Cell Injury ? Inflammation

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Cell Injury ? Inflammation
Bruce A. Fenderson, Ph.D. Jefferson Medical
College
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Inflammation movement of fluid and leukocytes
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Inflammation

• Inflammation is the reaction of a tissue and its
  microcirculation to a pathogenic insult.
• It is characterized by the generation of
  inflammatory mediators and the movement of fluid
  and leukocytes from the blood into extra-vascular
  tissues.
• The primary purpose of the inflammation response
  is to eliminate the pathogenic insult and remove
  injured tissue components.

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Basic Medical Terminology

• itis (eg hepatitis)
• oma (eg adenoma)
• emia (eg anemia)

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Possible Outcomes of Acute Inflammation

• Resolution
• Abscess (pus)
• Scar
• Persistent inflammation

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Cardinal Signs of Inflammation

• Rubor (redness)
• Calor (heat)
• Tumor (swelling)
• Dolor (pain)

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Acute Inflammation (Carbuncle)
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Mechanismsof Acute Inflammation

• Following injury, cytokines are released from
  tissues, inflammatory cells and microbes, an
  that change the structure of blood vessel walls
  leading to
• Leakage of fluid from the intravascular
  compartment (edema fluid).
• Emigration of leukocytes (polys/neutrophils) from
  the vascular space into the extravascular injured
  tissue.

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Acute Inflammation
Air spaces in lung filled with PMNs
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Neutrophils contain granules filled with powerful
enzymes and chemical mediators of acute
inflammation.
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Basic Medical Terminology

• Polymorpho-nuclear leukocyte
• PMN
• Poly
• Neutrophil
• By contrast, chronic inflammatory cells are
  lymphocytes, plasma cells macrophages.

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Mechanisms of Rubor - Tumor - Calor

• Vasodilatation of precapillary arterioles, which
  increases blood flow to the tissue, a condition
  known as hyperemia.
• Increase in permeability of endothelial cells
  (primarily postcapillay venule) results in
  leakage of fluid from the intravascular
  compartment into extravascular spaces (edema).

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(No Transcript)
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Increased Vascular Permeability

• Effusion (fluid accumulation in body cavity)
• Transudate (low protein and lipid)
• Exudate (high protein and lipid)
• Serous exudate (yellow color)
• Serosanguinous exudate (red color with RBCs)
• Fibrinous exudate (with fibrin precipitate)
• Purulent exudate (with neutrophils pus)
• Suppurative inflammation (associated with tissue
  necrosis and pus)

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Fibrinous and Purulent Exudates
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Chemicals that Regulate Inflammatory Edema Are
Derived From Both Cells and Plasma.
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Cell-Derived Mediators of Vascular Permeability

• Leukocytes (phospholipid metabolism generates
  arachadonic acid and metabolites via the
  cyclooxygenase and lipoxygenase pathways)
• Platelets (serotonin)
• Mast cells and basophils (histamine)
• Endothelial cells (PGI2 EDRF Endothelin)
• Monocytes/macrophages (PAF)

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Inhibitors of Arachidonic Acid

• Corticosteroids
• Nonsteroidal anti-inflammatory agents (NSAIDs -
  eg aspirin)

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Plasma-Derived Vasoactive Mediators

• Hageman factor (clotting factor XII)
• Plasmin and thrombin
• Plasma kallikrein and small kinins
• Complement systemproteins
• Classical pathway
• Alternative pathway
• Anaphylatoxins
• Bacterial opsonization

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Hageman Factor

• Hageman factor (clotting factor XII), generated
  within the plasma, provides an important source
  of vasoactive mediators.
• Hageman factor is activated by exposure to
  negatively charged surfaces, such as basement
  membranes, proteolytic enzymes, bacterial
  lipoplysaccharide.

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Hageman Factor Activation
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Complement System

• The complement system consists of a group of 20
  plasma proteins.
• They are integral part of the immune system and
  play an important role in host defense against
  bacterial infection.
• The activation cascade leads to the formation of
  lipid-soluble, pore-forming, macromolecular
  complex, termed the membrane attack complex.

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Anaphylatoxins

• Anaphylatoxins C3a, C4a, and C5a are important
  products of complement activation through the
  classical pathway.
• Each of these molecules has potent effects on
  smooth muscle and the vasculature including
  enhancement of smooth muscle contraction and
  vascular permeability.

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MAC
This slide illustrates how antibody and
complement proteins combine to target and kill
foreign cells via the MAC.
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Opsonization

• Bacterial opsonization is the process by which a
  specific molecule (e.g., IgG or C3b) binds to the
  surface of the bacterium.
• Coating of the pathogen with a molecule that
  enhances phagocytosis and the molecule is
  referred to as an opsonin.

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Leukocyte Accumulation

• The second phase of the acute inflammatory
  response involves the accumulation of leukocytes
  at sites of tissue injury via
• Margination of the cells along the vascular wall
  (mediated by selectins).
• Emigration through the vascular wall (mediated by
  integrins).
• Chemotaxis towards increasing concentrations of
  chemotactic agents.

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Leukocyte margination is mediated by carbohydrate
binding proteins called selectins..
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PMN Activation Pathways

• Neutrophil receptors react with
• Fc portion of IgG and IgM molecules
• Complement system components (C5a, C3b)
• Arachidonic acid metabolites (leukotriene B4)
• Chemotactic factors (IL-8)
• Cytokines (TNF)

G Protein Receptors JAK STAT Signaling NFKB
Transcription Factor Guanylate Cyclase
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Phagocytosis
NADPH Oxidase and Myeloperoxidase
Hypocholorous Acid
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Mechanisms of Phagocytosis

• Phagocytic cells exhibit anti-microbial
  activities that are oxygen independent,
  including
• Lysosomal hydrolases
• Defensins
• Lysozyme
• Phagocytic cells also generate toxic oxygen
  metabolites, including
• Hydrogen peroxide
• Hypochlorous acid

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Chronic Inflammation

• May occur as a sequel to acute inflammation or as
  a primary response to viral infection, autoimmune
  disease, or malignant neoplasm.
• Usually operates in conjunction with repair
  mechanisms - namely granulation tissue and
  fibrosis.
• Mediated by lymphocytes and macrophages.

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Granulomatous Inflammation

• Granulomatous inflammation is a mechanism for
  dealing with indigestible substances.
• It represents a failure of chronic inflammation
  to remove pathogens or foreign bodies.
• Granulomatous inflammation is mediated by
  macrophages, epitheliod cell, and lymphocytes.

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Granuloma and Langhans Giant Cell in Patient with
Tuberculosis
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Systemic Manifestations of Inflammation

• Fever (pyrogens - TNF? and IL-1)
• Shock (LPS, TNF)
• Leukocytosis (more leukocytes)
• Leukopenia (fewer leukocytes)
• Acute phase response (from Liver)

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Path Key Words

• Activation/Amplification
• Aspirin
• Cationic proteins
• Chemotaxis
• Complement system
• Degranulation
• H2O2-MPO-halide system
• Hageman factor
• Histamine
• Integrins

• Lymphocyte
• Membrane attack complex
• Opsonization
• Polymorphonuclear leukocyte
• Postcapillary venule
• Prostacyclin
• Pyrogen
• Thromboxane A2
• Tight junction