Immunity: Pathophysiology – Flashcards
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How are the defenses of immunity divided?
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The defenses of immunity are divided into: 1. 1st line of defense 2. 2nd line of defense 3. 3rd line of defense
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First Line of Defense
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Innate resistance
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Second Line of Defense
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Inflammation
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Third Line of Defense
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Adaptive (acquired immunity) -normal immune response
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What does the first line of defense consist of?
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1st line of defense=innate resistance -via physical and chemical barriers 1. skin 2. lining of GI, genitourinary and respiratory tract.
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Skin
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Part of the 1st line of defense of immunity -keeps a lot of things in our environment from getting into the internal organs. -skin also keeps fluid inside body and prevents dehydration
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A burn victim will also have leaky skin. Why?
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The skin, part of the first line of defense, has been removed. -Increased risk of pathogens entering body -Increased risk of dehydration (fluid volume deficiency) -need for decrement of necrotic tissue
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It is better to kill off some epithelial cells than noneptitheial cells, because epithelial cells will divide rapidly, while non epithelial cells don't.
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Lining of the GI tract, respiratory tract and genitourinary
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First line of defense (physical barriers) -sloughing off of cells -coughing and sneezing (particles out of respiratory tract) -flushing (UTI with water) -vomitting (stomach) -mucus and cilia (respiratory tract)
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If you have a UTI, you are recommended to drink a lot of water. Why?
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A lot of water will help to flush the bacteria out of the body and allow infection to heal faster.
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Biochemical barriers of first line of defense
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-synthesized and secreted saliva, tears, earwax, sweat, sebum -antimicrobial peptides (cathelicidins, defensins collectins) -normal bacterial flora
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Why does sweat contain salt?
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The more salt concentration, the less amount of microbial growth. This is why sweat contains a lot of salt, to keep microbial growth at bay.
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All first line defense of immunity is (specific or nonspecific)
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nonspecific
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Earwax
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biochemical barrier for the first line of defense. keeps insects out of the ear. earwax must be synthesized
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What is the second line of defense?
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Inflammatory response is the second line of defense
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Inflammatory response-what causes it?
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Inflammatory response is caused by many materials: -infection -mechanical damage -ischemia -nutrient deprevation -temp. extremes -radiation
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Inflammatory response is a _____ manifestation
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local
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What is the vascular response of inflammatory response?
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-blood vessels dilate -increased vascular permeability and leakage -white blood cells adhere to the inner walls of vessels and migrate through the vessels
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What are the goals of inflammation?
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-limit and control the inflammatory process -prevent and limit infection and further damage -interact with components of the adaptive immune system -prepare the area of injury for healing
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What are the major steps of inflammation?
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Major steps of inflammation include: 1. Increased vascular permeability 2. Emigration of neutrophils 3. antigen destruction and phagocytosis
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increased vascular permeability
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involves chemical mediators
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emigration of neutrophils to site of damage
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involves 1. chemotaxis 2. margination 3. diapedesis
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antigen destruction and phagocytosis
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involves -neutrophil -macrophage activation
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outside the vessel, and within the surrounding connective tissue
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extravascular
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where are mast cells found?
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Mast cells are ALWAYS found in connective tissue. YOU WILL NEVER find a mast cell in the blood stream.
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what are the cellular mediators in inflammatory response (i.e. the first step)?
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The cellular mediators in inflammatory response include: 1.
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Tissue injury will cause production of inflammatory mediator molecules-->
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1. vascular factor(cause increased vascular permeability, vasodilation and edema) 2. chemokines attract leukotrienes (actue inflammation and chronic inflammation)
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What are the cellular components of cell mediators in inflammation?
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Cellular components of cell mediators: -granulocytes -platelets -monocytes -lymphocytes
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Cell Surface Receptors
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PRP (pattern recognition receptors) PAMPS (pathogen associated molecular patterns) complement receptors scavenger receptors
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How do the WBC know to go to the site of injury?
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Every WBC contains a number of surface cell receptors.
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Cellular mediators of inflammation
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1. Cellular components -granulocytes -platelets -monocytes -lymphocytes 2. Cell Surface Receptors -PRP -PAMP -complement receptors -scavenger receptors
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chronic inflammatory cells
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lymphocytes, monocytes, macrophages, and plasma cells are all referred to as chronic inflammatory cells
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lymphocytes, monocytes, macrophages, and plasma cells
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chronic inflammatory cells
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acute inflammatory cells
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neutrophils (PMN's, eosinophils) are the acute inflammatory cells.
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Lymphocyte: acute or chronic inflammatory cell
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chronic
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monocyte: acute or chronic inflammatory cell
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acute
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PMN
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polymorphonuclear neutrophils -WBC (called polymorphous because 2-5 lobed nucleus)
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PMN's count
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PMN's during inflammation have a much higher count.
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When would a PMN count in the blood be high?
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PMN's count in the blood often increases greatly during a inflammatory process, ESPECIALLY TO A BACTERIAL INFECTION
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Neutrophil
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primary phagocyte that arrives early at the site of inflammation, usually within 90 minutes of injury. aka pmn's
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How long do PMN's last?
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PMN's are released from the bone marrow and circulating PMN's have a 10 hour life span, so they must be constantly replaced if their numbers are to remain adequate.
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Once you have injury extravascular, outside the vessel, what occurs?
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WBC (neutrophils or PMN's) will begin to: 1. marginate to the site of injury 2. adhesion of platelets 3. pavementing of neutrophils 4. emigration
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In response to acute bacterial infection in the periphery, more PMN, often less mature, are released into the circulation (leukocytosis). Recruited cells die in inflamed tissues; but PMN have a short half life, perhaps less than a day, even in normal tissue. PMN are programmed to undergo apoptosis and are then phagocytosed by tissue macrophages.
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Marginate to the site of injury
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leukocyte (PMN's) begin to slow their movement and begin to accumulate along the endothelial surface
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Why does margination of neutrophils occur?
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In response to injury, chemical mediators and cytokine are released that affect the endothelial cells and cause the leukotrienes to increase expression of adhesion molecules. The leukocytes begin to slow their movement and accumulate along the endothelial surface.
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As leukocytes (PMN's) accumulate, they begin to adhere to the endothelial vessel.
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2nd step of PMN's in inflammation
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After adhesion of platelets, _____ occurs.
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PAVEMENTING
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Pavementing
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strong adhesion of PMN's to the endothelial wall
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After pavementing, _____ occurs
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emigration of PMN's
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mechanism by which leukocytes change shape, insert pseudopods into junctions between endothelial cells and squeeze through the junctions.
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emigration (of PMN's)
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PMN's in inflammation:
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1. Margination 2. Adhesion 3. Pavementing 4. Emigration
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Emigration of leukocytes (PMN's causes)
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1. Increased permeability of vessel wall and increased hydrostatic pressure-->transudate 2. Emigration of leukocytes-->exudate 3. Diapedesis of leukocytes and movement by chemotaxis.
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Exudate
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after leukocytes has moved out into the extravascular considered exudate
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chemotaxis
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movement along the gradient of chemical attractants released by bacteria (Receptor mediated)
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Once PMN's get into extravascular tissue, how do they know where to go?
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PMN's once they get out, their movement is dictated by chemotaxis. Chemotaxis is the process which movement is followed along the gradient of chemical attractants that are released by bacteria. PMN's go to the greatest concentration of chemical attractions, receptor mediated.
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Mast cells are found in ________
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extravascular tissue only!!!! You will never find a mast cell circulating in the blood.
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Mast cells stay in the tissues.
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Cellular bags of granules that are located in the loose connective tissues close to the blood vessels
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mast cells
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where are mast cells found?
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mast cells are found everywhere in connective tissue and epithelium: skin, digestive lining and respiratory tract.
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How are mast cells activated?
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Mast cells are activated upon: -physical injury, chemical agents, immunologic process and toll-like receptors (receptor mediated)
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How is chemicals released from mast cells?
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There are two ways in which chemicals may be released from mast cells: 1. degranulation 3. synthesis of lipid-derived chemical mediators
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Mast cells are the 1st responders and start releasing quite amount of secretory granules.
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What is the main chemical released from mast cells?
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Histimine is the main chemical released from mast cells.
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a vasoactive biogenic amine (protein) that causes temporary, rapid dilation of blood vessels and post capillary venules
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histamine
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Histamine is one of the first mediators in inflammatory response
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causes dilation of arterioles, increased permeability of venules.
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What are the two receptors found on histamine?
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histamine has two types of receptors: 1. H1 receptor (found in two places) 2. H2 receptor
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H1 receptor
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found in both: 1. (smooth bronchial muscle cells) to constrict them 2. vessels->causes dilation and relaxation.
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In H1, there are two sites for histamine...
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but each has the opposite effect!
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H2 receptor
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predom. on parietal cells of the stomach mucosa -induces gastric acid secretion and food allergies.
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Is histamine the only thing released from mast cells?
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No histamine is not the only thing released from mast cells. -Chemotactic factors are also released: 1. Neutrophil chemotactic factor 2. eosinophil chemotactic factor of anaphylaxis (ECF-A)
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Neutrophil chemotactic factor
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released by mast cells upon degranulation. Attracts more neutrophils to the site of injury.
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ECF-A
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Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A) -released by mast cells upon degranulation -attracts eosinophils
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proteins that attract or signal for other certain types of cells
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chemotactic factor
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Derived from phospholipids through the action of phospholipases
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arachidonic acid
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Acarchidonic acid may be further metabolized...how?
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2 pathways to further metabolize arachidonic acid: 1. lipoxygenase pathway 2. cyclooxygenase pathway
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Where is arachidonic acid found?
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Release of arachidonic acid from membrane phospholipids in mast cells through enzymatic action of phospholipases.
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Mast cells also synthesize mediators of inflammation:
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1. leukotrienes 2. prostaglandlins 3. platelet-derived factor
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product of arachidonic acid from mast cell membranes, similar effects to histamine except occurs at a later stage. It serves to maintain the inflammatory response.
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Leukotrienes
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Function: chemotaxis, vascular permeability, bronchospasm -arachidonic acid derivative
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leukotrienes
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produce of arachidonic acid from mast cell membranes, similar effects to leukotrienes, but it may also induce pain.
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prostraglandins
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Function: smooth muscle contraction and trigger pain receptors -arachidonic acid derivative
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prostaglandins
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similar effect to leukotrienes and platelet activation
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platelet-activating factors
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Function: vasodilation, inhibition of neutrophil chemotaxis and monocyte adhesion Serves to control inflammation -arachidonic acid derivative
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lipoxins
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Function: Platelet aggregation to form clots and thromosis -arachidonic acid derivative
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thromboxane
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Function:Opposite effect as thromboxane -arachidonic acid derivative
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prostacyclin
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Monocytes are the garbage cleaners, the after party and clean up before healing may occur.
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If you don't remove damage with monocyte, then you won't obtain the proper healing
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secondary responders
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arachidonic acid derivatives -leukotrienes -lipoxones -thromboxones -prostaglandins -prostacyclin
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What to corticosteroid/steroids do?
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Corticosteroids will inhibit the phospholipase enzyme, which prevents production of arachidonic acid from membrane phospholipids. The inflammation will be reduced and joint will be movable. Less pain and more free movement will occur.
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Danger of steroids
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The area won't undergo a true healing until inflammation can occur. If you continually downplay inflammation, healing won't occur.
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What are the secondary mediators in inflammation? Where did they come from?
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arachidonic acid derivatives -leukotrienes -lipoxones -thromboxones -prostaglandins -prostacyclin
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How do mast cells move?
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Mast cells move up the [] gradient to the site of injury, via chemotaxis.
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Chemotaxis vs. chemotaxins
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chemotaxis is the process chemotaxins are the factors
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Where will you have the greatest concentration or amount of chemotaxtic factors?
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The site of damage or injury will prove the greatest amount of chemotaxtic factors.
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hormone-like proteins secreted by cells that enhance inflammatory actions
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cytokines
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when are cytokines secreted?
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cytokines are secreted after histamine to continue the inflammatory response.
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polypeptide products synthesized in many cell types
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cytokines
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What is the function of cytokines?
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Cytokines are secreted to enhance the inflammatory response: 1. leukocytic attraction-continue to attract PMN's to the site of injury 2. phagocytosis stimulation 3. vasodilation
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What are the primary cells that secrete cytokines?
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Cytokines are secreted by many cell types but mainly: 1. lymphocytes 2. macrophages
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subset of cytokines more specifically involved in chemotaxis; attract monocytes and leukocytes (PMN's) to the site of injury
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chemokines
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IL
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interluekins
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produced primarily by macrophages and lymphocytes to response to a pathogen or stimulation by other products of inflammation; usually indicate the end of acute inflammation and start of chronic inflammation
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interleukins (a subset of cytokines)
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usually indicate the end of acute inflammation and the start of chronic inflammation
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interleukins (a subset of cytokines)
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white blood cell count is high...what does this mean?
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WBC count is high when inflammation is occurring, because PMN (WBC) are leaving the vascular system into CT and site of injury. SO you need to replace the ones that are leaving
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Protein derived protein systems
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proteins that are circulating in plasma (blood) and when plasma leaks out are involved in inflammation.
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What are protein systems involved in inflammation?
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Protein systems: 1. complement system 2. coagulation system 3. kinnin system
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What is an important feature of the protein systems involved in inflammation?
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All the protein systems: contain inactive enzymes (proenzymes) -sequentially activated 1. proenzyme-->active enzyme 2. substrate of active enzyme becomes next component in series
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Complement system
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Unique: a protein system that may destroy something directly
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opsinization (complement)
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enhanced binding of antigen to antibody or complement IT flags thing down for destruction
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MAC in complement
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may function for cell lysis
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coagulation system
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a protein system that forms a fibrinous meshwork at the injured or inflamed site.
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Why is coagulation system important?
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The fibrin acts as a net over site of inflammation to keep it contained: 1. prevents spread of infection 3. keeps microorganisms and foreign bodies at the site of greatest inflame. cell activity 4. forms a clot that stops bleeding 5. provides a framework for repair and healing
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main substance in coagulation system, which is an insoluble protein
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fibrin
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acts as a net over the site of inflammation to keep it contained locally, produces a chicken wire frame so we can heal later.
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fibrin (product of coagulation system)
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Kinin system
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a protein system involved in inflammation: function to activate and assist inflammatory cells -primary kinin is bradykinin
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Function of bradykinin
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primary kinin of the kinin protein system involved in inflammation (protein from plasma). Activates pain receptors
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What are the only two molecules associated with pain?
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1. Bradykinin-from kinin system (protein system from plasma) 2. prostaglandin- from archaiconic acid, secondary mediator
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Function of bradykinin (important)
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Bradykinin functions to cause: 1. dilation of blood vessels 2. pain 3. smooth muscle contraction 4. vascular permeability 5. leukocyte chemotaxis
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FIRST STUDIED HOW CELLS GOT TO INFLAMMATION, NOW STUDY HOW CELLS WORK TO DESTROY AT THE SITE OF INFLAMMATION
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process by which a cell ingests and disposes of foreign material
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phagocytosis
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describe the movement of a phagocytic cell to the site of injury:
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Movement of phagocyte to site of injury: 1. phagocytes are in circulation 2.magination 3. adhesion and pavementing 4. diapedesis 5. exudation into inflamed tissue
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any fluid that filters from the circulatory system into lesions or areas of inflammation.
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exudate
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What are the steps of phagocytosis?
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Phagocytosis steps: 1. Opsonization 2. Recognition by the phagocyte 3. Adherence (receptor mediated) 4. Engulfment 5. Phagosome formation 6. Fusion with lysosomal granules-release all the hydrolytic enzymes 7. destruction of the target.
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What occurs when phagocytosis is unsuccessful??
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When lysosomes are unsuccessful at killing and more and more lysosomes bind and then the higher content of hydrolytic enzymes in the cytoplasm. The phagocyte will eventually rupture due to high enzyme concentration. This will cause the enzymes and bacteria to be released from the phagocyte to the cytoplasm. Bacteria is not killed and will be able to infect another cell, while cells around phagocyte are affected.
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Phagocytosis. The figure shows ingestion, digestion, and destruction of foreign particulate matter (a bacterium, in this example). A, Cell membrane receptors bind to antibody and complement molecules previously attached to the bacterial surface. B, The cell membrane creeps around the bacterium and envelopes it. C, The bacterium is trapped in a special space, the phagocytic vacuole, into which lysosomes discharge oxidants to kill it and digestive enzymes to dissolve it.
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The purpose of inflammation is to limit the extent and severity of injury, eliminate or neutralize the offending agent, and to initiate the repair process.
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What cells serve as phagocytes in the inflammatory response?
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Main phagocytes: 1. PMN (neutrophils) 2. Monocytes and macrophages
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Are neutrophils phagocytes?
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Neutrophils (PMN's) are phagocytes in early inflammatory response -Function to inject bacteria, dead cells and cellular debris.
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How long to neutophil phagocytes last?
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Neutrophil phagocytes last very short period of time and become component of purulent exudate.
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Monocytes vs. macrophages.
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monocytes=in circulation in vascular system same thing, just different location macrophages=in tissues inflammatory site
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Are monocytes or macrophages phagocytes?
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Macrophages are phagocytes in the inflammatory response. -takes 3-7 days to arrive after PMNS and initial tissue damage
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Once macrophages (phagocytes) get to the site of injury, 3-7 days later what occurs?
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Macrophage activation results in: -increased size -plasma membrane area -glucose metabolism -number of lysosomes -secretory products Once they get to the site, they basically explode
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Uncoiled chromatin
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indicates DNA is being transcribed into RNA
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Do eosinophils have phagaocytic activity?
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Eosinophils have some phagocytic activity. -defense against parasites and regulation of vascular mediators (viral infection)
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Basophils and lymphocytes have little to no phagocytic activity
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NK cells
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Natural killer cells
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function is to recognize and eliminate cells infected with the viruses and some function in eliminating cancer cells
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Natural killer cells
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cells that recognize something that is similar to self but has changed a little bit...i.e. cancer cells in the tissues
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NK cells
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______ cells are more tissue regulating than circulatory regulating.
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NK cells
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Platelets: ARe they phagocytes?
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Platelets are NOT phagocytes -activation results in degranulation and interaction with components of the coagulation system
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thrombocytes
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aka platelets
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Activation of platelets always stimulates...
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a small-scale of coagulation cascade
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In cancer, natural killer cells may be used....
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and stimulated to activate and recognize cells similar to self-cells but has changed a little. Overstimulate to kill in cancer.
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Pathogenesis of acute inflammation:
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1. Vasodilation (0-24 hours) 2. Edema (escadate and transdate) (24-34 hours is top swelling) 3. Peak of PMN's at 24-48 hours 4. Monocytes and macs begin to peak at days 3-4 to come for clean-up
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Cardinal signs of inflammation (local)
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1. Rubor=reddness 2. Tumor=swelling or inflammation 3. Calor=measurement of heat 4. Dolor=pain
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rubor
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reddness
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tumor
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swelling or inflammation
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calor
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measurement of heat
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dolor
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pain
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An exudate is any fluid that filters from the circulatory system into lesions or areas of inflammation.
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There is an important distinction between transudates and exudates. Transudates are caused by disturbances of hydrostatic or colloid osmotic pressure, not by inflammation. They have a low protein content in comparison to exudates. Medical distinction between transudates and exudates is through the measurement of the specific gravity of extracted fluid
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Transudate=caused by hydrostatic pressure Exudate=caused by inflammation
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For a clinical standpoint, one ma classify the exudative fluids:
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1. serous exudate 2. fibrinous exudate 3. purulent exudate 4. hemorrhagic exudate
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watery exudate, which indicates early inflammation because it hasn't become more complex or matured
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serous exudate (early in the inflammatory response)
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thick, clotted exudate, which indicates a more advanced inflammation; contains more fibrin deprevation
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fibrinous exudate
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exudate that contains pus; indicating a bacterial infection
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purulent exudate
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exudate that contains blood; indicated bleeding
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hemorrhagic exudate
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pus almost always indicates...
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a bacterial infection
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A local manifestation of inflammation (redness, pain, swelling and heat) may spill over into a systemic manifestation of inflammation.
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systemic manifestation of inflammation.
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1. fever 2. leukocytosis (Increase in # WBC) 3. increased plasma protein synthesis 4. malaise
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caused by exogenous and endogenous pyrogens of bacteria, which act directly on the hypothalmus
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fever
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increased # of circulating leukocytes
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leukocytosis
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increased plasma protein synthesis
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acute-phase reactants
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malaise
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down in the dumps bc inflammatory mediators in circulation they are going to change the function in the body
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Inflammatory response to infection
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a lot of inflammation is due to infections, which may be caused by: -bacteria -parasites -viruses
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Anatomic characteristics of acute inflammation
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1. Swelling 2. Edema 3. Reddness 4. Heat Useful in diagnositc
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Anatomic characteristics of systemic inflammation
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Not always visible, acute inflammation has much more visible and define anatomical characteristics.
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Collection of fluid on leg may be due to a lot of things.
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If fluid is not clear, no pain and no heath may be edema caused by congestive heart failure. If it is acute inflammation, you will expect to see heat, pain, swelling and reddness
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Triple Response of Lewis
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Intradermal effects of histamine: 1. Flush 2. Flare 3. Wheal
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Flush
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compression enough to cause cells injury. dull red line, indicates vasodilation due to local release of histamine
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flare
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red halo-->scratch expands and further dilation and increased flow. Fluid begins to move
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wheal
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swelling and blanching-edema
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blanching
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turn white in the middle of a wheal=
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What are anatomical characteristics of acute inflammation?
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In fibrinous pericarditis, acute inflammation: 1. tend to be swollen 2. may appear wet looking 3. fibrin meshwork caused by actute inflammation is pretty noticeable in organs
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absess
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localized pocket of inflammation
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sinus and fissure are open, while an abbess is closed, a pustule and somewhat isolated
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