Inflammation - Can't Live with it, Can't live without it!

Inflammation is a response to injured tissue.   By pathogens (E.g. bacteria, viruses, fungi, parasites), toxins/chemicals (E.g. air particulates), physical injury, burns, or by an overzealous immune system. Without inflammation, infections (incl. bacterial, viral, fungal and parasitic) would go unchecked and wounds (E.g.trauma, surgery, burns, damage inflicted by a saber tooth tiger!) would never heal

When you "catch" a cold (actually a viral infection) your throat becomes sore, your eyes water, and your sinuses are congested.  These are the physical signs of inflammation as fluid and cells build up, as a result of the immune system's fight against a hostile invader.

Inflammation is characterized by increased blood flow to the tissue causing:

✔ Increased temperature

✔ Redness

✔ Swelling.    As blood vessels leak fluid into surrounding tissues,  a process that helps isolate any foreign substance.

✔ Pain

Mast cells are key players in initiating inflammatory process

-   Found in tissues

-   Their surface is coated with a variety of receptors.   When engaged by the appropriate ligand (E.g. LPS/Endotoxin of Gram-negative bacteria, peptodoglycan of Gram-positive bacteria), it triggers release of granules (by exocytosis), some discharging their inflammatory mediators immediately, others later.

-   Mast cell cytoplasm is loaded with granules containing potent mediators of inflammation.   Dozens of these are released when stimulated by the immune system, which recruit all types of white blood cells to the site, many of which are activated to produce their own inflammatory mediators.

•  Monocytes.   They become macrophages (“big eaters”) when they leave the blood and enter the tissue

•  Neutrophils.    Squeeze through capillary walls and into infected tissue to kill invaders and then engulf the remnants by phagocytosis;

•  Antigen-presenting dendritic cells.   Main function is to process antigen material and present it on the cell surface to the immune system's T-cells, thereby acting as messengers between the innate and the adaptive immune systems).

•  All kinds of lymphocytes:

Natural Killer (NK) cells.    Specialized to kill certain types of target cells (esp. virally infected or cancerous host cells) in innate (1^st line of defense) immunity

B-cells and T-cells - leading to an adaptive immune response (2^nd line of defense);

•  Eosinophils.    Blood levels increase sharply with parasitic worm infections. Eosinophils release the cytoxic contents of their granules on the invader.

Some of the better known inflammatory mediators released by mast cells

 (which initiate inflammation or deal with the damage)

-   Histamine

✔ Released from mast cell granules in nearby connective tissues

✔ Increases blood flow to the area and the leakage of fluid, pathogen-fighting WBCs and proteins from the blood into the tissue space

✔ Produces redness, warmth and swelling

-   Bradykinin

✔ Produced from an inactive precursor always circulating in the blood

✔ Dilates blood vessels /lowers blood pressure (by stimulating NITRIC OXIDE), and increases blood vessel permeability.   To allow needed blood components to enter the tissue space; ACE inhibitor drugs reduce blood pressure by increasing bradykinin

✔ Contracts airway smooth muscle, is a potent bronchial vasodilator, stimulates mucus secretion and coughing.    Bradykinin activates release of neuropeptides from sensory nerves in airways, leading to reflex bronchoconstriction, coughing and neurogenic inflammation

Fuller RW, Dixon CM, Cuss FM, Barnes PJ. Bradykinin-induced bronchoconstriction in humans. Mode of action. Am Rev Respir Dis. 1987 Jan;135(1):176-80. PubMed

✔ Like histamine, effects produce redness, warmth and swelling

✔ Involved in pain mechanism

✔ Stimulates phospholipase.   Increases the production of prostaglandins (local “hormones”)

-   Prostaglandins, Leukotrienes

✔ Potent mediators of inflammation.   These hormone-like messengers are derived from specific dietary essential fats (EFAs) in local cell membrane phospholipids. Consuming a balance of both inflammatory (most omega-6 fats) and anti-inflammatory (omega-3 EPA and DHA, and omega-6 GLA) fatty acids will ensure a balanced response when dealing with injured tissue;

EFAs ==► Local Hormones - First Response Team

-   Tumor Necrosis Factor-alpha (TNF-α)

✔ Large amounts released by stimulated mast cells

 ✔ TNF-α used to regulate immune cells.    Induce fever, apotosis (natural cell death), sepsis (via IL1 & IL6 production), cachexia, inflammation and to inhibit tumorigenesis and viral replication

-   Reactive Oxygen Species (ROS)

✔ All inflammatory cells have receptors for TNF-α and are activated by it to synthesize more on their own.    This positive feedback quickly amplifies the response.

✔ Produced by activated phagocytes: macrophages and neutrophils

✔ Toxic to microorganisms, but can also lead to tissue injury

-   Interleukin-1 (IL-1)

✔ This cytokine is released by macrophages, monocytes and activated platelets

✔ Has paracrine effects on cells in the local vicinity:

▪ Causes cells to produce tissue factor to trigger blood clotting;

▪ Stimulates synthesis/secretion of other interleukins

▪ Helps activate T-cells in the adaptive (2nd line of defense) immune response;

✔ Has endocrine (hormonal) effects via the blood:

▪ Decreases blood pressure

▪ Induces fever (stimulates prostaglandinrelease, which affect hypothalamic temperature control);