Histamine, Prostaglandin, Leukotrienes, Bradkinin, PGE2 LTB4 Chemotactic Factors

There are a groups of inflammatory signals that play key roles in the early phases of acute inflammation. These signals cause the cardinal signs of inflamation and are involved in the inflammatory mechanism. The Cardinal Signs of Inflammation are the signs and symptoms that results directly from acute inflammation. * Fever is associated with inflamation and is caused by the release of PGE2 (Prostaglandin E2), however it is not a cardinal sign of inflammation. Histamine is released from mast cells in response to cell injury, complement activation, or membrane bound IgE being crosslinked by antigen. Histamine then increases venule permeability, dilates the arterioles and prepares the vessel wall for neutrophil extravasion. In other words, Histamine is the main signal that initiates the fluid phase (But it gets helps from other cytokines). Histamine is the mediator of type 1 hypersensitive reactions (anaphylaxis & allergies) and signals stomach acid to be secretion. Antihistamines that primarily antagonize the H1 Histamine receptors are used to treat allergic symptoms, while antihistamines that primarily antagonize the H2 Histamine receptor are used to treat things like GERD and Peptic Ulcer Disease. Histamine has the help of other signals during acute inflammation. Following injury, Coagulation Factor XII (Hageman Factor) is activated by exposed collagen in the vessel wall. Factor XII then initiates the Kinin-Kallikrein System that creates Bradykinin. Bradykinin plays an important role in pain, arteriole dilation and increased venule permability during acute inflammation. We will cover elsewhere the effect coagulation factor 12 has on clotting. Angiotensin Converting Enzyme (ACE) breaks down bradykinin. Therefore, ACE Inhibitors increase bradykinin levels which can cause cough, angioedema and vasodilation. Arachidonic Acid is created when cell membrane phospholipids are acted upon by Phospholipase A2. Arachidonic Acid which is acted upon by Cycloxygenase to create Prostaglandins or Lipoxygenase to create Leukotrienes. Both classes of signal molecule play a role in acute inflammation by contributing to the fluid phase (arteriole dilation and venule permeability). PGE2 (Prostaglandin A2) is involved in the signaling process for pain and fever. LTB4, a specific type of leukotriene, is also a Chemotactic Factors which means it attracts neurtophils to the site of injury (AKA leukocytosis). The other main Chemotactic Factors are IL-8 and C5a. We will discuss prostaglandins and leukotrienes in many other videos as they are involved with the pathophysiology and treatment of many disease. Leukotrienes are involved in the pathophysiology of Asthma and their action is antagonized by receptor blocker Montelukast. Both class of molecule can be reduced to lessen the pain and inflammation. Corticosteroids inhibit Phospholipase A2 to decrease the levels of prostaglandins and Leukotrienes. NSAIDs inhibit Cyclooxygenase to decrease prostaglandin levels. Synthetic prostaglandins can be used to keep a Patent Ductus Arteriosus open in a newborn (if they have a congential heart defect that requires that route of blood flow), while an NSAID like Indomethacin can be used to close a PDA. Nuetrophils are the predominant inflammatory cell in acute inflammation. They phagocytose (engulf) infected or necrotic cells and use free radicals to destroy them. They also release granules full of proteins and enzymes that help fight infection or clear cellular debris. Neutrophils are attracted to and activated by chemotactic factors (Leukotriene B4, C5a, and Interleukin-8) created during acute inflammation. Neutrophil extravasation (AKA Leukocyte extravasation) is the process by which neutrophils exit the circulatory system into the damaged tissue. Later in the inflammatory process Macrophages use these same steps to get to the effected tissue. Pictures Used: • Derivative of “Leukozytenmigration 01” by Armin Kübelbeck available at http://commons.wikimedia.org/wiki/Fil… via Creative Commons Attribution • “Lips Mouth Smile Teeth Happy Laugh Red White” available at http://pixabay.com/en/lips-mouth-smil… via Public Domain