slides on inflammation by 8Vf0LQoW

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									Inflammation
          an overview


          Hal Hawkins, Ph.D.,M.D.
 Basic Human Pathobiology Course, PATH 6266
               May 10, 20010
Inflammation has been defined

   as the reaction to injury

    of vascularized tissue.
ACUTE INFLAMMATION includes:

      Vasodilation and vascular leakage
      Cellular:
          Recruitment
          Activation
          Functions
          Tissue Injury
MICROVASCULAR ENDOTHELIAL CELL
Histamine
Leakage of venules marked with colloidal carbon
(India ink) after application of histamine
Triple Response of Lewis:
Vascular reactions account
for the classical cardinal
signs of inflammation:
       Tumor – edema due to plasma leakage

       Rubor – dilation of arterioles and engorgement of
        microvasculature

       Calor – increased local temperature

       Dolor –probably due to stretching and
        prostaglandins
Julius Cohnheim, 1839-1884
Time course of acute inflammation
Neutrophil Recruitment:

   MARGINATION

  ADHERENCE

  EMIGRATION AND CHEMOTAXIS
Experiments of
Cohnheim:

 The tongue of the frog
 provides an opportunity to
 see the microcirculation
 and the movements of
 neutrophils.
Selectins (responsible for rolling)
Integrins

(essential for firm adhesion and emigration)
Integrin activation, in detail
Transient opening of intercellular junctions
ADHESION and TRANSMIGRATION:
    Redistribution of adhesion molecules to the
     neutrophil cell surface:
      P-selectin from endothelial granules
      Mac-1 (CD11b/CD18) from neutrophil granules
    Increased avidity of binding of Mac-1 and LFA-1,
     another neutrophil integrin: “activation of
     integrins”
    Induction of adhesion molecules on endothelium:
      E-selectin, ICAM-1, VCAM-1
Neutrophil emigration does not produce vascular leakage!




         (from Marchesi and Florey)
Neutrophil Activation:
    Receptors (complement, IgG, etc.)
    PAF (platelet activating factor)
    Phospholipase 
     Inositol triphosphate  Ca++ release
     Diacylglycerol  Protein kinase C
Platelet-Activating Factor, PAF
Chemotaxis:
Migration toward higher concentration
Important chemotactic factors:

     Complement fragment C5a
     Bacterial formylated peptides
     Arachidonic acid products,
       e.g. Leukotriene B4
     Cytokines, e.g. IL-8
Relative potencies of chemotactic factors
Priorities among chemotactic factors
COMPLEMENT:
a central mediator of
inflammation and
immunity
Complement components
From Abbas’ textbook
Neutrophil Functions:

              PHAGOCYTOSIS

              FUSION OF
               GRANULES

              BACTERIAL KILLING
Opsonization by complement
stimulates phagocytosis
Phagocytosis
The Neutrophil Oxidative Burst
Bacterial Killing:
    O2-, superoxide
    H2O2, peroxide
    HOCl, hypochlorous acid 
    OH•, hydroxyl radical
    Acid hydrolases (enzymes)
    Bactericidal proteins, defensins,
    lactoferrin, lysozyme
MEDIATORS of INFLAMMATION:

    Plasma proteases, e.g. complement
    Vasoactive amines, e.g. histamine
    Platelet-activating factor PAF
    Arachidonic acid metabolites, e.g.
     prostaglandin E3
    Reactive oxygen and nitrogen species
    Cytokines and chemokines, e.g. IL-8
    Neuropeptides and endothelin
Prostaglandins and leukotrienes
   Products of arachidonic acid metabolism
   Potent vasodilators/vasoconstrictors
   Cyclo-oxygenase (COX), needed for
    prostaglandin synthesis, is inhibited by aspirin and
    selective COX2 inhibitors including the notorious
    Vioxx
   Important in fever and pain
   Lipoxygenase leads to leukotrienes,
    proinflammatory lipids active in asthma
Inflammatory Tissue Injury
   O2-, superoxide
 H2O2, peroxide
 HOCl, hypochlorous acid
 OH•, hydroxyl radical
 ONOO-, peroxynitrite
(reactive oxygen and nitrogen species)

   Lysosomal neutral hydrolases
Neutrophil apoptosis:

   Follows emigration and phagocytosis

   Minimizes tissue injury
Regulation of neutrophil apoptosis

            DELAY:
                GM-CSF G-CSF
                LPS, IL-1, IL-2
                IFN-gamma


            STIMULATE:
                IL-6
                Phagocytosis
                Oxidative burst
    Apoptosis is the key to
    prevention of tissue injury

   Cellular contents may not be released

   Clearance by macrophages stimulates
    activation of macrophages to secrete factors
    favoring wound healing
HEALING AFTER INJURY:
Repair and fibrosis
   Proliferation and migration of surviving cells
       Depends on connective tissue matrix
   GRANULATION TISSUE - “proud flesh”
       Proliferating capillaries
       Fibroblasts, migrating and proliferating
       Follows inflammation, often coexists
       CONTRACTS to close wound
Granulation Tissue
finis

								
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