Principles Of Inflammation

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abscess

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A swollen area within body tissue, containing an accumulation of pus

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acute phase protein

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Acute-phase proteins are a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (also called acute-phase response).

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adhesion molecules

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Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.

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anaphylatoxin

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Anaphylatoxins, or anaphylotoxins, are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system.

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bradykinin

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A compound released in the blood in some circumstances that causes contraction of smooth muscle and dilation of blood vessels. It is a peptide comprising nine amino-acid residues

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cytokine

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Any of a number of substances, such as interferon, interleukin, and growth factors, that are secreted by certain cells of the immune system and have an effect on other cells

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empyema

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The collection of pus in a cavity in the body, esp. in the pleural cavity

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epithelioid cell

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Epithelioid histiocytes (Epithelioid cells) are activated macrophages resembling epithelial cells:[1] elongated, with finely granular, pale eosinophilic (pink) cytoplasm and central, ovoid nucleus(oval or elongate), which is less dense than that of a lymphocyte. They have indistinct shape contour, often appear to merge into one another and can form aggregates known as giant cells

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erythrocyte sedimentation rate

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he rate at which red blood cells settle out in a tube of blood under standardized conditions; a high rate usually indicates the presence of inflammation

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giant cell

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A giant cell is a mass formed by the union of several distinct cells (usually macrophages). It can arise in response to an infection or foreign body.

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granulocytosis

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An inflammatory reaction, which consists predominantly of polymorphonuclear leukocytes.

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granuloma

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A mass of granulation tissue, typically produced in response to infection, inflammation, or the presence of a foreign substance

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histiocyte

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A stationary phagocytic cell present in connective tissue

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integrins

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Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle.

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kallikrein

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an enzyme required for the activation of factor XII to Xlla Kinin one of a group of peptides that cause vasodiltation and increase vascular permeability Kininogen the precursor of the kinins

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leukemoid reaction

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The term leukemoid reaction, also referred to as transient myeloproliferative disorder, describes an elevated white blood cell count, or leukocytosis, that is a physiologic response to stress or infection (as opposed to a primary blood malignancy, such as leukemia).

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leukocytosis

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An increase in the number of white cells in the blood, esp. during an infection

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lymphocytosis

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an abnormal increase in the number of lymphocytes in the circulating blood

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lymphokine

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A substance produced by lymphocytes, such as interferon, that acts upon other cells of the immune system, e.g., by activating macrophages

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macrophage

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A large phagocytic cell found in stationary form in the tissues or as a mobile white blood cell, esp. at sites of infection

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margination

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Blood vessels outlined with cuffs of neutrophils.

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monokine

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Powerful chemical substances secreted by monocytes and macrophages. These soluble molecules help direct and regulate the immune responses.

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opsonin

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An antibody or other substance that binds to foreign microorganisms or cells, making them more susceptible to phagocytosis

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pavementing

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...

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phagolysosome

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A phagolysosome is the membrane-enclosed organelle which forms when a phagosome fuses with a lysosome. After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome.

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phagosome

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A vacuole in the cytoplasm of a cell, containing a phagocytosed particle enclosed within a part of the cell membrane

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selectins

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Selectins are big molecules that help immune system cells find where they need to go. For example, selectins mark the part of a blood vessel near an infection.

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Neutrophils (Polys, PMN)

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Comprise 50-65% of circulating white blood cells
* Life span of 3-4 days in the blood and 1-2 days in extravascular tissue
* Phagocytize & destroy bacteria & elaborate chemotactic factors
* Produce enzymes to degrade & mop up necrotic cellular debris
* Undergo an oxidative burst to produce superoxide free radicals

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Eosinophils

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Comprise 1-5% of circulating white blood cells
* Have large eosinophilic cytoplasmic granules
* Produce major basic protein (MBP)
* Phagocytize antigen-antibody complexes
* Contain histaminases

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Basophils

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* Comprise 1% of circulating white blood cells
* Large blue staining (basophilic) cytoplasmic granules
* Contain MBP, lysophospholipase, serotonin, heparin, & histamine
* Produce & secrete plate activating factor (PAF)
* Cause vasodilation, increased permeability of venules, & synthesis of arachidionic acid metabolites
* Mast Cells – tissue-bound basophils
* Secrete mediators
* Located around small blood vessels & serous membranes
* Contain chemotactic factors for eosinophils

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Lymphocytes

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Small cells consisting of a round hyperchromatic nucleus w/ little cytoplasm
* Comprise 30-40% of circulating white blood cells
* Key mediators in both humoral & cell-mediated immune responses
* Synthesize chemical mediators (lymphokines)

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T-lymphocytes (T-cells)

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* Comprise 75% of circulating lymphocytes
* “Programmed” by passage through the thymus gland
* Unique DNA sequence for its surface T-cell antigen receptor
* Ability to recognize the major histocompatibility complex (MHC) antigens of the host in order to identify self tissues
* Populate the paracortical regions of the lymph node

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T-Helper Cells (CD4+)

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* Stimulate B-cell proliferation & differentiation into plasma cells

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T-Suppressor/Cytotoxic Cells (CD8+)

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* Kill virally-infected cells & tumor cells
* Dampen antibody production against a specific antigen by inhibiting B-cell proleration or by restaining T-helper cell activity

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T-Memory Cells

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* Confer life-long memory of antigens

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B-Lymphocytes (B-cells)

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15% of circulating lymphocytes
* “Programmed” in bone marrow
* Germinal centers of lymph nodes
* Reside in the splenic white pulp
* Mature into plasma cells
* Produces antibodies (immunoglobulins) direct against certain antigens
* Can become B-memory cells
* Gene rearrangement of the immunoglobulin genes allow for extensive antigen specificity

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Natural Killer (NK) cells

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10% of circulating lymphocytes
* “Mixed bag” of membrane markers
* Not dependent on antigen stimulation
* Directly cytotoxic
* Bind to foreign cells & lysine the cell membrane
* Important in transplant rejection & tumor surveillance

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Monocytes

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4-8% of circulating white blood cells
* Major source of tissue macrophages
* Resting (Histiocytes) & Reacting (macrophages)
* Phagocytize large particular matter
* Pinocytosis of soluble material
* Surface receptors similar to those of neutrophils
* Process & present antigens to T- & B- lymphocytes
* secrete numerous monokines

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List the 5 classical signs and symptoms of acute inflammation and discuss the underlying events that lead to each.

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Heat (calor)
Redness (rubor)
Swelling (tumor)
Pain (dolor)
Loss of function (function laesa)

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Describe in sequence the series of events that comprise the acute inflammatory response and the mechanisms by which they occur.

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Textbooks describe "acute inflammation" as lasting from moments to a maximum of 1-2 days. This is a simplification, as anyone with a persistent pimple knows. The hallmarks of acute inflammation are (1) vasodilatation and increased vascular permeability; (2) entry of neutrophils into the tissues.
The first event is transient arteriolar constriction, lasting a few seconds (if at all; scratch yourself and see) up to a few minutes This vasoconstriction helps control blood loss in case vessels have been severed.
When the arteriolar constriction phase is over, the arterioles dilate and stay dilated as long as acute inflammation continues. This produces the redness and (since heart's blood is warmer than exposed body parts) the sensation of heat. The slightly increased pressure that this cause in the capillaries may produce some transudation of fluid into the tissue spaces.
Hyperemia is a generic term for extra blood in an organ due to dilation of the arterioles.
Soon after injury, the small vessels (mostly the venules 20-60 microns) become permeable to some or all plasma proteins. This increases the osmotic ("oncotic") pressure of the interstitial fluid, water is drawn out of the vessels, and inflammatory edema ("swelling") results.
As protein leaks out into the interstitial spaces, the local concentration of cells in the blood increases. Red cells pack small vessels ("red cell stasis"), neutrophils stick to endothelium, and the viscous blood flows more slowly ("stasis"). The water which follows the protein out of the vessels contributes to edema. Much of this fluid will return to the circulation only via the lymphatics.
The physicochemical changes that cause the increased permeability to protein are only partly understood. The key seems to be opening gaps in the intercellular junctions ("endothelial cell contraction"). Another factor seems to be loss of various polyanions from the basement membrane surrounding the endothelial cells. Of course, if the vessels are damaged by the first injury, or by the neutrophils, or are themselves regenerating, they will leak.
The worse the injury, the larger the protein molecules that can pass through the vessel walls. In the worst injuries (and, of course, if the vessel is severed), fibrinogen escapes into the tissue fluids, and under these circumstances is certain to be transformed to fibrin (by your clotting cascade, of course).
The final key event in acute inflammation is the accumulation of neutrophils ("polys", "segs"; nobody calls them * "microphages" nowadays) in the injured tissue. (Most of the time, these predominate for the first 24-48 hours after injury, and are more or less replaced by macrophages after this time.)
The laws of physics cause neutrophils to marginate ("pavement", i.e., lie along the inner walls of vessels) whenever blood flow is slowed. They roll along for a while. Adhesion to the walls of vessels, especially venules, results when leukocyte adhesion molecules on the surface of the neutrophils interact with endothelial adhesion molecules on the endothelial cells.
Leukocyte adhesion molecules go by names such as LFA-1 and MO-1. These are members of a homologous set, and their deficiency states are known.
Emigration ("diapedesis") of neutrophils from the vessels into the tissues occurs when the cells squeeze through the widened endothelial cell gaps, then get through the basement membrane by digesting it with enzymes. (Of course this damages the blood vessels, but the endothelial cells repair the damage soon enough.) The other white cells also leave vessels by this route.
Various chemical mediators cause chemokinesis (increased random locomotion) and chemotaxis (directional migration) of neutrophils and other cells. Chemotactic agents include a plethora of bacterial breakdown products, complement components (remember C5a), and leukotriene B4. Most small molecules which are chemotactic for neutrophils are also chemotactic for macrophages and vice versa.
Once they have found their way to the tissues, the neutrophils phagocytize things that shouldn't be there. They also degranulate, releasing enzymes into the interstitial fluid.
Phagocytosis requires that the particle be recognized and attach to the neutrophil. Most particles must be coated (opsonized) by IgG (subtypes 1 or 3) or C3b. There are receptors for both on the neutrophil surface. The particle will then be engulfed and a lysosome membrane fused with the phagosome membrane, causing digestion within the phagolysosome. (If only C3b is present in the opsonin, additional molecules will be required to trigger engulfment.) Some of the lysosomal enzymes will leak out of the neutrophil and into the intercellular fluid.
Killing of phagocytized bacteria is mediated through the H2O2-myeloperoxidase-halide system and other, less-effective oxygen-dependent and oxygen-independent systems. (We retain ancient microbe-killing proteins including lysozyme and lactoferrin.)
Neutrophil products, including lysosomal enzymes, H2O2, free radicals, and arachidonic acid metabolites are released during the process by "regurgitation during feeding", "frustrated phagocytosis" (i.e., the neutrophil tries to eat something too big, such as a huge immune complex or a splinter; it can't engulf it so it drools), and "cytotoxic release". The latter is a euphemism for stuff leaking out of dead cells.
Once acute inflammation has begun, there are four possible outcomes:
1. Complete resolution, i.e., there has been no damage to the connective tissue framework or non-recoverable cells of any part of the body.
2. Healing by scarring (see below)
3. Abscess formation. Pus in a confined space is called an "abscess". As proteases continue to work on the fluid itself, the osmotic pressure within the abscess becomes greater and greater, causing it to swell ("ripen" -- ever had a pimple?) While the body might succeed in walling it off, usually you still have to drain pus.
4. Progression to chronic inflammation (see below). This happens when, and only when, the neutrophils and their fast-acting molecular allies cannot remove the noxious agent.

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. Describe the steps involved in the isolation and destruction of an infectious agent by polymorphonuclear leukocytes

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Once they have found their way to the tissues, the neutrophils phagocytize things that shouldn't be there. They also degranulate, releasing enzymes into the interstitial fluid.
Phagocytosis requires that the particle be recognized and attach to the neutrophil. Most particles must be coated (opsonized) by IgG (subtypes 1 or 3) or C3b. There are receptors for both on the neutrophil surface. The particle will then be engulfed and a lysosome membrane fused with the phagosome membrane, causing digestion within the phagolysosome. (If only C3b is present in the opsonin, additional molecules will be required to trigger engulfment.) Some of the lysosomal enzymes will leak out of the neutrophil and into the intercellular fluid.
Killing of phagocytized bacteria is mediated through the H2O2-myeloperoxidase-halide system and other, less-effective oxygen-dependent and oxygen-independent systems. (We retain ancient microbe-killing proteins including lysozyme and lactoferrin.)
Neutrophil products, including lysosomal enzymes, H2O2, free radicals, and arachidonic acid metabolites are released during the process by "regurgitation during feeding", "frustrated phagocytosis" (i.e., the neutrophil tries to eat something too big, such as a huge immune complex or a splinter; it can't engulf it so it drools), and "cytotoxic release". The latter is a euphemism for stuff leaking out of dead cells.

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Discuss the source(s) and the role(s) that chemical mediators play in acute inflammation.

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Chemical mediators constitute the bridge b/t injury and host inflammatory responses. There is a multitude of mediators that act independently or by interaction w/ others. Mediators can be preformed cellular products (histamine, serotonin, lysosomal enzymes), synthesized cellular products (PA, arachidonic acid metabolites, cytokines) constituents of plasma (products of the coagulation, complement, and kinin systems), or products of tissue injury.

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Serous –

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this is often the result of mild injury and consists of the extravasation of an exudates derived from serum or the mesothelial cells lining body cavities.

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Catarrhal –

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this is associated w/ a profuse secretion of watery or mucoid fluid from a mucous membrane. (Runny nose)

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Fibrinous-

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this results in a fibrin-rich exudates which forms shaggy fibrin strands that may ultimately produce adhesions

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Serosanguinous/Hemorrhagic –

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this occurs w/ highly virulent or fulminating infections where extensive vascular damage may occur resulting in the extravasation of red blood cells (meningococcal septicemia)

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Suppurative (Purulent) –

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this indicates the presence of pus which consists of tissue breakdown products, neutrophils, and in most cases microorganisms (furuncles, carbuncles)

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Ulcerative –

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this refers to a localized sloughing of inflammatory and necrotic debris from cutaneous or mucosal surfaces (decubitus ulcer, peptic ulcer)

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Gangrenous –

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this implies enzymatic and bacterial decomposition (putrefaction) of necrotic (usually ischemic coagulation necrosis) tissue.

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Membranous/Pseudomembranous –

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this refers to the formation of “membranes” composed of matter fibrin, mucus, and inflammatory cells on focally necrotic epithelial surfaces (pseudomembrane of diphtheria or clostridia infections)

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Describe the systemic effects of acute and chronic inflammation and briefly discuss the underlying mechanisms that produce those effects.

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Obviously, there are differences among inflammatory reactions. Acute inflammation is almost completely stereotyped -- over minutes to a few days, blood vessels dilate and leak, and neutrophils enter the surrounding tissues. Chronic inflammation is more variable, with variable participation by lymphocytes, plasma cells, macrophages, and healing cells (fibroblasts and angioblasts).

The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells ("mononuclear cells", "round cells", i.e., monocytes, lymphocytes, and/or plasma cells). Generally, good tissue has been (and is being) destroyed, and there will be some evidence of healing (scarring, fibroblast proliferation, angioblast proliferation).
In clinically significant disease, we believe that the tissue macrophages are almost all recruited directly from the bloodstream monocytes. Plasma cells produce antibodies against the persistent antigen or the altered tissue components. Lymphocytes are likely to be present even where there is no involvement of the immune system.
Plasma cells appear in chronic inflammation as a result of T-helper cells activating B-lymphocytes. Interleukin 1 causes the B-cells to divide. The transformation into plasma cells is mediated (at least in part) by interleukin 4.
If IgE or worms are involved, you will probably see eosinophils. Their granules contains several alkaline ("basic") proteins which are noxious to worms. You may also see some neutrophils.
Acute inflammation is a stereotyped response to most kinds of noxious stimuli. Something a part of the body does when it knows it's been hurt.
Textbooks describe "acute inflammation" as lasting from moments to a maximum of 1-2 days. This is a simplification, as anyone with a persistent pimple knows. The hallmarks of acute inflammation are (1) vasodilatation and increased vascular permeability; (2) entry of neutrophils into the tissues.

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Discuss the role of the clinical laboratory in diagnosing acute inflammation in terms of expected laboratory findings.

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...

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Compare and contrast non-specific chronic inflammation and granulomatous inflammation in terms of etiology, morphologic appearance, clinical implication, and outcome.

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Granulomatous inflammation is a special kind of chronic inflammation which occurs in the presence of indigestible material and/or cell-mediated immunity ("type IV hypersensitivity”). A granuloma is an abnormal structure built from at least two activated macrophages adhering to one another. Such macrophages are (confusingly) called epithelioid cells. Granulomas serve to wall off stuff (splinters, the caseous debris of TB)
In the absence of a very large foreign body, a granuloma will almost always contain at least a few T-lymphocytes (though this is not absolutely mandatory).
The cells in a granuloma are activated by gamma-interferon (and/or α-TNF or whatever).
Granulomas can (but need not) contain syncytial giant cells (polykaryons). These fused clusters of epithelioid cells which take a week to form. For our purposes, there are two kinds. Langhans giant cells have their nuclei arranged in a horseshoe around the edge, and foreign body giant cells, with nuclei dispersed more or less evenly. The distinction is of no known significance.
The giant cells of granulomas occasionally contained altered cytoskeletal components in the shapes of stars, or asteroid bodies. They are pretty, but of no known significance. Or you may see laminated calcified nuggets, called Schaumann bodies, also of no known significance.
The classic granulomatous diseases include tuberculosis, leprosy, foreign body reactions (* including the reactions to everything from sutures to schistosome eggs), the deep fungal infections, berylliosis, and the mysterious disease "sarcoidosis".
The newly-described entity "immune restoration syndrome" is seen in AIDS patients who go on highly-active anti-retroviral therapy.