and macrophagesIncreased (~tenfold) drainage into lymphatic system

PMN infiltration into damaged tissue

BLOOD CELLSType Function Cells/ml bloodRed Blood Cells

Erythrocytes transport O2, CO2 5 X 1012

White Blood Cells (leukocytes)Granulocytes

PMNs/neutrophils phagocytose bacteria 5 X 109

Eosinophils allergic response 2 X 108

Basophils release histamine/serotonin 4 X 107

Monocytes become macrophages 4 X 108

LymphocytesB-cells make antibodies 2 X 109

T-cells cell-mediated immunity 1 X 109

Platelets blood clotting 3 X 1011

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Effectors of InflammationInterleukins - signaling peptides

IL-1: released by macrophages & other cells after injuryActivates phospholipase -> prostaglandin synthesisSynthesis of IL-8 & ELAM

IL-8: chemotactic factor - attracts PMNs, PMN adhesion

Prostaglandins: from arachidonic acid -vasodilationSensitizes nerve endings to pain

Leukotrienes: chemotactic factors from arachidonic acid

Histamines: -> permeability of capillary entothelial cells

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PMN infiltration into damaged tissue

IL-1 & Histamines -> endothelial cells

IL-8 & leukotrienes -> PMNs

Injury IL1syn.

ELAMsyn.

IL8syn.

PhospholipaseAcitvity

HistamineRelease

Leukotrienesyn.Prostaglandinsyn.

AttractPMNs

PMN Adhesion toEndothelial Cells

Fenestration

DilationEdema

PMNInfiltration

Overview of the Inflammatory Response

IL = interleukinsyn. = synthesis

ELAM = entothelial leukocyte adhesion moleculePMNs = polymorphonuclear leukocytes

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Linkage of inflammation to other systems

Complement system - activated by antibody-antigen complexes, activation of proteases that can damage normal tissue

Clotting/fibrinolytic system - intimately linked to late stages of inflammation as part of the healing process

Resolution of inflammationThe normal scenario: inflammation as part of healing

PMNs phagocytose foreign organism or agentElimination through lymphatic systemProduction of inflammatory effectors ceasesInflammation, PMN infiltration & edema subsides

Chronic inflammation:Inflammatory stimulus not removed by PMNsPMNs continue to release degradative enzymesDamage to normal tissue, more inflammationThis chronic, maladaptive inflammation must be

controlled pharmacologically

Inflammatory disease: rheumatoid arthritis

A disease of inflammation and autoimmunityAffects the joints - localized to synovial membrane

Initiating event - unknown - genetic predispositionRheumatoid factor

An IgM antibody against IgGPresent in most rheumatoid patientsProduced by B-cells in synovial fluid

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Rheumatoid arthritis - Progression

Rheumatoid factor complexes trigger complement-> tissue damage

Attract PMNs & macrophages

Pannus: PMNs + macrophages + fibroblasts form scarlike tissue that accumulates in the joint

IL-1 and TNFα produced by pannus -> proliferation and bone resorption by osteoclasts (from macrophages)

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RA: treatment with NSAIDs(nonsteriodal antiinflammatory drugs)

NSAIDs inhibit cyclooxygenase (COX) -> block prostaglandin synthesis -> reduce sensitivity to pain

No effect on radiographic progression of joint disease

1st generation: aspirinCovalent COX modification (acetylation) -> irreversible inhibitionGI side effects - increased acidity, decreases mucous

2nd generation: propionic acid derivatives, e.g. IbuprofenReversible binding & COX inhibitionReduced GI effects

NSAIDs

Injury IL1syn.

ELAMsyn.

IL8syn.

PhospholipaseAcitvity

HistamineRelease

Leukotrienesyn.Prostaglandinsyn.

AttractPMNs

PMN Adhesion toEndothelial Cells

Fenestration

DilationEdema

PMNInfiltration

Overview of the Inflammatory Response

IL = interleukinsyn. = synthesis

ELAM = entothelial leukocyte adhesion moleculePMNs = polymorphonuclear leukocytes

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RA: treatment with NSAIDs(nonsteriodal antiinflammatory drugs)

3rd generation: longer-acting COX inhibitorse.g., nabumetone (Relafen), naproxen (Alleve)half-life ~1-2 days -> less frequent dosage

4th generation: selective COX-2 inhibitorscelecoxib (Celebrex), rofecoxib (Vioxx)COX-1: basal activity in all normal tissuesCOX-2: very low basal activity, greatly increased

in inflamed tissueMinimal GI side effectsOccasional hepatotoxicity - monitor function

RA: treatment with DMARDs(disease-modifying antirheumatic drugs)

DMARDs can actually arrest or slow RA progression(i.e., joint erosion as seen on X-rays)

More toxic than NSAIDS

1st generation: gold compounds, e.g., aurothioglucoseAccumulate in monocytes & macrophagesInterfere with migration and phagocytosisToxicity: colitis, immune dysfunctionsWeekly IM injections

2nd generation: cytotoxic B/T cell inhibitorse.g., methotrexate, leflunomideBlock synthesis of pyrimidines (used to make DNA)Prevent B and T cell proliferation -> rheumatoid

factor not produced

RA: treatment with DMARDs(disease-modifying antirheumatic drugs)

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IL-1 + TNFα (from macrophages) stimulate osteoclastsOsteoclasts resorb bone -> joint destructionEtanercept (Enbrel) - soluble form of TNFα receptorInfliximab - monoclonal antibody to TNFαEither drug binds TNFα, prevents it from binding to

receptors on osteoclasts -> bond resorption preventedToxicities - Hepatotoxicity, opportunistic infections

from inhibition of immune function, esp. TuberculosisWork best if given immediately upon diagnosisProteins: need to be given by injectionCost: ~$10,000/yr

RA: treatment with DMARDs3rd generation: TNFα antagonists (“biologicals”)

TNFα activates TNF receptor

(boneresorption)

cell membrane

outside

inside

Enbrel is a decoy that competes with the TNF receptor for binding TNFα

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Changing concepts in RA treatment

Old paradigm: Treat conservatively with NSAIDs as long as these are effective; switch to DMARDs only when necessary in later more severe stages of the disease

New paradigm: Treat aggressively with DMARDs as soon as RA diagnosed - early “window of opportunity”

Mechanism: block transcription of IL-1 in response to injury and of IL-8 in response to IL-1

Dramatic, rapid suppression of inflammationSerious toxicities -> only given as last resort when

other treatments fail or as a temporary measure while DMARDs take effect

Systemic administration - suppresses immune response overall; can suppress symptoms of serious illness

Intra-articular injection - promotes cartilage degeneration if given repeatedly

RA: treatment with steroids

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Injury IL1syn.

ELAMsyn.

IL8syn.

PhospholipaseAcitvity

HistamineRelease

Leukotrienesyn.Prostaglandinsyn.

AttractPMNs

PMN Adhesion toEndothelial Cells

Fenestration

DilationEdema

PMNInfiltration

Overview of the Inflammatory Response

IL = interleukinsyn. = synthesis

ELAM = entothelial leukocyte adhesion moleculePMNs = polymorphonuclear leukocytes

Steroids

Inflammatory disease: GoutInflammation of joints - similar to RAInflammatory stimulus is deposition of sodium salt of

uric acid

Uric acid - end product of purine metabolismHyperuricemia - necessary but not sufficient for gout

Purine metabolism yields uric acid

XanthineOxidase

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PMN attempting to ingest a uric acid crystal

Gout - treatment with colchicineColchicine - a natural product

Inhibits microtubule formation, blocks cell in mitosisInhibits migration of PMNs, macrophages

Toxicity - inhibits division of GI epithelial cells

Gout - treatment with allopurinolAllopurinol - a synthetic purine analogueBlocks final step in uric acid synthesis Given orally, little toxicity, rapidly absorbed

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Purine metabolism yields uric acid

XanthineOxidase

Gout - treatment with probenecid

Probenecid acts directly on nephrons in the kidney to promote uric acid excretion