Comprehensive Notes on the Inflammatory Response and Plasma Protein Systems

Overview of Inflammatory Response and Plasma Protein Systems

• The inflammatory response and plasma protein systems are complex defensive mechanisms involving vascular and cellular components.
• The lecture focuses on the inflammatory response, specifically the clotting and fibrinolytic cascades, with brief mentions of the coagulation and complement systems.

Cellular Mediators in the Tissue and Blood

• Skin Cells: Act as the initial anatomical barrier.
• Capillaries: Small blood vessels where the inflammatory process facilitates the movement of immune cells into the interstitial space. Walls are composed of epithelial cells.
• Dendritic Cells:     - Do not belong to the neurovascular system or the brain.     - Function as a main antigen-presenting complex.     - Acts as phagocytes that eat bacteria and present them to white blood cells to speed up destruction.
• Mast Cells:     - Located near the skin surface.     - Responsible for releasing histamine.     - Degranulation or desensitization of mast cells can be triggered by physical injury, chemicals, or immunologic invaders.
• White Blood Cells (Leukocytes):     - Circulate in the blood and move to sites of infection.     - Neutrophils: The most abundant white blood cell, making up $75\%$ of all circulating white blood cells. They are the primary responders that attach to antigens presented by dendritic cells.     - Macrophages: Large molecules that engulf and destroy bacteria; they may be attached to antibodies on their cell membrane or exist as free immunoglobulins.
• Platelets:     - Bits and pieces of broken-up cells called megakaryocytes.     - Megakaryocytes are one of the $10$ types of cells produced in the bone marrow.     - Platelets create a platelet plug to limit bleeding, but they require a mesh-work (fibrin) to hold the plug in place.

The Role of Histamine and Vascular Changes

• Histamine Functions:     - Causes classic allergic symptoms: runny nose, teary eyes, sneezing, and coughing.     - Increases cell permeability: It generates gaps between the epithelial cells of the capillary walls.     - Causes vasodilation: Dilation of the vessels increases blood flow to the site of injury.
• Vascular Components of Inflammation:     - Hemostasis: The first step is vasoconstriction to limit blood loss.     - Active Inflammation: Follows vasoconstriction. Vasodilation occurrs due to histamine release.     - Blood Pooling: Increased blood pressure and blood flow to the local area cause the redness and heat associated with inflammation.
• Cell Migration:     - Margination/Sticking: Proteins on the inside of the capillary wall cause white blood cells to stick to the wall.     - Extravasation: The process where white blood cells slide through the gaps in the capillary wall into the interstitial space.

Prostaglandins and Leukotrienes

• Leukotrienes:     - Vasoactive amines composed of short-chain proteins.     - Act as bronchoconstrictors and stimulate airway mucus secretion.     - Highly effective at increasing the permeability of post-capillary vessels.
• Prostaglandins:     - Derived from arachidonic acid (which is also derived from lactic acid).     - Consists of a group of approximately $20$ different lipids attached in a ring structure.     - Active in the inflammatory response and primarily responsible for pain perception.

Plasma Protein Systems: The Complement System

• A complex system found in blood plasma that complements the immune system.
• Operates as a positive feedback loop.
• C3 Complement: Circulates in the blood and is produced via two pathways:     - Classic Pathway: Triggered by an antigen-antibody complex binding to a complement component.     - Alternate Pathway: A separate trigger mechanism.
• C3B: Once activated, it coats the outside of the foreign cell, making it easier for macrophages to engulf the target.
• C4A and C5A: Stimulate smooth muscle contraction and increase vascular permeability.
• MAC (Membrane Attack Complex):     - The final product of the complement system.     - Perforates the bacteria by creating a tube or channel through the cell membrane.     - Allows fluid to enter the cell, causing the bacteria to swell and burst (cell lysis).

The Coagulation (Clotting) Cascade

• The primary goal is the formation of a blood clot via a fibrin network.
• Fibrin (Clotting Factor I):     - A small complex that is self-adhesive.     - If active fibrin were always present, it would create unnecessary networks throughout the body.
• Fibrinogen: The inactive form of fibrin that circulates in the blood with a protective "capsule" to prevent unneeded attachment.
• Thrombin (Clotting Factor II):     - Produced at the site of injury.     - Cleaves the "capsule" off fibrinogen to convert it into active fibrin.
• Triggering Inflammation: Inflammation is a direct trigger for the clotting cascade and fibrin formation.

Fibrinolysis and Clinical Applications

• Fibrinolysis: The process of dissolving a clot once a vessel has repaired itself.
• Plasmin: The active enzyme that dissolves fibrin.
• Plasminogen: The inactive form of plasmin circulating in the body.
• tPA (Tissue Plasminogen Activator):     - A drug used for stroke and cardiac patients.     - It activates plasminogen to become plasmin to break up life-threatening clots.

The Kinin System and Hagman's Factor

• Kinin System: Leads to the formation of vasoactive proteins like bradykinin and kallikrein.
• Kallikrein: An enzyme found in blood, plasma, urine, and tissues in an inactive state. When activated, it helps form bradykinin.
• Bradykinin:     - Increases vascular permeability.     - Dilates blood vessels.     - Stimulates the production of prostaglandins (inducing pain).
• Hagman's Factor (Factor XII):     - A clotting factor that triggers the intrinsic part of the clotting cascade.     - It is activated when blood is exposed to collagen or other sub-endothelial substances.

Vessel Anatomy and Aspirin Mechanism

• Vessel Layers:     - Tunica Adventitia: The outermost layer.     - Tunica Media: The middle layer, primarily containing collagen.     - Tunica Intima: The innermost layer (endothelium).
• Collagen: A sticky substance in the tunica media. If the intima is damaged, blood contacts collagen, causing platelets to stick and form a clot.
• COX-2 (Cyclooxygenase-2):     - A protein coating/enzyme on the outside of red blood cells and platelets that allows them to attract each other.
• Aspirin (Acetylsalicylic Acid):     - Acts as a COX-2 inhibitor.     - By inhibiting this protein, aspirin makes the cells "slippery," preventing them from sticking together to form clots.

Phases and Signs of Inflammation

• Intravascular Phase: Leukocytes move to the sides of blood vessels and attach to endothelial cells.
• Extravascular Phase: Leukocytes travel through the wall to the site of inflammation to kill organisms.
• Cytokines: Chemical signals that affect other cells.     - Interleukins: Attract white blood cells to a specific site of injury.     - Interferon: Produced by cells infected by viruses or cancer. It is released via exocytosis to warn neighboring cells and prevent the virus from replicating.     - Lymphokines: Stimulate leukocytes; includes Macrophage Activating Factor, which signals macrophages to engulf and destroy bacteria.
• Clinical Signs:     - Redness and Heat: Caused by increased blood flow and vasodilation.     - Swelling: Caused by plasma leaking into the tissues and the engorgement of blood.     - Pain: Caused by the release of prostaglandins.     - Pus: Composed of dead white blood cells after the infection is resolved.
• Phagocytosis Process:     - The macrophage engulfs the antigen, creating an encapsulated lymphoblast.     - The antigen is broken down and then presented on the cell surface for recognition by helper T cells, starting the broader immune activation.