Inflammation 2: Inflammation 2 - Columbia University · Inflammation 2:Inflammation 2 1. Chemical...

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1 Inflammation 2 Inflammation 2: 1. Chemical mediators 2. Systemic effects 3. Chronic inflammation damaged cell Key Players in Inflammation mac L mast cell Injurious agent Microbe Toxin Radiation Burn blood vessel plasma proteins endothelial cell resident WBC’s Extracellular matrix (ECM) leukocytes (& their mediators)

Transcript of Inflammation 2: Inflammation 2 - Columbia University · Inflammation 2:Inflammation 2 1. Chemical...

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Inflammation 2Inflammation 2:

1. Chemical mediators2. Systemic effects3. Chronic inflammation

damagedcell

Key Players in Inflammation

mac

L

mastcell

Injurious agent•Microbe•Toxin•Radiation•Burn

blood vessel

plasmaproteins

endothelial cell

resident WBC’s

Extracellular matrix (ECM)

leukocytes(& their mediators)

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Cell-Derived Mediators

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Plasma Protein-Derived Mediators

Vasoactive Amines HistamineSerotonin (5-OH-tryptamine)

Vasodilation

widened gaps

endothelialcontraction

mast cell

histamine

platelet

serotonindense body granules platelet

aggregation serotoninrelease

Px injury: heat/traumaIgE bindingC3a + C5aHistamine-releasing prot.Neuropeptides (subst.P)IL-1, IL-8

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RobbinsBasic Pathology8/e Fig. 2-15

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hydroperoxy-eicosatetraenoic acid

hydroxyeicosatetraenoicacid

chemotacticfor PMN’s

inhibit

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PG’s protectiveagainst acid COX-1 inhib. ulcers

COX-1 expressedin gastric mucosa

Adverse effects of anti-inflammatory drugs

COX-2 inhibitors pro-thrombosis(e.g. cor. arteries)

phospholipase A2

PAF•vasodilation• vascular permeab.•leukocyte adhesion•chemotaxis

endothelium mac

plts

PMN

Platelet Activating Factor (PAF)

PAF & the 5 P’s:•Platelet activating factor•Pro-inflammatory•Phospholipase A2 involved•Permeability ( vasc. permeab.)•Polys (neutrophil chemotaxis)

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TNF

IL-1

cytokines

mac

L LPS

adhesion molecules

systemic acute-phasereaction

activatesfibroblasts ECM

thrombogenicityof endothelium

Cytokines:•polypeptides•from many cells—esp. mac’s and lymphocytes•e.g. interleukins (communicate between leukocytes)

Chemokines•Chemoattractant cytokines•Small: 8-10 kD•Bind to G-protein-coupled receptors on target cells

Recruitment

Eos

L

PMN

Increase affinity ofintegrins for adh. molecules

on endothelium

Organize B & T cellareas in l.n.’s/spleen

T B

•lymph node•spleen

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Chemokines

CXC CC----cys-a.a.-cys---- --cys-cys--

PMN’se.g.

IL-8

acts on

mac

endomast

fibroblast

IL-1TNF

monocytes

act on

MCP-1: monocytechemoattractantprotein-1

MIP-1α:macrophageinflammatory protein- 1α

e.g.

Tmemory CD4+

RANTES: regulated onactivation normal T-expressed and secreted

eosEOTAXIN

chemokine

LPSact on

acts on

sepsis

MPO Cl-

OClhypochlorous radical

NADPHoxidase

arginineiNOS

NOnitric oxide

Modified from RobbinsBasic Pathology 8/eFig. 1-20

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ROS

high levels causetissue injury

thrombosis endothelialpermeability

damageendothelium

•protease activation•anti-protease inact.

breakdown ECM

directcell injury

•catalase•superoxidedysmutase

•glutathione

anti-oxidants

Nitric Oxide (NO)free radical gas

L-arg O2 NADPH

NO

NOS(nitric oxide synthase)

•nNOS (neuronal; not inflammatory)•iNOS (inducible; by IL-1, TNF,IFNγ)

--present in macs/endothel.•eNOS (endothelial)

•sm. m. relaxation•vasodilation

inhibit plt. adhesion,agg. & degranulation

WBC recruitment

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Lysosomal enzymes of leukocytes

acid proteases(in phagolysosomes)

neutral proteases•elastase•collagenase•cathepsin

elastin, collagen,basement membrane,other matrix proteins

degradeC3 + C5

C3a + C5akininogen

bradykinin-likepeptides

act on

Neuropeptides

nervefibers

substanceP

•Transmit pain signals•Regulate vessel tone•Modulate vasc. perm.

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Plasma Protein-Derived Mediators

Complement•Present in plasma as 9 inactive proteins

C1 – C9•Progressive conversions from inactive to

active forms (C1 C1a, C3 C3a + C3b,etc.)•Membrane attack complex: C5-9

forms channel in lipid membranesentry of fluid & ions, cell lysis

•Activation pathways:1. Classical (Ag-Ab complexes; IgG/IgM)2. Alternative (bacterial polysaccharides,

e.g., endotoxin, cell wall components)3. Lectin (plasma mannose-binding lectin

binds to mannose residues on microbes)

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Complement roles in inflammation

VascularC3a + C5avasc. permeab.

vasodilation

mastcell

histamineC3a + C5a as“anaphylatoxins”

LeukocyteChemotaxis

C5achemotaxis

PhagocytosisC3biC3b (inactive)

opsonize

Bact.

C3biC3b

RR

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Robbins Basic Pathology 8/e Fig.2-19

• vasc. permeability•chemotactic for WBC’s

vascularpermeability

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Systemic Effects of Inflammation

Fever

plasma acute-phase proteins

Leukocytosis

hypothalamus

neurotransmittersreset temp. setpoint higher

PGE2LPSexogenouspyrogen

cyclo-oxyg.

endogenouspyrogen

TNFIL-1

macAA

IL-6C-reactive protein

CRPSerum Amyloid A

SAA

fibrinogen

CRPSAA

complement

RBCrouleaux

ESR: erythrocyteSedimentation rate

Bact.

15,000-20,000 / µL(normal 5-10,000)

Leukemoid reaction:40,000 – 100,000

Periph. Blood WBC:

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Chronic InflammationChronic Inflammation

Acute Cell /

TissueInjury

Vascular phase

Cellular phase

Acute Inflammation Chronic inflammation

L PLmac

PMN

Exceptions:allergy/drugs/parasites

viral infections

eos

lymphocytes

De novo chronic diseaseautoimmune, etc.

Hours---days Weeks---mos---years

Resolution

Abscess

Fibrosis(scar)

persistentinfection persistent

exposure

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thyroid

CD4+T

HelperT cellsensitization

CD8+T

mac

IFN-γ

Ab’splasma

cell

Chronic lymphocyticthyroiditis

(Hashimoto thyroiditis)

Autoimmune attackagst. the thyroid

follicularepithelium

Normal thyroid Chronic thyroiditis

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Normal

Chronic thyroiditis

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HBV

hepatocyte

virusuncoating

MHC

ViralAg’s

T

Chronic viral hepatitis

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