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2 Cellular Infiltration The movement of cells from their original region to a new region is called cellular infiltration. In our case, this applies to the cells that migrate to the region of inflammation leaving their original position, this mainly applies to neutrophils and macrophages. At the early stages of the inflammation ( 24 hours) neutrophils would be the predominant cells seen, but they have a very short life-span (a maximum of 2 days) so after that macrophages become predominant. In allergic reactions and parasitic infections eosinophils are the main white blood cells involved. The actions of the 5 R processes (Recognition, Recruitment, Removal, Regulation, Resolution) are all coordinated through receptor systems. This system is now becoming a target for new therapies dealing with many diseases especially cancer. Phagocytosis The third R's (removal of the enemy) main mechanism is phagocytosis, the main function of neutrophils and macrophages. Following are the steps of phagocytosis: 1- Recognition and attachment to the enemy through receptors (mannose, TLRs, etc.). Opsonins are chemical mediators of phagocytosis that make the processes more effective. Some agents help in carrying this "Opsonisation" process [ Immunoglobulins and c-3b of the complementary system]. 2- Engulfment of the enemy. The white blood cells form pseudopodia surrounding the enemy and "eating" it. The enemy enters the cell in a vacuole called a "phagosome". The phagosome then fuses with a lysosome (contains enzymes that can kill the enemy). 3- Killing and degradation of the enemy is mainly using ROS (reactive oxygen species/radicals) in both neutrophils and macrophages. NO and H₂O₂ are also used, but the most potent killer in neutrophils is MPOhalide [Myeloperoxidase-halide] especially with bacteria. 2

3 Nitric Oxide It was discovered in mid 90's [this led to the discovery of the action of Viagra drug]. It is a soluble gas synthesised from arginine using nitric oxide synthase enzyme. This enzyme is present in many different cells and given a different symbol according to its location. enos = Nitric oxide synthase in epithelial cells, nnos = Nitric oxide synthase in neuronal cells, inos =Inducible Nitric oxide synthase, found in the liver.(الدكتور ما كان متأكد من األيخرر وحكى اشي ثاني تماما بس دورت علرها وطلعت شغلة ما النا فرها ( Note that when the macrophages are activated by cytokines e.g: IFN- or microbial products, inos induces the release of NO which reacts with superoxide radical O * to form radical peroxynitrite ONOO*. Granule Enzymes In monocytes and neutrophils these granules make part of the cells' normal structures. These granules are stored in the lysosomes and are divided to two types: 1- Primary: These are larger than the secondary granule enzymes and contain MPO and other enzymes. 2- Secondary: These are smaller than the primary granule enzymes and contain lysozyme and other enzymes. If these enzymes exit the cells then they can cause tissue damage so they are neutralised by inhibitors (the 4 th R, regulation) this step is important to minimise the tissue damage associated with inflammation, but the tissue damage is not removed completely, there always is some tissue damage associated with inflammation. These neutralising materials are coordinated through a feedback loop system األمراض ( deficiencies organised by the hypothalamus in the brain. Congenital α-1 can cause problems to the regulation step [e.g. (التي رحملها الشيخص منذ والدت antitrypsin deficiency]. Neutrophil Extracellular Traps (NETs) When a neutrophil dies it releases a viscous and thick substance that traps the pathogen and allows other white blood cells to attack the pathogens while localising the damage, this process is called NETosis. If there is a problem in NETosis sepsis can develop الدم) (تسمم [pneumonia can cause sepsis]. Most critical sepsis is the one caused by gram-negative bacteria, but any other bacteria can cause it. Dysfunction in neutrophils leads to an autoimmune disease; systemic lupus erythematosus (SLE). 3

4 Leukocytes Mechanisms of Inducing Injury Leukocytes may induce tissue injury and turn an acute inflammation into a chronic one via one of the 3 following mechanisms: 1- Prolonged inflammation: this could be due to the pathogen being virulent so the inflammation stays for a longer period. This is seen in tuberculosis and hepatitis. [Side Note: The main cause of chronic liver disease is hepatitis C in middle east, in the western world it is alcohol]. 2- Inappropriate inflammatory response: autoimmune diseases lead to attacking one's own cells. 3- Exaggerated response: asthma and allergic reactions are good examples in which the body over-reacts to normal things it must not be responding to in the first place. [in such situations anti-histamines are given to the patient as histamine is the main molecule behind inflammation]. Functions of Activated WBC's Cytokines produced by the WBC's amplify (usually at the beginning of the inflammatory action) or inhibit (usually towards the end of the inflammatory action) the effect of the reaction. Growth factors are released by WBC's and aid in the repair process by stimulating the production of collagen fibers from fibroblasts (fibrosis). A T-lymphocyte, namely T-helper 17, produces interlukin-17 which plays a role in acute inflammation and a deficiency in this lymphocyte can cause diseases. Turning Mediators Off The inflammation mediators cannot remain active forever, this would damage the body and disrupt its homeostasis greatly. There are 7 mechanisms in which the inflammation mediators' work is stopped (this is for acute inflammation): 1- Mediators are produced in rapid bursts, so they also are "used up" quite quickly. 2- The mediators presence is stimulus dependent, if we remove the stimulus the mediators are gone. 3- They have short half-lives. 4- Enzymes degrade these mediators after they are released. 4

5 5- Polymorphonuclear leukocyte (PMN, a granular leukocyte) has a short half-life and quickly dies by apoptosis. 6- Signals to produce the mediators are stopped. 7- Neural inhibitors inhibit the production of the mediators. Mediators of an Inflammation The following mediators are produced from macrophages, dendritic cells and mast cells: General features of Mediators Are mostly produced by the cell at the site of the inflammation (can be released by granules from a different place and move to the site of مو هرك السالردات بتحكي بس هرك الدكتور حكى occasions. inflammation in rare (بالمحاضر Plasma proteins are usually in an inactive state and need to be activated. Active mediators need to be stimulated Mediators have short life spans (نفس الحكي اللي في النقطة األولى it, One can activate the other (or inhibit [Kinins is one of the important mediators for it causes vasodilation, increases vascular permeability, brings about smooth muscle contraction and gives a pain sensation]. Arachidonic Acid Some of the metabolites (products of the reactions) of arachidonic acid play a role in inflammation. This diagram shows all the metabolic pathways (that we are concerned with) of arachidonic acid (the small red arrow next to some enzyme names points to the name of the inhibitor of that enzyme): 5

6 Apparently the bold names are to be memorized (with their functions), doctor paid a lot of attention to the first enzyme (phospholipase), which forms the arachidonic acid, and its inhibitor (steroids). Explaining the above picture: Prostaglandins and thromboxanes. Products of the cyclooxygenase pathway include prostaglandin E2 (PGE2), PGD2, PGF2α, PGI2 (prostacyclin), and thromboxane A2 (TXA2), each derived by the action of a specific enzyme on an intermediate. Some of these enzymes have a restricted tissue distribution. For example, platelets contain the enzyme thromboxane synthase, and hence TXA2, a potent platelet-aggregating agent and vasoconstrictor, is the major prostaglandin produced in these cells. Endothelial cells, on the other hand, lack thromboxane synthase but contain prostacyclin synthase, which is 6

7 responsible for the formation of PGI2, a vasodilator and a potent inhibitor of platelet aggregation. The opposing roles of TXA2 and PGI2 in hemostasis are discussed further in Chapter 3. PGD2 is the major metabolite of the cyclooxygenase pathway in mast cells; along with PGE2 and PGF2α (which are more widely distributed), it causes vasodilation and potentiates edema formation. The prostaglandins also contribute to the pain and fever that accompany inflammation; PGE2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever. Leukotrienes. Leukotrienes are produced by the action of 5-lipoxygenase, the major AA-metabolizing enzyme in neutrophils. The synthesis of leukotrienes involves multiple steps (Fig. 2 16). The first step generates leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages and is a potent chemotactic agent for neutrophils. LTC4 and its subsequent metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause bronchoconstriction and increased vascular permeability. Lipoxins. Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes. Platelets that are activated and adherent to leukocytes also are important sources of lipoxins. Platelets alone cannot synthesize lipoxins A4 and B4 (LXA4 and LXB4), but they can form these mediators from an intermediate derived from adjacent neutrophils, by a transcellular biosynthetic pathway. By this mechanism, AA products can pass from one cell type to another. Anti-inflammatory Drugs That Block Prostaglandin Production. The central role of eicosanoids in inflammatory processes is emphasized by the clinical utility of agents that block eicosanoid synthesis. Nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin and ibuprofen, inhibit cyclooxygenase activity, thereby blocking all prostaglandin synthesis (hence their efficacy in treating pain and fever). There are two forms of the cyclooxygenase enzyme, COX-1 and COX-2. COX-1 is produced in response to inflammatory stimuli and also is constitutively expressed in most tissues, 7

8 where it stimulates the production of prostaglandins that serve a homeostatic function (e.g., fluid and 8 electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). By contrast, COX-2 is induced by inflammatory stimuli but it is absent from most normal tissues. Therefore, COX-2 inhibitors have been developed with the expectation that they will inhibit harmful inflammation but will not block the protective effects of constitutively produced prostaglandins. These distinctions between the roles of the two cyclooxygenases are not absolute, however. Furthermore, COX-2 inhibitors may increase the risk for cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGI2), an inhibitor of platelet aggregation, but leave intact the COX-1 mediated production by platelets of TXA2, a mediator of platelet aggregation. Glucocorticoids, which are powerful anti-inflammatory agents, act in part by inhibiting the activity of phospholipase A2 and thus the release of AA from membrane lipids. 8