Lecture 3

Inflammation

Introduction to Inflammation

• Inflammation is a non-specific innate immune response to tissue injury.
• It is a part of the body's immune response.
• Purpose: to cause healing and resolve injury, destroy non-self agents, and form scar tissue (fibrosis).
• Physical characteristics:
  • Redness
  • Swelling
  • Heat
  • Pain
  • Loss of function

Changes in Vasculature

• Changes in vasculature (blood vessel wall) occur following injury.
• Release of inflammatory mediators (e.g., histamine).
• Histamine:
  • Causes vasodilation of blood vessels, increasing blood flow, leading to redness and heat.
  • Increases blood vessel permeability, allowing proteins and fluid to move to the extracellular space, causing swelling.

Acute (Short-Term) Inflammation

• Two major components:
  • Vascular events
  • Cellular events

Vascular Events

• Involve blood vessels.
• Release of histamine.
• Local blood vessels dilate.
• Local blood vessels become leaky.
• Accumulation of protein and fluid in the extracellular space.
• Inflammatory mediators released: bradykinin, prostaglandins, complement proteins.

Cellular Events

• Associated with cells.
• Resident macrophages entrap and kill pathogens, releasing chemical signals.
• Increased movement of WBCs (neutrophils and monocytes) into the infected area.
• Phagocytosis and destruction of foreign agents.

Cellular Events Associated with Inflammation

• Purpose: destruction of non-self agents.
• Act to bring WBCs to the inflamed tissue and kill the non-self agent.
• Steps:
  1. Margination of WBCs: move to the edge of blood vessels
  2. Tethering and rolling of WBCs: attaching of WBC to endothelial cells and slow rolling along the vessel
  3. Activation of WBCs and endothelial cells: involves expression of proteins on the surface of neutrophils and endothelial cells.
  4. Arrest/firm attachment of WBCs to endothelial cells: neutrophils bind to complementary proteins on endothelial cells and stop rolling.
  5. Emigration/diapedesis: WBCs squeeze between adjacent endothelial cells to exit the blood vessel and move into the tissue spaces.
  6. Chemotaxis of WBCs: WBCs move toward the site of inflammation by chemotaxis, a process of cell movement in response to specific molecules or chemical attractants.
  7. Recognition of “non-self” by WBCs: WBCs recognize foreign agents by recognizing chemical molecules on their surface.
  8. Phagocytosis of “non-self” pathogen by WBCs: foreign pathogens or bacteria are engulfed by neutrophils.

Migration of Neutrophils to the Site of Infection

*Slide shows the stages of Macrophage Movement from the Blood to the Tissues as listed in previous slide

Chemotaxis and Chemo-attractants

• Chemotaxis: the ability of WBCs to move against a concentration gradient (low → high concentration) in response to chemical factors; they move towards the source of a chemotactic substance.
• Chemotactic factors (chemo-attractants): chemical factors that attract WBCs to the site of inflammation.

Destruction of Non-Self Agent at the Site of Inflammation

Role of Phagocytes

• Phagocyte: a cell that can eat other non-self pathogens or dying cells by engulfing them with temporary cytoplasm-filled extensions of the plasma membrane (pseudopodia).
  • Examples: monocytes, macrophages, dendritic cells, and neutrophils.
• Steps involved in phagocytosis:
  1. Recognition of substance to be ingested: macrophages have cell-surface receptors that recognize certain molecules on the surface of various pathogens.
  2. Attachment of phagocyte to the substance to be ingested: this activates the process of phagocytosis.
  3. Pseudopodia reach around the substance and come together to form a phagosome inside the phagocytic cell.
  4. Fusion of the phagosome to a lysosome to form a phagolysosome.
  5. Destruction of ingested substance by lysosomal enzymes.
  6. Release of end products into the cell or out of the cell by exocytosis.

Recognition of Bacteria by Phagocytes

• Phagocytic cells (e.g., macrophages) have pattern recognition receptors or toll-like receptors.
• Receptors recognize a specific pattern of molecules expressed on bacteria, so they do not have to recognize a specific bacteria.

Role of Opsonization

• Opsonins:
  • Molecules added to the surface of a bacteria to help in speeding up the rate of phagocytosis by macrophages or other phagocytic cells
  • Produced by self or host body.
  • Opsonins may be antibodies or complement-type proteins.
• Opsonization: coating of the bacteria with opsonins (either antibodies or complement-type proteins) produced by the host body, which then facilitates the attachment and phagocytosis of the bacteria by the phagocytic cell.

Steps of Phagocytosis

*Slide shows the steps of phagocytosis again

Killing by Neutrophils

• Neutrophils:
  • Important in immune response.
  • Kill bacteria by:
    1. Oxygen-dependent process
    2. Oxygen-independent process
• Oxygen-dependent killing: corrosive oxygen free radical products are synthesized to destroy a foreign body.
• Oxygen-independent killing: use different bactericidal enzymes.
  • Lysozymes: enzymes which work inside phagolysozomes to degrade entire bacteria by proteolytic breakdown.
  • Lactoferrin: binds to iron and reduces iron in the environment so that bacteria cannot grow.
  • Defensins: drill holes on the surface of a bacteria.