- these result in a fairly uniform reaction regardless of the type of injury

Local directors (chemical mediators) of inflammation

- regulating the expression of these is an important way of controlling inflammation

- most mediators bind to these in order to produce their results

Receptors

- important results of many mediators is the release of these

More Mediators

- most mediators have short lives

- this occurs by these two methods

Rapid deactivation or deterioration

- Activation of circulating inactive plasma proteases, pre-formed mediators stored in granules, and mediators produced in response to stimulation

Categories of chemical mediators

- Complement system, Kinin system, Coagulation system, and Fibrinolytic system

Circulating plasma proteases that undergo activation to become effective

- major inflammatory products are C3a, C3b, and C5a

- increased vascular permeability by way of Histamine release (C3a, C5a)

- WBC activation including increasing avidity of WBC integrins (C5a) and upregulation of lipoxygenase (AA) pathway (C5a)

- chemotaxis (C5a) and Opsonization (C3b)

Complement system

- activated by Factor XII

- active products include:

- kallikreins (activates bradykinin, Factor XII, Plasmin and C5-->C5a)

- Bradykinin (increases vascular permeability, produce pain, smooth muscle contraction)

Kinin system

- activated by Factor XII

- Active products include:

- Thrombin (serotonin release from platelets, enhances WBC adhesion, fibroblast proliferation)

- Fibrinopeptides from fibrinogen-->fibrin (vascular permeability, chemotaxis)

- Factor Xa (vascular permeability)

Coagulation System

- activated by Kallikrein

- active products include:

- Plasmin (cleaves C3 to C3a, fibrin to produce fibrin split products, activate Factor XII, activate Transforming Growth Factor-B in wound healing)

- Fibrin split products from breakdown of fibrin (vascular permeability)

Fibrinolytic System

- Vasoactive amines (histamine and serotonin)

- WBC lysosomal proteases

- stored in granules

Pre-formed mediators

- histamine and serotonin

- vasodilate arterioles (constrict large arteries) and increase vascular permeability of venules

- found pre-formed in granules in basophils/mast cells (histamine) and platelets (serotonin & histamine)

Vasoactive Amines

- release of histamine from these cells is stimulated by immune reactions (IgE receptors), complement fragments (C3a/C5a), and cytokines (IL-1, IL-8)

Mast cells

- release of histamine/serotonin from these cells stimulated by thrombin, contact with collagen (wounds w/ damaged vessels), and platelet activating factor (from mast cells)

Platelets

- most important product that helps keep lysosomal proteases in check is this

alpha-1-antitrypsin

- Arachidonic Acid Metabolies (eicosanoids), oxygen-derived free radicals, platelet activating factor (PAF), nitric oxide (NO), cytokines, neuropeptides (substance P)

Mediators produced in response to stimulation

- 20 carbon polyunsaturated fatty acid attached to membrane phospholipids, cleaved by phospholipases to produce metabolites

- actions include pain, fever, vasodilation (prostaglandins), vascular permeability (leukotrienes), and chemotaxis (leukotriene B4)

- COX (prostaglandins, thromboxanes) or Lipoxygenase pathways (leukotrienes)

Arachidonic Acid Metabolites ("Eicosanoids")

- cleave AA to produce metabolites from membrane phospholipids

- inhibited by corticosteroids

- stimulated by platelet activating factor (PAF)

Phospholipases

- inhibit the COX pathway and the production of prostaglandins

NSAIDs

- derived from leukocytes, endothelial cells, and injured cells

- mediated thru G-protein coupled receptor

- increases vascular permeability and vasodilation (release of vasoactive amines)

- "primes" WBCs by enhancing adhesion molecules, AA metabolism, motility, oxidative burst, and degranulation

Platelet Activating Factor (PAF)

- short-lived factor produced by 3 different synthetases (eNOS, nNOS, iNOS)

- causes vascular smooth muscle relaxation (vasodilatation) via iNOS

- reduces platelet aggregation and adhesion (reducing inflammation) via eNOS

- cytotoxic free radical production (microbe killing)

Nitric Oxide (NO)

- expressed constitutively with increased production of NO when there is an influx of calcium

- endothelial and neuronal based

- endothelial important in reducing inflammation

eNOS & nNOS

- induced when activated by cytokines such as TNF-a and INF-y

- induces vasodilation and contributes to septic shock

- macrophages

iNOS

- polypeptide products of many cells

- major inflammatory are: IL-1, TNF-a, chemokines (IL-8)

- IL-1 & TNF-a cause:

- acute phase reactions (fever, increased sleep, neutrophilia, elevated acute phase reactants)

- endothelial cell "activation" (increased leukocyte adherence, eicosanoids, NO, growth factors, vasoactive amines)

- fibroblast effects (proliferation, increased collagen synthesis)

Cytokines

- small peptide (11 aa's) produced by nervous systems

- primarily works in lung and GI tract

- activates AA pathway

- powerful mediator of increased vascular permeability

Neuropeptides (substance P)

- prostaglandins (endothelial cells, leukocytes)

- histamine/serotonin (mast cells, basophils, platelets)

- nitric oxide (NO, endothelial derived relaxing factor)

Mediators of Vasodilation

- endothelial cell contraction, producing gaps between endothelial cells

- increased transcytosis

- endothelial cell damage

Mechanisms of increased vascular permeability

- Vasoactive amines (histamine/serotonin)

- C3a, C5a (complement activation)

- Bradykinin (Kinin cascade)

- Leukotrienes (mast cells, basophils, macrophages)

- Platelet activating factor (injured tissue cells, endothelium, WBCs)

- Substance P (neuropeptide)

Mediators of Increased Vascular Permeability

- Vasodilation --> Increased Vascular Permeability --> Leukocyte Adhesion --> Leukocyte Emigration/Chemotaxis --> Leukocyte Activation --> Phagocytosis --> Release of Products --> Fever --> Acute Phase Protein Production --> Pain

Inflammatory Actions of Chemical Mediators

- in leukocyte adhesion endothelial cell activation occurs with increased selection of these

- at first, adhesion of leukocytes to endothelium is loose ("tethering, rolling") involving these

Selectins

- After initial adhesion leukocytes "latch" onto endothelium using these

ICAMs & Integrins

- Adhesion stimulation is mediated by these for leukocyte adhesion molecules and these for endothelial adhesion molecules

C5a (leukocyte) and IL-1 (endothelial)

- re-distribution of adhesion molecules from cytoplasmic storage (Weible-Palade bodies) to cell surface (minutes)

- induction of increased production of adhesion molecules (hours)

- increased zealousness of adhesion molecules (integrins) by conformational or other changes

Mechanisms for changes in adhesion

- motility in chemotaxis caused by this

- chemotactic agent binds to leukocyte

- activates G-proteind mediated pathway using Ca & phosphoinositol

- triggers actin-regulating elements (filamin, gelsolin, prolifin, calmodulin) and actin-myosin contraction

Pseudopod (lamellipod)

- bacterial products (N-formylated peptides)

- complement fragments (C5a)

- leukotrienes (LT B4 from AA metabolism)

- Chemokines (IL 8 from macrophages)

Chemotactic agents

- production of AA metabolites

- degranulation & release of lysosomal contents

- activation of the "oxidative burst" associated with phagocytosis

- modulation of adhesion molecules

- leukocyte "priming"

Mechanisms of Leukocyte Activation

- TNF-a, C5a, PAF

Leukocyte activators

- Fc Fragment of IgG

- C3b, C3bi (complement fragments)

Opsonins

- Recognition and attachment --> Engulfment

- extraneous substances coated with serum factors (opsonization)

- involves similar processes as chemotaxis (ligand-receptor complex, G-protein mediated messengers)

Phagocytosis

- produces localized tissue damage

- amplifies the effects of inflammation by releasing stimulary mediators

- lysosomal enzymes, oxygen radicals, eicosanoids release

Release of Leukocyte Products into interstitium

- mediated primarily through cytokines (IL-1, TNF-a)

- act on thermoregulatory center of hypothalamus

- core body temp is raised (vasoconstriction of skin vessels, decrease dissipation of heat)

- improves efficiency of bacteria killing, decreased bacterial replication, enhanced leukocyte mobility

Fever

- stimulates prostaglandin synthesis in hypothalamus which then alters the body temperature set-point

IL-1

- acts by stimulating release of IL-1 and on hypothalamus directly

TNF

- this organ produces most of the acute phase proteins

- mediated by action of IL-6

- products include C-reactive protein, Serum amyloid A, Complement, Coagulation factors (fibrinogen)

- results in an increased erythrocyte sedimentation rate

Liver

- mediated by prostaglandins and bradykinin

- results from stimulation of local nerve endings

Pain

- works to activate macrophages

Interferon-gamma