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									 Chemical Mediators of
Glut of inflammatory mediators
• Mediators may be circulating in the plasma
  (typically synthesized by the liver) or may
  be produced locally by the cells at the site
  of inflammation
  – Plasma derived mediators are inactive
    precursors – must undergo proteolytic
    cleavage to acquire their biological properties
  – Cell-derived mediators are:
     • Normally sequestered in intracellular granules that
       are secreted upon activation (histamine from mast
     • Synthesized de novo in response to a stimulus
• Most mediators induce their effects by
  binding to specific receptors on target cells.

• However, some have direct enzymatic
  and/or toxic activities
  (lysosomal proteases or reactive oxygen species)
• Mediators may stimulate target cells to
  release secondary effecter molecules
  – These secondary molecules may have similar
    properties as of initial effecter molecule
  (In such case they may amplify a particular response)
  – On the other hand, they may have opposing
  (act to counter-regulate the initial stimulus)
• Mediators may act on only one or a very
  few target or may have widespread activity

• There may be widely differing outcomes
  depending on which cell type they affect
• Mediator function is generally tightly
  – Once activated and released from the cell,
    most activators quickly decay (AA
  – Inactivated by enzymes (bradykinin is
    inactivated by kininase)
  – Eliminated (antioxidants scavenge toxic
    oxygen metabolites)
  – Inhibited (complement inhibitory proteins)
• A major reason for the checks
  and balances is that most
  mediators have the potential to
  cause harmful effect
              1-Vasoactive Amines
 • Histamine – widely distributed – mast cells,
   basophils, and platelets – released in response:
     –   Physical injury
     –   Immune reaction, particularly IgE
     –   C3a and C5a (anaphylatoxins)
     –   Leukocyte derived histamine releasing proteins
     –   Neuropeptides (e.g., substance P)
     –   Certain cytokines (e.g., IL-1 and IL-8)
Arteriolar dilation, principal mediator of initial phase of increased
permeability, including venular endothelial contraction and endothelial gaps

          Soon after its release it is inactivated by histaminase
• Serotonin (5-hydroxytryptamine)
  – It is also a preformed mediator, with effects
    similar to those of histamine
  – It is found primarily within platelets
  – Release during platelet aggregation
• These are small proteins like substance P
• Transmits pain signals
• Regulate vessel tone and modulate
  vascular permeability
• Nerve fibers that secrete neuropeptides
  are especially prominent in the lungs and
  gastrointestinal tract
     3- Arachidonic Acid Metabolites:
 Prostaglandins, Leukotriens, and Lipoxins
• Products derived from metabolism of AA affect a variety
  of biological processes, including inflammation and
• They can be thought of as short-range hormones that act
  locally at the site of generation and then rapidly
  spontaneously decay, or are enzymatically destroyed
• AA is a 20-chain poly unsaturated fatty acid derived
  primarily from dietary linoleic acid and present mainly in
  its estrified form as a component of cell membrane
• It is released from these phospholipids via cellular
  phospholipases that have been activated by mechanical,
  chemical, or physical stimuli, or by inflammatory
  mediators such as C5a
• AA metabolism proceeds along one of two
  major pathways:
  – Cyclooxygenase, synthesizing prostaglandins
    and thromboxanes
  – Lipooxygenase, synthesizing leukotriens and



                                                                 Mast cells

 Hydroxy eicosa tetra enoic acid = HETE
 Hydroperoxy eicosa tetra enoic acid = HPETE   COX-1--- Gastric Mucosa
• AA metabolites (also called eicosanoids) can
  mediate virtually every step of inflammation
  Platelet Activating Factor (PAF)
   Acetyl Glycerol ether phosphocholine
• Phosopholipid derived mediator
• Generated from phospholipids of
  neutrophils, monocytes, basophils,
  endothelium, and platelets by action of
  phospholipase A2
• Platelet stimulation (aggregation),
  vasoconstriction, and bronchoconstriction
• It is 10,000 times more potent than
              4- Cytokines

• Polypeptides - products of many cell
  types, principally activated lymphocytes
  and macrophages
• modulate the function of other cell types
• Produced during immune and
  inflammatory response
• Different cells are affected differently by
  the same cytokine (pleiotropic)

               Classes of Cytokines
1.       Cytokines that regulate lymphocyte function, such as
         activation, growth, and differentiation
     •     IL-2, which stimulates proliferation
     •     Transforming growth factor β, which inhibits lymphocyte
2.       Cytokines involved in innate immunity, that is, the
         primary response to injurious stimuli
     •     These include two major inflammatory cytokines TNF and IL-1
3.       Cytokines that activate inflammatory cells (in
         particular, macrophages) during cell-mediated immune
         responses, such as interferon-γ (IFN- γ) and IL-12
4.       Chemokines that have chemotactic activity for various
5.       Cytokines that stimulate hematopoiesis, including
         granulocyte-monocyte colony-stimulating factor (GM-
         CSF) and IL-3
Major effects of IL-1 and TNF
• Small (8-10 kD), structurally related proteins
  that act primarily as activators and
  chemotactants for subsets of leukocytes

• Unique combinations of chemokines recruit the
  particular cell populations present in a given
  inflammatory site (e.g., neutrophils vs.
  eosinophils vs. lymphocytes)

• Chemokines can stimulate hemopoietic
  precursor cells

• Recruit and activate mesenchymal cells such
  as fibroblasts and smooth muscle cells
• Many chemokines bind to extracellular matrix;
  their presence in the extracellular matrix
  maintain the chemotactant gradients necessary
  for the directed migration of recruited cells

• Chemokines mediate their activities by binding
  to specific G-protein-coupled receptors on target
  – Two of these chemokines receptors (called CXCR4
    and CCR) are important co-receptors for binding and
    entry of the human immunodeficiency virus (HIV) into

 Groups of chemokines classified according to the
arrangement of highly conserved cysteine residues
   –   Have one amino acid separating the conserved cysteines
   –   Act primarily on neutrophils
   –   IL-8 is typical of this group
   –   It is produced by the activated macrophages,
       endothelium, or fibroblasts, mainly in response to IL-1
       and TNF
• CC
   – Have adjacent cysteine residues and include monocyte
     chemotactant protein 1 (MCP-1) and macrophage
     inflammatory protein 1α (MIP-1 α)
   – Both are chemotactants for monocytes
   – Regulated on activation of normal T expressed and
     secreted (RANTES ----Regulated upon Activation,
     Normal T-cell Expressed, and Secreted). )
   – Chemotactic for memory CD4+ T cells and monocytes,
     and eotaxin (chemotactic for eosinophils)
     5- Nitric Oxide and
Oxygen-Derived Free Radicals
              Nitric Oxide
– Short-lived (seconds), soluble, free radical
  gas produced by a variety of cells and
  capable of mediating a bewildering number of
  effecter functions
– In CNS, it regulates neurontransmitter release
  as well as blood flow
– Macrophages use it as a cytotoxic metabolite
  for killing microbes and tumor cells
– In endothelium it activates guanylate cyclase
  in vascular smooth muscle, resulting in
  increased cyclic guanosine monophosphate
  (cGMP), and ultimately smooth muscle
  relaxation (vasodilation)
Nitric oxide synthatase
    Oxygen-derived free radicles
• Synthesized via the NADPH oxidase pathway
• Released from neutrophils and macrophages after
  stimulation by chemotactic agents, immune complexes,
  or phagocytic activity
• At low levels reactive oxygen species can increase
  chemokine, cytokine, and adhesion molecule expression
• At high levels, they cause (i) endothelial damage with
  thrombosis and increased permeability; (ii) protease
  activation and antiprotease inactivation; (iii) direct injury
  to other cells (tumor cells, erythrocytes, parenchymal
NADPH oxidase
                                    Myeloperoxidase (MPO)
2O2 + NADPH  2O2¯ + NADP + H¯
                                    Cl- + H2O2  HOCl¯ + OH
O2¯ + 2H+  H2O2

Antioxidants protective mechanisms to minimize toxicity
e.g., catalase, superoxide dismutase, and glutathione peroxidase
      6- Lysosomal Constituents
• Released after cell death, by leakage during the
  formation of the phagocytic vacuole, or by frustrated
  phagocytosis against large, indigestible surfaces

• Acid proteases have specific pH optima and are
  generally active only within phagolysosomes

• Neutral proteases are active in the extracellular matrix,
  and cause destructive, deforming tissue injury by
  degrading elastin, collagen, basement membrane, and
  other matrix proteins
            (elastase, collagenase, and cathapsin)

• Neutral proteases can also cleave C3 and C5 directly to
  generate the C3a and C5a anaphylactoxins and can
  promote the generation of bradykinin-like peptides from
• If the initial leukocyte infiltration is left unrestrained,
  substantial vascular permeability and tissue damage
  may result

• These effects are checked, however, by a series of
  antiproteases present in the serum and extracellular

• These include:
   – α2-macroglobin
   – Antiprotease α1- antitrypsin

• Deficiencies of these inhibitors may result in sustained
  activation of leukocyte proteases, potentially resulting in
  tissue destruction at sites of leukocyte accumulation
       7- Plasma Proteases
• Kinins
• Clotting system
• complement
    All linked by Hageman Factor (factor XII)
                                                                Injury !


                                                             Increased vascular
                                                             permeability &
HMWK                                                         leukocyte emigration

Bradikinin, like histamine, causes increased vascular permiability, arteriolar
dilation, and bronchial smooth muscle contraction – also causes pain
• Bradykinin
  – Increased vascular permeability, arteriolar
    dilation, and bronchial smooth muscle
  – It also causes pain
  – Short-lived because it is rapidly inactivated by
    degradative kininases present in plasma and
• Clotting system
  – The resultant factor XIIa-driven proteolytic cascade
    causes thrombin activation, which in turn cleaves
    circulating soluble fibrinogen to generate an insoluble
    fibrin clot
  – Factor Xa, an intermediate in the clotting cascade,
    causes increased vascular permeability and leukocyte
  – Thrombin participates in inflammation by enhancing
    leukocyte adhesion to endothelium and by generating
    fibrinopeptides that increase vascular permeability
    and are chemotactic for leukocytes
• Fibrinolytic system
  – Hageman factor also activates fibrinolytic system
  – Counter regulates clotting by cleaving fibrin –
    solubilize clot
  – Plasminogen activator released from endothelium,
    leukoctes, and other tissues
  – Kallikrein cleave plasminogen, a plasma protein
    bound up in the clot, to plasmin
  – Plasmin is multifunctional protease that cleaves fibrin
  – Fibrin degradation products increase vascular
    permeability, cleaves the complement C3 to C3a,
    resulting in vasodilation and increased permeability
  – Plasmin also activates Hageman factor
• The complement system (C1 – C9)
  – Present in the plasma in inactive form
  – Critical biological function of complement is
    the activation of C3
  – C3 cleavage occurs (i) via the classical
    pathway triggered by the fixation of C1
    antigen-antibody complex or (ii) through the
    alternate pathway, triggered by bacterial poly
    sacchrides ----

The structure of C1 and its role in interacting with
 anti bodies to initiate the classical complement
Classical Complement Pathway

                       (Classic C3 convertase)


 One molecule of
 C4b2b can split 200
 molecules of C3
 The Alternate Complement Pathway. Surface-bound C3b
may either be destroyed, as normally happens, or activated
         by the presence of an activating surface

                                       Surfaces deficient
                                       in sialic acid

Protease                                           Protease
Formation of poly C9
– Vascular effects:
  • C3a and C5a (anaphylatoxins) increase vascular
    permeability and cause vasodilation by causing
    mast cells to release histamin
  • C5a also activates lipoxygenate pathway of AA
– Leukocyte activation, adhesion, and
  • C5a activates leukocytes and increase affinity of
    their integrins, thereby increasing adhesion
  • It is also potent chemotactic agent
– Phagocytosis
  • C3b act as opsonin, by augmenting phagocytosis
    by cells bearing C3b receptors
• The significance of C3 and C5 (and their
  activation products) is further increased by the
  fact that they can also be activated by proteolytic
  enzymes present within the inflammatory
• They include lysosomal hydrolases released
  from neutrophils, as well as plasmin
• Thus chemotactic effect of complement and the
  complement activating effects of neutrophils can
  potentially can set up self-perpetuating cycle of
  neutrophil emigration
Inflammation Induced Tissue Injury
• Lysosomal enzymes leakage
• Reactive oxygen species leakage
• Products of AA metabolism
 Outcomes of Acute Inflammation
• Resolution
• Fibrosis / scarring
• Progression to chronic inflammation

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