Acute Inflammation Flashcards
What are general features of acute inflammation?
- Involves the reaction of:
- blood vessels
- accumulation of fluid and leukocytes in extravascular tissues - intertwined with the process of repair (anti inflammatory- balance)
- regeneration
- scarring-fibrosis, extracellular material, collagen - protective response
- rid body of initial cause of injury and consequences
- may be potentially harmful (chronic) - inflammation occurs in vascularized connective tissue
- plasma, circulating cells, blood vessels, cell and extracellular constituents of connective tissue
What is an organ that prevents inflammation?
eye
- scarring would contribute to blindness
- tight junctions prevent leaks
What do mast cells do?
they release histamines that allow the blood vessel to leak leukocytes to attack an infection
What is the most important cell in acute inflammation?
neutrophils
-innate immunity
what is acute inflammation?
- short duration
- minutes to several hours to a few days
- associated with fluid and plasma proteins (edema- swelling)
- emigration of leukocytes, particularly neutrophils
What is chronic inflammation?
- longer duration
- associated with presence of lymphocytes and macrophages
- proliferation of blood vessels
- fibrosis and tissue necrosis
What mediates vascular and cell responses?
chemical factors derived from plasma cells
What is the healing response?
macrophages secrete proteins that activate fibroblasts to make collagen to heal damaged area
4 cardinal signs of inflammation?
- rubor- redness
- tumor- swelling
- calor- heat
- dolor- pain
What are the three major components of acute inflammation?
- alterations in vascular caliber leading to increased blood flow
- structural changes permitting plasma proteins and leukocytes to leave the circulation
- emigration of leukocytes from the circulation and accumulation at site of injury
Edema? Two types?
- swelling in tissues
1. Transudate- fluid with low protein content (albumin) and specific gravity less than 1.012, leaking fluid - ultra filtrate of blood plasma- results from hydrostatic imbalance across endothelial, the permeability of endothelium is normal
- not inflammatory response, just increased blood pressure
- clear
2. Exudate- inflammatory extravascular fluid with high protein content, cell debris and specific gravity above 1.020 - purulent exudate (pus)
- inflammatory response- reason for high protein
- cloudy
What part of blood vessels are most leaky?
venule
- capillaries have tighter junction complex
- venule has thinner wall, less smooth muscle, movement of fluid is easier
What causes increased vascular permeability?
- gaps due to endothelial contraction
- venules
- vasoactive mediators (histamine, C3a, C5a)
- most common
- fast and short lived - Direct injury
- arterioles. capillaries, venules
- toxins, burns, chemicals
- fast and may be long lived - leukocyte dependent injury
- mostly venues
- pulmonary capillaries
- late response
- long lived - increased transcytosis
- venules
- vascular endothelium derived growth factor - new blood vessel formation
- angiogenesis
- persists until intercellular junctions form
Sequence of leukocytic (neutrophils) events in inflammation?
- glycoprotein bind to P-selectin and E-selectin molecules on endothelial cell surface, constitutively expressed all the time
- rolling occurs, stoppage, integrin cell adhesion molecules (ICAM-1 and VCAM) open, then firm binding (high avidity)
- trigger events inside WBC
What does laminar blood flow do?
maintains leukocytes against venular wall
What do integrins bind to? what do glycoproteins bind to?
integrins- ICAM or VCAM, adhesion
glycoproteins- selectins, rolling interactions
What are examples of mediators of neutrophil extravasation, increased avidity?
- weibel palade bodies in the presence of histamine and thrombin redistribute the P-selectins to allow for stickier binding
- cytokines induce endothelial adhesion molecules (ICAM, VCAM) which lead to higher avidity binding
- chemokines increase avidity of integrins
Sequence of events following acute injury?
- edema
- neutrophils come in
- macrophages/monocytes replace neutrophils
Why is actin broken down in cells?
in order to change its shape to fit through smaller spaces
Ways that leukocyte are activated?
- N formyl methionyl peptides, chemokines, lipid mediators increase intern avidity, and induce cytoskeletal changes which lead to chemotaxis and migration into tissues
- microbe on cell surface interacts with receptor (toll like) to produce cytokines and reactive oxygen intermediates, which activates leukocyte to kill the microbe
- microbe attaches to mannose receptor which induces phagocytosis, leukocyte activation, kill microbe
Phagocytosis and destruction in the WBC (vacuole)?
- microbe is moved into phagocytic vacuole
- superoxides ions, hydroxyl ions and hypochlorous ions are made
- fenton reaction: iron with peroxide broken down into hydroxyl radicals
- radicals are very reactive, will bind to organisms lipids, proteins, to destroy it
- NO can be damaging too, break down lipids
- lysosomes also ingest microbe with many enzymes to break it down (phagolysosome)
Can genetic defects affect a person’s immune response?
yes they can affect how a person responds to a an infectious agent, with an inflammatory response
What are chemical mediators of inflammation?
- preformed -produced in liver
- within circulating cells - newly synthesized
- produced locally in response to stimuli
examples of preformed chemical mediators? sources?
histamine:
-mast cells, basophils, platelets
serotonin:
-platelets lysosomal
enzymes:
-neutrophils, macrophages
Examples of newly synthesized chemical mediators? sources?
prostaglandins:
-leukocytes, platelets, EC
leukotrienes:
-leukocytes
platelet activating factors:
-leukocytes, EC
activated oxygen species:
-leukocytes
nitric oxide:
-macrophages
cytokines:
-lymphocytes, macrophages, EC
what chemical mediators come from the liver?
- major source of plasma mediators Factor XII activation:
- kinin system (bradykinin)
- coaglation/fibrinolysis system
- complement activation:
- anaphylatoxins
- membrane attack complex
interrelationships between plasma mediator systems?
- activate this pathway from inflammation due to infection
- kinin cascade or anti clotting (fibrinolytic system)
- clotting cascade
- both paths activated when initiation of inflammation and involved in exacerbation of inflammatory response
point of clotting cascade?
- trying to get to fibrin (key clotting component)
- blood can clot -can also get fibrinopeptides
what activates the fibrinolytic system? what is the point?
- kinin cascade (factor 12a)
- convert plasminogen to plasmin (strong enzyme)
- plasmin can convert C3 to C3a in complement cascade
- plasmin can breakdown fibrin to dissolve clot away
what is bradykinin?
- key molecule in inflammation
- creates pain
Where can arachidonic acid metabolites be generated?
from lipids in cell membrane when inflammation is initiated.
- What do phospholipases convert cell membrane phospholipids into?
- what do pain killers such as aspirin inhibit?
- what do steroids inhibit?
- arachidonic acid
- cyclooxygenase, pathway is inhibited
- steroids inhibit phospholipases
Describe the cyclooxygenase pathway?
- leads to breakdown of arachindonic acids into metabolites (prostaglandins)
- prostaglandins are secreted from the cell, lead to vasodilation and increased edema in inflammatory response, more leaky vessels
- prostacyclins are also made which cause vasodilation, but inhibit platelet aggregation (for infection)
- thromboxanes are also made which cause vasoconstriction but promote platelet aggregation (for bleeding)
- there is a balance, depends on injury which is made
Describe the lipoxygenase pathway?
- lipoxygenase activity creates eicosanoids which are for allergic reactions and asthmatic reactions
- leukotrienes are made
- leukotriene B4 is for chemotaxis, more WBC move to area of damage
- other leukotrienes lead to vasoconstriction but bronchospasm, inability to breathe (asthma drugs inhibit this path), increased permeability
- 12 lipo path can lead to lipoxins which are for vasodilation, inhibit neutrophil chemotaxis
what major inflammatory actions does platelete activating factor (PAF) do?
- increased vascular permeability
- leukocyte aggregation
- leukocyte adhesion
- leukocyte priming/chemotaxis
- platelet activation
- stimulation of other mediators (LT, superoxides)
What are leukocyte effects of IL-1 and TNF-alpha?
-increase cytokine secretion (IL-1, IL-6)- proinflammatory
What are the fibroblast effects of IL-1 and TNF-alpha?
- increased fibroblast proliferation
- increased collagen synthesis
- increased collagenase (breakdown collagen to make more mature collagen)
- increased protease
- increased PGE synthesis
What are the endothelial effects of IL-1 and TNF-alpha?
- increased leukocyte adherence
- increased PGI synthesis
- increased procoagulant activity
- decreased anticoagulant activity
- increased IL-1, IL-8, IL-6, PGDF
Acute phase reactions of IL-1 and TNF-alpha?
- fever (hypothalamus controls it)
- increased sleep
- decreased appetite
- increased acute phase proteins
- hemodynamic effects (shock)
- neutrophilia
What are the three nitric oxide enzymes? functions of each? what is NO a product of?
- endothelial nitric oxide synthase (eNOS)- lead to vasodilation of vessels (viagra)
- neural NO synthase(nNOS)- made in nervous system, used as a neurotransmitter
- inducible NO synthase(iNOS) - macrophage, neutrophils, activated in inflammatory process, NO produced, NO is used to combine with O2 to make peroxinitrite
- NO is a product of nitric oxide synthase acting on L-arginine
What are the different neutrophil granules?
- specific granules
- azurophil granules
- if no binding, hard to kill infectious agent
Acute inflammatory mediators source, vascular leakage, chemotaxis, and other outcomes?
see chart
more Acute inflammatory mediators source, vascular leakage, chemotaxis, and other outcomes?
see chart
Outcomes of acute inflammation?
see chart
