Chemical Mediators Of Inflammation, Acute & Chronic

Front 1

Cardinal signs of inflammation

Back 1

Function laesa – loss of fxn

Rubor – redness

Tumor – swelling

Calor – heat

Dolor – pain

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Inflammatory response in general

Back 2

= complex rxn to injuries caused by microbes, damaged cells (tissue-based startle rxn to trauma)

- consists of vascular responses, migration, activation of leukocytes, systemic rxns

Innate immunity -> DC's -> adaptive immunity (T cells)

Front 3

Purposes of inflammation

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- recruitment & equipment of other cells

- liquefication of surrounding tissue --| microbial metastasis

- beginning of the healing process

Front 4

Pathology of inflammation

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- Tissue dmg due to inflammatory response

- Aggregates of chronically activated lymphocytes & macrophages -> granuloma --| organ fxn

- Distortion of the repair mechanism (fibrosis)

- Neoplastic transformation -> cancer

Front 5

Chemical mediators of inflammation - origins

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- Already present in circulation (plasma) - zymogens -> cleavage -> active (complement & coagulation cascades, inhibitors)

- Cell-derived - rapid release: pre-synthesized & present in cells (histamine)

- Cell-derived - slow release: require de novo synthesis (LPS -> cytokines)

Front 6

Chemical mediators of inflammation - mechanisms of activity

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- Binding to specific R's (chemokines, cytokines)

- Direct enzymatic activity (lysosomal proteases)

- Oxidative damage induction (H2O2)

(- Regulation)

Front 7

Leukocyte extravasation

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Selectins -> rolling

Integrins -> adhesion, diapedesis

- α & β chain dimers

- regulated by chemokines

Front 8

Histamine

Back 8

- synthesized & stored in mast cells in CT (also in basophils & platelets)

- physical stimuli, immunobiological signals

-- IgE x-linking

-- anaphylatoxin signaling (C3a, C5a)

-- cytokines (IL-1)

-- chemokines (IL-8)

-> release -> H(1)-R -> vasodilation, permeability

Front 9

Serotonin

Back 9

- stored in platelets -> aggregation -> release

-> ↑ vascular permeability

Front 10

Complement

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- mediates humoral immunity & inflammation

- role in cytolysis (MAC), opsonization, solubilization & clearance of Ab-Ag complexes

- constitutes of proteolytic enzymes

- Ab/pathogens -> activaion -> amplification

- C3a & C5a: anaphylatoxins -> histamine release

- C5a: chemotaxis, adhesion, lipoxygenase pwy

Front 11

Eicosanoids

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- local hormones (leukotriens, prostaglandins, lipoxins) produced via arachidonic A cascade; rapid & short λ

- formed in lipid bodies; tissue-restricted

- COX-1/2 pwy -> prostaglandins

- lipoxins require >1 type of cell for sunthesis -> restricted to sites of inflammation

Front 12

Chemokines

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- activate & chemoattract leykocytes, integrin adhesion; spatial & temporal resolution

- 4 classes based on cys residue relative placement: CXC (α), CC (β), C (γ), CxxxC

- produced by macrophages & endothelium -> proteoglycans -> gradient

- bind to 7-TM R's = GPCR's

- specificity & promiscuity

Front 13

NO (nitric oxide)

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- Ca++ influx -> released from endothelial cells

- short λ, potent paracrine vasodilator

- binds to hemoglobin (NO sink?)

- produced from L-Arg by NOS: e-NOS, n-NOS ~ constitutively made but inactive (Ca++); iNos ~ inducible, produced by macrophages (IFN-γ)

- non-specific reactive species x IC bacteria

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Platelet Activating Factor (PAF)

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= lipid molecule -> ↑ vascular permeability, cell aggregation, adhesion, chemotaxis

- binds to ligand-specific 7 TM GPCR's

Front 15

Cytokines

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- produced by WBC's

- mediate inflammatory responses

- macrophages activation -> IL-1, TNF-α -> R's -> NF-κB -> fever, sleep, loss of appetite, ↑ acute phase proteins, hemodynamic effects (shock), neutrophilia, endothelium activation, PGI synthesis, endothelial cytokine production, fibroblast proliferation, collagen synthesis

Front 16

Therapeutic interventions

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- glucocorticoids -> I-κB

- aspirin --| COX-2 & I-κB degradation

--| NF-κB

- humira --| TNF-α

Front 17

Acute inflammation

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= rapid host response that serves to deliver leukocytes & plasma proteins (Ab's, etc.) to sites of infection or tissue injury; major components:

- increase in blood flow

- structural changes -> proteins & leukocytes leave the circulation -> accumulation @ the site of injury

Front 18

Sequence of events in acute inflammation

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- Stimulus infections (bacterial, viral, fungal, parasitic), tissue necrosis, foreign bodies, immune rxns

- Vascular changes - BF & caliber, vascular permeability, lymph drainage

- Leukocyte extravasation & chemotaxis = exudate (fluid & protein leakage) -> swelling (edema); margination; cytokines & chemokines

- Recognition & removal of offending agents - phagocytosis, engulfment, killing, degradation

- Termination - regeneration / repair

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Mechanisms of exudative edema

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- retraction of endothelial cells

- endothelial injury (burns)

- leukocyte-mediated vascular injury

- ↑ transcytosis (<- VEGF)

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Adhesion molecules

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Selectins - P-selectin (platelets, endothelium), E-selectin (endothelium), L-selectin (leukocytes); bind:

Glycoproteins - PRGL-1, ESL-1, CD34, Glycam-1

Immunoglobulins (endothelium) - ICAM-1, VCAM-1, PECAM-1 (CD31); bind:

Integrins (leukocytes) - LFA-1, MAC-1, VLA-4 (αβ)

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Transmigration

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(= diapedesis)

Chemokines -> leukocytes:

=> express PECAM-1 (CD31)

-> migration through interendothelial spaces

- secrete collagenase -> cross BM

- adhere to ECM (via integrins & CD44)

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Chemotaxis

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= locomotion along a chemical gradient

Exogenous - bacterial products (peptides, lipids)

Endogenous - chemical mediators (cytokines [IL-8], complement [C5a], Arachidonic A metabolites [LTB4])

-> bind to G-proteins on surface of leukocytes -> polymerization of actin

Front 23

Nature of inflammatory infiltrate over time

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- Edema (0-6 hrs)

- PMN's (6-24 hrs)

-- Neutrophils: infections, infarcts

-- Eosinophilia: allergy, asthma, parasite

-- Lymphocytosis: viral

- Monocytes, macrophages (24-48 hrs)

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Recognition of microbes & dead tissue

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TLR's - recognize bacterial/viral products, stimulate microbicidal substances & cytokines

GPCR's - recognize bacterial peptides, chemokines, lipid mediators; induce migration & activate microbicidal respiratory burts

Opsonin R's - recognize opsonins (IgG, C3b, etc.)

Cytokine R's - recognize IFN-γ

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Phagocytosis & engulfment

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Recognition & attachment:

- opsonin R's

- mannose R's

- scavenger R's

Engulfment

- phagosome formation -> fusion w/ lysosome => phagolysosome

- mediated by polymerization of actin filaments

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Killing & degradation

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- Respiratory burst = coupling of phagocytosis & rapid oxidative rxn -> ROS w/in the lysosome

- Activating stimuli => cytosolic proteins localize to lysosomal membrane

-> form phagocyte oxidase -> ox. NADPH & red. O2 -> superoxide

- NOS induced => Arg -> NO

- other substances in leukocyte granules (lysozyme, elastase, MBP, ...)

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Collateral damage

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Normal - appropriate defense rxn against difficult to eradicate pathogens (TB, virus)

Autoimmunity - inappropriate defense rxn X host tissue (RA, Goodpasture's syndrome)

Allergy - excessive defense X harmless environmental substances (asthma)

Toxic agents - prolonged exposure to non-degradable exogenous/endogenous toxic agents

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Defects in leukocyte fxn

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LAD (defective adhesion molecules) -> recurrent bacterial infections

CGD

- catalase + organisms -> ingested but not killed

- catalease - org. -> bacterial metab. -> H2O2

Chediak-Higashi syndrome (LYST) - defective fusion of phagosomes & lysosomes

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Defects in leukocyte fxn

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Bone marrow suppression

- leukemic infiltrate

- radiation, chemotherapy

- aplastic anemia (idiopathic, autoimmune, ...)

Chronic disease - diabetes, malignancy, sepsis, dialysis

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Termination

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Passive - neutrophils & mediators are short-lived & are degraded

Active

- AA metabolites: pro-inflammatory -> anti-

- macrophages (M2): anti-inflam. cytokines

- anti-inflammatory lipid mediators

- n. impulses (ACh) --| macrophage (M1) TNF

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Chronic inflammation

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- Prolonged iInflammation where tissue injury & repair attempts coexist

- characterized by mononuclear (lymphocytes, plasma cells, macrophages) cell infiltrate, tissue destruction, angiogenesis, fibrosis

- unresolved acute infl. -> crhonic low-grade

-> carcinogenesis & degenerative diseases

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Causes of chronic inflammation

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Persistent infections - delayed type hypersensitivity rxn X difficult to eradicate path'.

Immune-mediated inflammatory disease - autoimmunity, allergy

Prolonged exposure to toxic agents - endogenous/exogenous

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Cells of chronic inflammation

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Macrophage: tissue -> activated -> M1 (inflammatory)/M2 (restorative)

T-cells - CD4+ & macrophages, CD8+ (viral)

B-cells -> lymphoid follicles

Plasma cells - produce Ab X perssistent Ag's

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Granuloma

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= collection of macrophages

- often appear "epitheloid" ~ transformed

- contain fused giant cells:

-- Lagerhans-type (peripheral nuclei)

-- foreign body-type (random nuclei)

- surrounded by a "collar" of lymphocytes & plasma cells