Mediators of Inflammation Flashcards
What are mediators of inflammation?
Substances that initiate and regulate inflammatory reactions
Which cells secrete inflammatory mediators?
Macrophages, dendritic cells, mast cells
- other cells could also be induced: platelets, neutrophils, endothelial cells, epithelial cells
Where are mediators located inside cells?
Sequestered in intracellular granules for rapid secretion (histamine) or may be synthesized de novo (prostaglandins, leukotrienes, cytokines)
Mediators of inflammation are produced only _________
In response to various stimuli
How do inflammatory mediators function?
Bind to receptors on target cell to secrete additional inflammatory mediators
General characteristics of inflammatory mediators
- have short half lives and quickly decay
- are enzymatically destroyed
- are scavenged by antioxidants
T/F: one mediator can stimulate the release of other mediators
True
Prostaglandins, leukotrienes, and PAF are from the ______
Plasma membrane
Nitric oxide is from ______
Macrophages
Defensins are produced ______
At the epithelial surface, will up regulate production when cell is induced
Inflammatory mediators from plasma proteins are constantly being secreted by the ________
Liver as precursors
- activated via proteolytic cleavage in circulatory system
Look at list of mediators and their source!!!
1st ppt
What are the 2 preformed inflammatory proteins?
Histamine: mast cells, basophils, platelets
Serotonin: mast cells, platelets
What are the functions of histamine?
- vasodilation
- increased vascular permeability
What are 3 synthesized mediators?
- cytokines
- chemokines
- arachidonic acid metabolites
Cytokines
Primarily produced by activated macrophages, lymphocytes, dendritic cells
- regulate immune and inflammatory rxns
- acute inflammation: TNF, IL-1, IL-6!!!
Functions of cytokines
- endothelial activation
- leukocyte recruitment
- leukocyte activation
- systemic acute phase response
TNF
Macrophages, mast cells, T cells
- stimulates expression of endothelial adhesion molecules
- secretion of other cytokines = systemic effects
IL-1
Macrophages, endothelial cells, some epithelial cells
- similar to TNF, greater role in liver
IL-6
Macrophages
- systemic effects (acute phase response)
Chemokines
Cytokines that promote leukocyte chemotaxis and migration
- IL-8: secreted by activated macrophages, endothelial cells = chemotaxis of neutrophils
Arachidonic acid metabolites
Lipid mediators (prostaglandins, leukotrienes) produced from arachidonic acid present in membrane phospholipids
What do prostaglandins and leukotrienes release?
Mechanical, chemical, physical stimuli releases AA from the membrane
- prostaglandins: cyclooxygenase
- leukotrienes and lipoxins: lipoxygnease
AA metabolites function
Mediate virtually every step of acute inflammation!
- vasodilation: prostaglandins
- vasoconstriction: leukotrienes, thromboxane
- increased vascular permeability: leukotrienes
- chemotaxis, leukocyte adhesion: leukotrienes
Which is more potent: leukotrienes or histamine?
Leukotrienes!
- more important for increasing vascular permeability
Steroids inhibit ____
Phospholipases
COX1 and COX2 inhibitors, aspirin, indomethacin inhibit _______
Cyclooxygenase
Prostacyclin (PGI2)
Causes vasodilation, inhibits platelet aggregation
Thromboxane A2
Causes vasoconstriciton, promotes platelet aggregation
PGD2, PGE2
Causes vasodilation, increased vascular permeability
= pain, fever
Leukotriene receptor antagonists inhibit
Leukotrienes C4, D4 and E4
- funciton in bronchospasm, increased vascular permeability
5-HETE
Chemotaxis
Complement
Collection of soluble proteins and membrane receptors that function in host defense
- present in inactive forms in the plasma, activated via antibody detection or direct microbe binding
What are 3 functions of complement?
- inflammation: C3a and C5a to stimulate histamine release (anaphylatoxins) –> C5a is a chemotactic for leukocytes
- opsonization and phagocytosis: C3b when fixed to microbial cell wall acts as opsonin and promotes phagocytosis
- cell lysis: deposition of membrane attack complex, kills by making cells permeable to water
Activated factor XII (Hageman factor)
Activates intrinsic coagulation and catalyzes formation of kallikrein
Brakykinin
- short lived
- increased vascular permeability
- vasodilation
- pain
Kallikrein acts on ______ to form ______
Plasminogen; plasmin
- breaks down fibrin polymers and cleaves C3
Coagulation factors require _______
Balance between formaiton and degradation of fibrin
- fibrin polymers provide a surface to facilitate phagocytosis and prevent spread of infectious agents
- excessive fibrin obstructs the microvasculature resulting in ischemic injury
- excessive activation of fibrinolytic system leads to depletion of fibrinogen and possibly hemorrhage
Oxygen derived free radicals
Released from neutrophils and macrophages following exposure to chemokines and after phagocytosis
- lipid peroxidation
- DNA damage
- can alter signaling molecules (increase/decrease cytokines)
- antioxidant mechanisms in place to minimize damage
Nitric oxide
Synthesized by endothelial cells and macrophages
- vasodilation
- inhibits platelet aggregation and adhesion
- oxidizes lipids
Platelet activating factor
- phospholipid derived mediator
- leukocytes, platelets, endothelial cells can elaborate the factor
- vasoconstriction and bronchoconstriction
- 100 to 1,000x more potent than histamine!!
Vasodilation
- histamine
- prostaglandins (PGI2)
Increased vascular permeability
- histamine
- serotonin
- C3a and C5a by liberating vasoactive amines from mast cells
- leukotrienes
Chemotaxis, leukocyte recruitment and activation
- TNF, IL-1, IL-8 (neutrophil chemotaxis)
- chemokines
- C3a, C5a
- leukotriene B4
Fever
- IL-1, TNF
- prostaglandins
Pain
- prostaglandins
- bradykinin
Tissue damage
- lysosomal enzymes of leukocytes
- reactive oxygen species
