Lecture 2: Inflammation

Inflammation

UNIT OUTCOMES:

  • Examine the body’s key defense mechanisms and outline the vascular and cellular change associated with inflammation

  1. Human Defenses (3): lines of defense can overlap each other

    • PHYSICAL BARRIERS & SECRETION: prevents outside particles from getting inside your body

      • E.g. skin, mucous membrane, secretions (tears, sweat, saliva, acidic gastric secretions), normal flora (healthy bacteria)

    • INFLAMMATORY RESPONSE: localized, non-specific response triggered when tissues are injured or foreign material is identified in the body

      • Conditions usually end in -itis

    • ADAPTIVE IMMUNE RESPONSE:highly specific, systemic rxn typically in response to an antibody-antigen association

      • Has memory

      • Systemic = whole body rxn

*the first 2 lines of defense are part of our innate immune response*

*INNATE: always ready to go*

*ADAPTIVE: have to get exposed to a pathogen to build immunity defenses*

  1. ACUTE INFLAMMATORY RESPONSE: activated by MAST CELLS!

    • Responds to cell injury, to:

      • remove cause

      • remove damaged tissue

      • initiate tissue repair

    • Response is immediate (seconds)

      • May last for 8-10 days

      • Chronic inflammation not good >> around 2 weeks

    • MAST CELLS >> guard dogs

      • Recognize foreign particles >> make chemical noise

      • Derived from the same stem cells as basophils (Never.Let.M.onkeysEat.Bananas)

        • Neutrophils, Leukocytes, Monocytes,Eosinophils, basophils

      • Typically located at site pathogen used to enter body

        • Near skin surfaces

        • Mucous membrane

        • Around blood vessels

  2. MAST CELLS: initiate acute inflammatory response

    • Contain stores of inflammatory chemicals (e.g. histamine) in visible granules

  3. MAST CELL DEGRANULATION (VASCULAR STAGE):

    • DEGRANULATION: Emptying of pre-formed granules containing histamine and chemotactic factors to ECM (mast cells release degranulators)

      • Pre-formed biochemical mediators that work immediately:

        1. Histamine

        2. WBC chemotactic factor

        3. Other cytokines

    • Release of HISTAMINE: (3 rxns)

      1. Blood vessel dilation: increases blood flow to area = more cell and protein to areas

        • causes redness and warmth

      2. Capillary endothelial retraction: Leads to space forming between the cells > allows cells and proteins to enter tissue (exudation)

        • RBCs, leukocytes, platelets, and clotting factors

        • Limit the spread of m/o

        • We see edema, pain, and impaired fxn

      3. Mucus production: Traps the foreign objects

    • Release of chemotactic factors: “chemo” = chemical; “taxis” = movement

      1. Chemotaxis: Attracts NEUTROPHILS and EOSINOPHILS to the site of injury towards area of higher concentration of signal

        • Different WBCs

        • Chemotactic factors leave a bread crumb trails for WBCs to follow

        • These WBCs act like phagocytes! >> Eat up dead cell, debris >> clean up the area

          • NEUTROPHILS are first PHAGOCYTES to show up to the area >> v important for acute inflammation

            • Most abundant WBC >> call other WBCs

            • Short-lived (10h), die, removed as pus


  4. EOSINOPHILS: are important for parasitic inflammation

    • MONOCYTES/MACROPHAGE: travel as monocytes; become macrophages in tissue (similar fxn as neutrophile)

      • Arrive later >> 2-7 days

      • Increased number during _______


  5. MAST CELL SYNTHESIS:

    • Synthesis of Membrane-Derived Lipid Mediators

      • Membrane lipid metabolism takes place over minutes – what is the importance of this?

        • Prolonged inflammation

      • Synthesis of 3 important inflammatory chemicals:

        1. Leukotrienes: Produced from phospholipids, converted to arachidonic acid

          • Similar vascular effects as histamine, but…SLOWER + PROLONGED:

increase vascular permeability

induce blood vessel dilation

  • Also promotes neutrophil and eosinophil chemotaxis

    1. Prostaglandins: Like leukotrienes, derived from phospholipids, converted to arachidonic acid and then into prostaglandins

      • Prolonged “histamine-like” effects: INDUCE PAIN by directly acting on neurons

  1. increase vascular permeability

  2. induce blood vessel dilation

    • platelet activation factor (PAF): Produced from phospholipids mainly by mast cells (but also by other WBCs)

      • Similar effects to histamine, with an emphasis on activating platelets (hemostasis -- BLOOD CLOTTING)

  3. ACTIVATION OF MAST CELLS: 2 Responses

    1. Vascular Response: Involves the arterioles, capillaries and venules of microcirculation >> vasodilation, endothelial cell retraction

      • Causes ⬆microvasculature permeability at site of inflammation causing protein-rich fluids to fill extravascular space

      • Activates 3 main plasma protein proenzyme systems:

        1. Complement system - OPSONIZATION - “Tags” bacterial capsules with proteins and renders it susceptible to phagocytosis

          • Act as anaphylatoxin >> Causes degranulation of mast cells and increases inflammatory response

          • Cause direct death of pathogen >> Acts as membrane attack complex and perforates bacterial cell membrane

        2. Clotting system: Activated by cell injury as well as bacterial products

          • Activating fibrinogen causes the production of ______ that forms insoluble clot

          • Prevents spread of infection and stops bleeding

        3. Kinin system: Activation similar to clotting system

          • Bradykinin:

Induces pain (along with PGs)

Promotes leukocyte chemotaxis

Prolonged phase of inflammation with histamine-like effects: Dilates blood vessels and increases vascular permeability

  • Cellular Response:

    • Involved cells:

      1. mast cells (basophils)

      2. neutrophils

      3. monocytes, macrophages

      4. eosinophils

      5. lymphocytes + NK cells

      6. Platelets

    • WBCs normally circulating in the blood

    • Stimulated by inflammatory responses and cell injury to produce adhesion molecules and migrate into the local tissue (chemotaxis)

    • MARGINATION (pavementing): WBC sticks to the endothelial cells lining the blood vessels

    • Diapedesis (exudation): Move between retracted endothelial cells

      1. Migrate to inflammatory site - chemotaxis

  1. LOCAL MANIFESTATION

    • Cardinal signs of inflammation (PRISH)

      • Pain: stimulation of nerve endings

      • Redness: capillary dilation (hyperemia) >> increase in heat

        • Bring more O2, nutrients, and WBCs

      • Impaired fxn >> edema >> joint stiffness

      • Swelling (edema) >> increase blood vessel permeability

        • Extravasation of vascular proteins, including ______ >> water follows and moves into tissues

  2. HEAT >> SYSTEMIC MANIFESTATIONS

    • Fever: usually accompanied by malaise, fatigue, anemia

    • Leukocytosis: primarily of _________

    • Increased plasma proteins

    • Muscle catabolism

  3. Chronic Inflammation:

    • Caused by a relatively milder, more persistent stress or injury

    • Characteristics of chronic inflammation:

      • Lasts _______ or longer (>years)

      • Less hyperemia, less edema

      • Primarily lymphocytes and macrophages

      • More fibrosis, less exudate

      • Could have granuloma formation (walled off site with fibrous deposits)