Post on 05-Jun-2018
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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