Immune Response and Inflammation PDF

Acute and Chronic inflammation Dr. Inas Almazari Clinical Pharmacy Zarqa University  Inflammation The inflammatory response is a complex, multistep reaction involving the accumulation of phagocytes and plasma proteins at a site...

Acute and Chronic inflammation Dr. Inas Almazari Clinical Pharmacy Zarqa University  Inflammation The inflammatory response is a complex, multistep reaction involving the accumulation of phagocytes and plasma proteins at a site of infection, toxin exposure, or tissue injury. The purpose of this response is to: – Isolate, destroy or inactivate infectious microbes – Remove tissue debris – Promote tissue repair  Inflammation The cardinal signs or symptoms of inflammation include: Rubor  redness due to increased blood flow to the affected area Tumor  Swelling due to increased capillary permeability and fluid accumulation in the affected area Calor  increased temperature (Heat)  as a result of increased blood flow. Dolor  Pain Functio laesa  altered or impaired function of the affected area  Inflammation The inflammatory response involves a series of steps that are similar in most instances. – Defense by tissue macrophages – Localized vasodilation – Increased capillary permeability – Localized edema – Walling-off the inflamed area – Infiltration of phagocytes  Defense by tissue macrophages A small number of macrophages can be found in the body’s tissues at any given time. These macrophages provide the first step in protection from infection by phagocytizing invading microbes.  Localized vasodilation Vasodilation of arterioles increases blood flow to the affected area, resulting in the increased delivery of phagocytes and plasma proteins, and is caused, primarily, by histamine released from activated mast cells as well as by activated bradykinin. Mast cells are found in connective tissues, particularly in areas of potential microbial entry to the body such as the lungs, skin, and gastrointestinal tract. Vasodilation in the inflamed area leads to redness and heat.  Increased capillary permeability In addition to vasodilation, histamine and bradykinin cause the pores between the endothelial cells to increase in size, resulting in an increase of capillary permeability and the movement of plasma proteins into the tissue spaces.  Localized edema Vasodilation and increased capillary permeability lead to localized edema. Vasodilation and increased blood flow lead to an increase in capillary pressure (Pc). Furthermore, the presence of escaped plasma proteins within the tissue spaces leads to an increase in interstitial fluid colloid osmotic pressure (πi). The increase in Pc and πi → fluid moves out of the capillaries and accumulates in the tissue. In addition to redness and heat (due to increased blood flow), symptoms of edema include swelling and pain (due to distension of the tissue).  Walling-off the inflamed area Several types of plasma proteins (clotting and anticlotting factors) escape from the vascular compartment and enter the tissue spaces. The inactive plasma protein fibrinogen is converted into the active fibrin, which forms clots within the tissue spaces. This effectively walls off the injured area and prevents or delays the spread of infection. Subsequently, anticlotting factors, which are activated more slowly, dissolve these clots when they are no longer needed.  Infiltration of phagocytes Increased numbers of phagocytes are needed to engulf and destroy infectious microbes, remove tissue debris, and prepare the injured area for healing and repair. This step is facilitated by the increase in blood flow and the increase in capillary permeability. Neutrophils arrive first, typically within 1 hour. Monocytes arrive within 8–12 hours and proceed to swell and mature into macrophages within the next 8–12 hours. The emigration of phagocytes from the vascular compartment, toward the injured area, involves three steps: 1. Margination: phagocytes adhere to the endothelial cells of the capillary wall. 2. Diapedesis: phagocytes squeeze through the capillary pores and enter the tissue space. 3. Chemotaxis: phagocytes move through the tissue up a concentration gradient of chemotaxins that are released at the site of injury.  Opsonization Opsonization is the process by which bacteria are marked for phagocytosis. The two most important opsonins, or chemicals, that bind to and label the bacteria, are antibodies and complement protein C3b. Opsonization by way of C3b is a form of innate immunity. The concentration of C3b in the injured area is increased due to the increased capillary permeability and leakage of plasma proteins into the tissue space.  Opsonization This complement factor binds nonspecifically with the invading bacteria. In addition, there are receptors specific for C3b on the surface of the phagocytes. Binding of the C3b with its receptor creates a linkage between the bacterium and the phagocyte that prevents the “escape” of the bacterium. In this way, bacteria are more readily and more efficiently engulfed by phagocytes.  Phagocytosis Phagocytosis is the process of ingestion and digestion of bacteria, foreign particles, and tissue debris. These substances are internalized within a vesicle formed from the plasma membrane, termed an endocytic vesicle. The vesicle will ultimately fuse with a lysosome, an organelle filled with hydrolytic enzymes. Phagocytes have an abundance of lysosomes. The enzymes degrade the substances within the vesicle.  Phagocytosis Inevitably, some amount of these destructive enzymes escapes into the cytoplasm and kills the phagocyte itself. Neutrophils are capable of engulfing 5–25 bacteria before they are killed by the enzymes. Macrophages engulf and destroy as many as 100 bacteria before they die. Pus is a fluid found in an infected wound that consists of living and dead phagocytes, necrotic tissue, and bacteria.  PHARMACY APPLICATION: ANTI-INFLAMMATORY DRUGS In some instances, the inflammatory response may be exaggerated, prolonged, or inappropriate. Inflammation in these situations is without benefit and may cause serious injury to the tissue or impair the tissue’s function. Nonsteroidal anti-inflammatory drugs (NSAIDs) include a chemically heterogeneous group of compounds with antiinflammatory, analgesic, and antipyretic effects. The prototype drug in this class is aspirin. The major mechanism of action of these drugs involves the inhibition of cyclooxygenase, the enzyme involved in the synthesis of prostaglandins (compounds that contribute to and exacerbates the inflammatory response).  Most over-the-counter medications, such as ibuprofen (Advil®, Motrin®) and naproxen (Aleve®), inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The inhibition of COX-2 mediates the therapeutic effects of these drugs. However, the inhibition of COX-1 may lead to undesired side effects such as gastric ulcers. Selective COX-2 inhibitors, which include celecoxib (Celebrex®), rofecoxib (Vioxx®), and valdecoxib (Bextra®), were effective therapeutically and caused fewer gastric side effects. However, they may be associated with an increased risk of serious cardiovascular events such as heart attack and stroke. Both rofecoxib & valdecoxibm have been removed from market. Glucocorticoids can prevent or reduce inflammation in response to mechanical, chemical, infectious, and immunological stimuli.  They are useful in treating inappropriate immune responses such as allergic reactions (poison ivy rash, asthma) and inflammation associated with arthritis. The use of glucocorticoids does not address the underlying cause of the inflammation, only the symptoms. The mechanism of action of glucocorticoids involves decreasing the release of substances that contribute to the inflammatory response (histamine, prostaglandins, cytokines, and endothelial leukocyte adhesion molecule-1 (ELAM-1)), resulting in a reduction of vasodilation, leukocyte extravasation, and chemotaxis. The activation of T cells and antibody production is decreased. Therefore, an undesired effect of this immunosuppression is an accompanying increased risk of infection.  Inflammatory mediators Histamine and mast cells 1. Prostaglandins and Leukotrienes 2. Cytokines Interleukins: Interferons Tumor Necrosis Factor-alpha 3. Chemokines: 4. Nitric Oxide 5. Fever  Histamine and mast cells Mast cells are essentially sac-like cells filled with granules that contain various inflammatory mediators. Mast cells are located in numerous tissues and “degranulate” or release their contents in response to stimuli such as injury, chemical/toxin exposure, heat, or antibody binding in the case of anaphylaxis. Histamine is a major component of mast cell granules. Once released, the major effects of histamine include vasodilation, increased vascular permeability, and constriction of bronchial smooth muscle.  Histamine and mast cells Mast cell granules also contain two chemotactic factors, neutrophil chemotactic factor and eosinophil chemotactic factor, which help attract leukocytes to the inflamed or injured tissue. Activated mast cells will also synthesize other inflammatory mediators: – Cytokines – prostaglandins – leukotrienes – platelet-activating factor, which stimulates platelet aggregation and increases vascular permeability.  1.Prostaglandins and Leukotrienes The prostaglandins and leukotrienes are eicosanoid inflammatory mediators derived from the 20-carbon unsaturated fatty acid arachidonic acid that is a component of the phospholipids found in cell membranes. Arachidonic acid is released from the mast cell membrane when there is tissue injury or damage. There are two key enzymes involved in the conversion of arachidonic acid: – cyclooxygenase (COX) – lipoxygenase (LOX).  1.Prostaglandins and Leukotrienes cyclooxygenase (COX) COX converts arachidonic acid into the prostaglandins (e.g., PGD2, PGI2, PGE). The prostaglandins enhance inflammation, contract smooth muscle, increase capillary permeability, and cause vasodilation. Certain prostaglandins are also pyrogenic and can raise body temperature. In platelets, COX converts arachidonic acid into thromboxane A2, a potent platelet activator and enhancer of platelet aggregation.  1.Prostaglandins and Leukotrienes lipoxygenase (LOX) The lipoxygenase enzyme converts arachidonic acid in the leukotrienes (e.g., LTA4, LTB4, LTE4). The leukotrienes also enhance inflammation, increase vascular permeability and cause vasodilation. They are also potent bronchoconstrictors that play a key role in asthma. LTB4 is also involved in the chemotaxis of neutrophils.  1.Prostaglandins and Leukotrienes Aspirin and nonsteroidal anti-inflammatories (e.g., ibuprofen) inhibit the production of prostaglandins and thromboxane through the inhibition of the enzyme cyclooxygenase. Corticosteroids exert a highly potent anti-inflammatory effect because they inhibit the release of arachidonic acid from the cell membrane, thus inhibiting the formation of all eicosanoid inflammatory mediators.  2. Cytokines Cytokines are small proteins produced by a number of different cell types within the body. Three major cytokines are released by human cells: 1. interleukins (ILs) 2. interferons (IFNs) 3. tumor necrosis factor-alpha (TNF-α)  Interleukins (ILs) Interleukins are produced primarily by activated macrophages and immune cells. A number of interleukins such as IL-1 are pro- inflammatory. They can also cause fever and attract leukocytes through chemotaxis. A number of interleukins also act upon the bone marrow to stimulate the proliferation of immune cells.  Interferons (IFNs) Interferons are also small proteins produced primarily by cells that are infected with a virus. They function as endogenous antiviral proteins that help protect uninfected cells from viral infection. They may also enhance the inflammatory response by stimulating the activity of immune cells such as macrophages. There are three interferons produced in humans, IFN-α, IFN-β, and IFN-γ. The interferons are used clinically but have a number of significant side effects at pharmacologic doses that limit their overall usefulness  Tumor necrosis factor-alpha (TNF-α) TNF-α is a very potent inflammatory mediator produced by activated macrophages. Release of TNF-α leads to increased expression of adhesion molecules in the vascular endothelium that in turn leads to neutrophil aggregation. TNF-α can stimulate release of cytokines, eicosanoids and chemokines from endothelium. TNF-α can exert systemic effects including fever, anorexia, and muscle wasting. Excess production of TNF-α is believed to play a key role in the development of the wasting syndrome cachexia that is observed in patients with metastatic cancer and AIDS.  3. Chemokines Chemokines are a family of small peptides that mainly function as chemotactic substances for immune cells. They are produced by a number of cell types including endothelial cells, macrophages and fibroblasts in response to the release of pro- inflammatory cytokines.  4. Nitric Oxide Nitric oxide (NO) is a short-lived substance produced by a number of tissues, including the vascular endothelium. NO causes vasodilation through the relaxation of vascular smooth muscle but is also a potent mediator of inflammation that can inhibit leukocyte aggregation, platelet adhesion and cytokine release. NO also exerts free-radical scavenging properties.  5. Fever Fever is a systemic response to inflammation or infection. A number of endogenous substances such as the cytokines (e.g., IL-1) and prostaglandins are pyrogenic Exogenous pyrogens include bacteria and bacterial toxins. Both endogenous and exogenous pyrogens may raise body temperature through direct interaction with the thermoregulatory centers in the hypothalamus. Although the beneficial effects of fever are uncertain, there is some evidence that significant changes in body temperature may impair the activity of infectious microorganisms or their toxins that are sensitive to changes in temperature