(From Dr.Twedell, 7 Sept 2000, by Brian Buschman)
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Signs of inflammation include:
1) Calor (heat)
2) Tumor (edema)
3) Rubor (redness)
4) Dolor (pain)
5) Loss of function
Exudate is an extracellular fluid that contains proteins and cellular debris. It escapes from capillaries and tissues that are damaged.
There are five mechanisms of increased permeability:
1) Endothelial cell contraction
2) Endothelial retraction
3) Direct injury (trauma)
4) Leukocyte-mediated endothelial change
5) Leakage from regenerating capillaries
When the gaps between the cells of the endothelium begin to close eventually leukocytes cannot fit through and end up plugging the holes.
Table 3-1 (P. 58)
There are various molecules that play a large role in the process of leukocytes leaving the blood stream enroute to infection. We care about four molecules in two classes.
1) P-selectin and E-selectin function in leukocyte adhesion to the endothelium. The selectins help the leukocytes stick to the endothelium which causes the rolling along the capillary walls.
2) ICAM (intracellular adhesion molecule) and VCAM (vascular cell adhesion molecule) are two mediators of transmigration. That is they cause the cells to cross the endothelium.
Weibel-Palade bodies are bunches of P-selectin inside vacuoles in endothelial cells. When they are stimulated by histamine or thrombin the vacuoles merge with the P.M. and place the P-selecting on the outside. Obviously this causes leukocyte adhesion.
There are two forms of leukocyte adhesion deficiency (LAD).
1) LAD I is the deficiency of b2 integrin which is a factor in ICAM. In LAD I there is a problem with transmigration.
2) LAD II is characterized by a deficiency of Sialyl Lewis factor which is the receptor on the leukocytes for P-selectin and E-selectin. With LAD II there is a deficiency with adhesion.
Leukocyte activation and chemotaxis require receptor activated phospholipase-C which gives DAG and IP3. IP3 increases intracellular Ca2+. Ca2+ causes chemotaxis and formation of arachidonic acid. Arachidonic acid causes be used to make leukotrienes and prostaglandins. DAG goes to cause degranulation.
Phagocytosis involves a few steps:
1) Attachment of opsonized particles to receptors that bind FC and C3b on the leukocyte surface.
2) Engulfment by leukocytes.
3) Fusion of lysosomal granules with phagosomes causing degranulation.
4) Killing/degradation of the bacteria.
The actual antigen killing is done by one of two mechanisms but we will only look at the O2-dependant reaction. NADPH powers NADPH peroxidase to convert O2 into O2- (superoxide) and then onto H2O2. MPO granules (myeloperoxidase) granules converts H2O2 into HOCl which is brutal to the antigen.
There are a number of leukocyte diseases we need to know:
1) LAD I is the shortage of b2 which is a component of ICAM.
2) LAD II is the shortage of Sialyl-Lewis factor which is the acceptor for E-selectin and P-selectin.
3) Chronic granulomatous disease causes decreased oxidative burst.
4) Neutrophil specific granule deficiency.
5) Chediak-Higashi Syndrome.
The syndrome includes:
Sialyl-Lewis is related to:
· Diabetes
Some of the chemical mediators that are used in the immune response are preformed like:
Other are synthesized as needed like:
Various eicosanoids mediate various processes in the inflammatory response:
1) Vasoconstriction is mediated by TxA2, LTC4, LTD4, LTE4.
2) Vasodilatation is mediated by PGI2, PGE2, PGE4, PGD2.
3) Vascular permeability is mediated by LTC4, LTD4, LTE4.
4) Chemotaxis is mediated by LTB4 and HETE.
For a more complete list of factors see tables 3-4 (P. 73) and 3-5 (P. 74). Note that the factors that increase vascular permeability also function for vasoconstriction.
1) The compliment system is a major set of plasma proteins that function in the immune response. Vascular permeability is increased by C3a, C4a and C5a. These same factors are also activate the lipoxygenase pathway in PMNs and monocytes. C3b acts as an opsonin.
2) The kinin system makes kininogens that act on kallikrein to produce bradykinin which increases vascular permeability. Hence kinin increases vascular permeability. Kinin also activates the final common pathway of clotting.
3) The clotting pathway is activated with damage causing exposure to the basement membrane for factor XII. This combination initiates the clotting mechanism. Some factors have other roles then just clotting.
a. Thrombin increases vascular permeability and is chemotactic for PMNs.
b. Factor X also causes increased vascular permeability and PMN exudation.
Lipoxygenase and cycloxygenase mediate inflammation and make arachidonic acid. Aspirin inhibits the formation of arachidonic acid. NSAIDS block the pathway to convert AA into prostaglandins hence more leukotrienes are made.
As you can guess PAF increases vascular permeability, leukocyte aggregation, platelet action and such. PAF works through a G-protein and is increased by tobacco smoke. This means that smoking causes increased clotting and thicker blood. This is why smoking is bad for your CV system.
Cytokines include various mediators from many cells. They include ILs, TGF, TNF and IFN. Hematopoiesis is stimulated by IL-3 and IL-7. Inflammatory mediators include IFN-g, TNF-a, TNF-3, IL-5, 10 and 12.
Endothelium derived relaxing factor is NO. Overproduction of NO causes reduction of PMN recruitment.
Specific granules have specific contents like collagenase or lactoferrin that will be secreted. Azurophilic granules contain hydrolyses and peroxidases which will bind with phagosomes to digest stuff intercellularly.
As the inflammation is going down there are a number of final outcomes:
1) Complete resolution. All heals and it goes back to normal with no scar.
2) Replacement by C.T. and scaring since the tissue is damaged beyond what can be repaired.
3) Abscess formation
4) Progress to chronic inflammation
Chronic inflammation is inflammation lasting weeks or months caused by persistent infection, prolonged exposure to the toxic substance or an autoimmune response.
Histologically you see:
1) Infiltration of mononuclear cells.
2) Tissue destruction.
3) C.T. replacement, angiogenesis and fibrosis of tissues.
Macrophages are the primary mononuclear cell of chronic infection. They are the most important cell in the mononuclear phagocyte system (MPS). They are attracted by the usual factors but mostly by cytokines like IFN-g from activated T-cells. I.E. the T-cells call them over.
At the site they secrete products to fight invaders such as:
1) Neutral proteases
2) Acid hydrolyses
3) Compliments
4) Factors
5) All of the usual (reactive Ox, cytokines, GFs, NO, PG, IL, etc.)
Lymphocytes are attracted by adhesion molecules like ICAM, VCAM and RANTES. They produce lymphokines which stimulate monocytes.
Plasma cells come along to make their Ab’s.
Eosinophils are mediated by IgE. They have granules of MBP which is toxic to parasites and their host cell.
Mast cells have surface receptors for FC and IgE which may help lead to anaphylaxis.
Granulomas are a type of chronic inflammation that histologically looks like a small nodular collection of modified macrophages. Some are necrotic looking and have abundant pink cytoplasm and are called epitheloid cells. They may join to form giant cells or Langhans-type cells.
There are two types of granulomas:
1) Foreign body granulomas are formed because of insertion of an inert foreign body. The granulomas forms around it.
2) Immune granulomas are formed by T-cell responses to poorly degradable antigens.
Granulomas are formed from many types of infection including:
1) Tuberculosis
2) Leprosy
3) Syphilis
4) Cat0scratch disease (gram-negative bacillus)
5) Sarcoidosis.
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