Inflammation PDF

Inflammation Introduction Inflammation [Latin, inflammatio, to set on fire] is an important nonspecific defense reaction to tissue injury, such as that caused by a pathogen or wound Acute inflammation is the immediate response of the body to injury or cell death. The gross features were described o...

Inflammation Introduction Inflammation [Latin, inflammatio, to set on fire] is an important nonspecific defense reaction to tissue injury, such as that caused by a pathogen or wound Acute inflammation is the immediate response of the body to injury or cell death. The gross features were described over 2,000 years ago and are still known as the cardinal signs of inflammation These signs include redness (rubor), warmth (calor), pain (dolor), swelling (tumor), and altered function (functio laesa).  Redness Pain Heat Swelling (edema) Loss of function Acute-phase proteins activated (complement, cytokine, kinins) - chemical messengers Vasodilation (histamine, kinins, prostaglandins, leukotrienes) - bring in more help Margination and emigration of WBCs Tissue repair Chemicals Released by Damaged Cells Histamine Vasodilation, increased permeability of blood vessels Kinins Vasodilation, increased permeability of blood vessels Prostaglandins Intensity histamine and kinin effect Leukotrienes Increased permeability of blood vessels, phagocytic attachment  Beginning of Inflammatory Response The acute inflammatory response begins when injured tissue cells release chemical signals (inflammatory mediators) that activate the inner lining (endothelium) of nearby capillaries Within the capillaries selectins (a family of cell adhesion molecules) are displayed on the activated endothelial cells—first P-selectin and then E-selectin These adhesion molecules randomly attract and attach neutrophils to the endothelial cells, slow the neutrophils down, and cause them to roll along the endothelium As the neutrophils roll along the endothelium, they encounter the inflammatory mediators that act as activating signals These signals activate integrins (adhesion receptors) on the neutrophils The neutrophil integrins then tightly attach to endothelial adhesion molecules such as the intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM- 1). Continue… This causes the neutrophils to stick to the endothelium and stop rolling The neutrophils now undergo dramatic shape changes, squeeze through the endothelial wall (extravasation) into the interstitial tissue fluid, migrate to the site of injury, and attack the pathogen or other cause of the tissue damage. Neutrophils and other leukocytes are attracted to the infection site by chemotactic factors or chemotaxins such as substances released by bacteria and mast cells, and tissue breakdown products Depending on the severity and nature of tissue damage, other types of leukocytes (e.g., lymphocytes, monocytes, and macrophages) may follow the neutrophils.  Inflammatory Mediators The inflammatory mediators that are released by the injured tissue cells also raise the acidity in the surrounding extracellular fluid This decrease in pH activates the extracellular enzyme kallikrein, which splits bradykinin from its long precursor chain Bradykinin binds to receptors on the capillary wall, opening the junctions between cells and allowing fluid and infection-fighting leukocytes to leave the capillary and enter the infected tissue Simultaneously bradykinin binds to mast cells in the connective tissue associated with most small blood vessels This activates the mast cells by causing an influx of calcium ions, which leads to degranulation and release of preformed mediators such as histamine If nerves in the infected area are damaged, they release substance P, which also binds to mast cells, boosting preformed-mediator release. Histamine Histamine in turn makes the intercellular junctions in the capillary wall wider so that more fluid, leukocytes, kallikrein, and bradykinin precursors move out, causing edema Bradykinin then binds to nearby capillary cells and stimulates the production of prostaglandins (PGE2 and PGF2) to promote tissue swelling in the infected area Prostaglandins also bind to free nerve endings, making them fire and start a pain impulse. Changes in Cells The change in mast cell plasma membrane permeability associated with activation allows phospholipase A2 to release arachidonic acid Arachidonic acid is then metabolized by the cyclooxygenase or lipoxygenase pathways, depending on mast cell type The newly synthesized mediators include prostaglandins E2 and F2, thromboxane A2, slow-reacting substance (SRS), and leukotrienes (LTC4 LTD4) All play various roles in the inflammatory response Series of Events During acute inflammation, the offending pathogen is neutralized and eliminated by a series of events, the most important of which are the following: 1. The increase in blood flow and capillary dilation bring into the area more antimicrobial factors and leukocytes that destroy the pathogen. Dead cells also release antimicrobial factors. 2. The rise in temperature stimulates the inflammatory response and may inhibit microbial growth. 3. A fibrin clot often forms and may limit the spread of the invaders so that they remain localized. 4. Phagocytes collect in the inflamed area and phagocytose the pathogen. In addition, chemicals stimulate the bone marrow to release neutrophils and increase the rate of granulocyte production.  Chronic Inflammation Chronic inflammation is a slow process characterized by the formation of new connective tissue, and it usually causes permanent tissue damage Superficially, the difference between acute and chronic inflammation is one of duration Regardless of the cause, chronic inflammation lasts two weeks or longer Chronic inflammation can occur as a distinct process without much acute inflammation The persistence of bacteria by a variety of mechanisms can stimulate chronic inflammation For example, the mycobacteria have cell walls with a very high lipid and wax content, making them relatively insensitive to phagocytosis The bacteria that cause tuberculosis, leprosy, and syphilis often survive within the macrophage In addition, some bacteria produce toxins that stimulate tissue-damaging reactions even after bacterial death Characteristics of Chronic Inflammation Chronic inflammation is characterized by a dense infiltration of lymphocytes and macrophages If the macrophages are unable to protect the host from tissue damage, the body attempts to wall off and isolate the site by forming a granuloma [Latin, granulum, a small particle; Greek oma, to form] Granulomas are formed when neutrophils and macrophages are unable to destroy the microorganism during inflammation Infections caused by some bacteria (listeriosis, brucellosis), fungi (histoplasmosis, coccidiodomycosis), helminth parasites (leishmaniasis, schistosomiasis), and large antibody-antigen complexes (rheumatoid arthritis) result in granuloma formation and chronic inflammation.